(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2018/118197 Al 28 June 2018 (28.06.2018) W !P O PCT

(51) International Patent Classification: Published: A23K 20/116 (2016.01) A61K 31/568 (2006.01) — with international search report (Art. 21(3)) A61K 31/352 (2006.01) (21) International Application Number: PCT/US20 17/056685 (22) International Filing Date: 14 October 2017 (14.10.2017) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/437,239 2 1 December 20 16 (2 1. 12.20 16) US 62/482,196 26 July 2017 (26.07.2017) US (72) Inventor; and (71) Applicant: POSTREL, Richard [US/US]; 5244 N. Bay Rd, Miami Beach, FL 33 140 (US).

(74) Agent: JONES, George; 11761 North Shore Dr, Reston, VA 20190 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG).

Declarations under Rule 4.17: — of inventorship (Rule 4.17(iv))

(54) Title: HEALTHIER AGING IN DOMESTICATED ANIMALS (57) Abstract: This invention provides compositions, systems and methods that improve and/or optimize the health and performance of animals, especially mammals including humans, canines, equines, felines, etc. Key aspects of the principle invention and its parts include the monitoring, management and modulation of the body's natural cannabinoid systems through its native mechanisms thereby optimizing its processes by supplementation with endogenously occurring components and/or by administering synthetic compounds. — The invention selects from multiple available resources to modify and/or rebalance an individual system or it may be applied across interconnected systems. The encompassing system that is intricately involved in the operations and intensities, e.g., the balancing of most other systems of our bodies, relates to cannabinoid compounds and their receptors. The cannabinoid pathways can be coordinated in rebalancing multiple and various metabolic pathways. Extending Life and Its Vitality

BACKGROU ND

Qua lity of life, especia lly in mam mals, is extended using thera pies relating to aging, food allergies, pain and reduced vigor. These thera pies as set forth in describing the invention reba la nce molecu la r, cel lu lar and subcel lular biochemica l requirements of mitochondria and other organel le processes

Mam mals are large com plex organisms made of tril lions of cel ls. These cel ls com prise high ly specia lized differentiated cel ls and less differentiated cel ls that might act as stem cel ls to produce one or more high ly specia lized differentiated cell. The cells differentiate t o maximize their abilities for assigned tasks while leaving other essentia l functions to other specia lized cel ls. The cel ls specia lize by emphasizing certain activities and eschewing others.

They do this by selective induction of the proteins the individua l cel l makes and uses. We categorize cel ls, tissues, enzymes, etc. by assigning by designating them as belonging to one of more systems - i.e., groups interacting t o perform related functions.

For exa mple, the respiratory system has the task of ha rvesting oxygen and disposing of carbon dioxide. The respiratory system has severa l su bsystems including the lu ngs and their alveoli that exchange gas molecu les in air with those dissolved in blood. It also includes a pa rt of the muscu lar system, the muscles that pu mp the air in and out of the alveoli. There is another subsystem, part of the respiratory system that provides the mucous and keeps the cell su rfaces healthy and damp. The cells of the lu ng each have ion excha nge systems that maintain cell volu me and are importa nt for muscle movement and secretions. The respiratory system is but one "system" of the com plex mam malia n body. Animals also need a circulatory system, a lym phatic system, a digestive system, an immu ne system, an integu menta ry system, a skeleta l system, a muscular system, a nervous system, a urina ry system, an endocrine system and a reproductive system. Each of these systems com prises multiple layers of su bsystems. Specia lized grou ping of cel ls performing related tasks are assem bled into structures ca lled orga ns. Many orga ns and their cel ls ca n be pa rticipa nts in more than one system. Coordinating the various systems t o act in concert for the survival of the orga nism is a complicated task requiring consta nt monitoring and rebala ncing activities of the numerous su bsystems and their su bsystems and the individua l cel ls that perform the systemic tasks. Each cel l itself is required t o accom plish several functions. The plasma membra ne sepa rates the cell from the outside; regions withi n the cel l, e.g., nucleus, golgi, endoplasmic reticulum, mitochond ria, etc. have specia lized functions that they perform. Nutrients must be internalized, while harmfu l or unnecessa ry compounds must be excluded. The right proteins must be made at the right time and delivered to the right place. Every reaction involves chemica l and physical energy which must be available. The intracellu lar systems or activities like those of the la rger orga nism, also involve com plicated bala ncings and rebalancings t o meet im mediate needs of the cel l, the orga n and the animal. This system of consta nt reba la ncings has t o be almost insta nta neously flexible for ra pid response t o the thousa nds of chemica l reactions occu rring every second. One importa nt vector system for the control and reba la ncing tasks uses several compou nds, such as ana nda mide, 2- arachidonoylglycerol and their receptors. These were the first two com pou nds identified as players in our endoca nna binoid system. There are severa l other cannabinoids now identified that bind these receptors or one of severa l other receptors now identified as active in the can na binolic systems.

Mam malia n cel ls are eukaryotic cel ls and therefore, like in euka ryotic organisms genera lly, these cells and their host orga nisms rely on their mitochondria t o produce adenosine triphosphate (ATP). Mitochondria (a nd chloroplasts in plants) have their own genomes, DNA genes, that replicate independently from DNA of a cel l's nucleus. But the mitochondrial genome only provides coding instruction for 1% of the proteins that are active in a mitochond rion. This is another illustration of the interdependence between the meta bolic pathways in a cel l. Virtua lly all processes of the orga nisms and of each of the cel ls of each organism require numerous overlapping pathways for continuing life and function of the organism. The overlapping pathways ca nnot be considered in isolation. All pathways require severa l inputs of energy. At a minimu m, every protein involved in a pathway required energy from high energy phosphate molecules for its synthesis. The energy source most often is mitochond ria lly derived ATP. Enzymatic reactions are genera lly cou pled with ATPase or GTPase activities that drive the biochemica l reactions. The mitochondria themselves can not exist in isolation. The majority of the proteins and lipids constituting the mitochondrial meta bolic machinery, its transport protei ns, enzymes and membra nes, are provided by the hea lthy operation of numerous cel l pathways that themselves are reliant on mitochond rial ATP production. The systems must coordinate to provide the pa rts t o the other systems o n demand. When one system malfunctions one o r more back-up systems must alter their operations to meet the new needs.

Aging is a progression of seria l brea kdown events, general ly commencing with one of the cells in a system failing t o meet the needs of other cells. Each breakdown requires opportu nistic remedies t o add ress each minor failing. Cumu latively, the agi ng process is a gradua l decline, as back-up after back-up is activated. But each back-u p is less efficient tha n the previous with the result that performa nce conti nuously declines, the decline accelerates and vitality eva porates. When remaining back-ups are insufficient, death of cel ls, their tissues/orga ns, and eventual ly of the organism itself, results. Add ressing the process at early stages by reba la ncing nascent su boptima l systems wil l significa ntly slow o r prevent the aging progression and maintain qua lity of life for extended periods into our prolonged yea rs. Rebala ncing the processes at earlier stages while significa nt back-up mecha nisms remain availa ble is more effective and by being more effective diminishes the rate that the back-up su b-systems are depleted. The present invention hel ps fine tune our natu ra l systems for rebalancing and homeostatical ly maintaining optima l functionalities across multiple intercon nected cel lula r, subcellu la r and whole orga nismic systems.

In each mitochond rion at the mitochondria l inner membra ne, electrons from NADH and succinate are tra nsported by the Electron Transport Chain (ETC) to oxygen, which, when it accepts the electrons, is reduced t o combine with hydrogen t o make water. Along the way the ETC comprises severa l donor and receptor enzymes in series, eve ntual ly depositing the electrons with the oxygen. Passing electrons from donor to acceptor releases energy in the form of a proton (H+) gradient across the mitochond ria l mem bra ne. This availa ble ion flux has the potentia l t o do work. This meta bolic process is known as oxidative phosphorylation and results in production of adenosi ne triphosphate, aka, ATP. The mitochondrion is important t o cel l metabolism by supporting each of the cellu lar systems and consequently su pporting surviva l of the organism. [Detailed descriptions of mitochond ria l pathways are known o r ca n be found in the art and need not be repeated here.]

This interdependence between the cel lu lar systems and of the systems of cel ls is an illustration of the chemica l and spatia l com munications required for each cel l t o maintai n its life and the life of the orga nism. And as mentioned previously, in macroorga nisms, which include, mamma ls, am phibians, fish, arthropods, birds, and the like, individual cells do not function independently; the skin segregates the organism from its environ ment; the digestive system processes fuels and eliminates food waste; the circulatory system con nects far reaches of the body to control temperatures and t o deliver and remove the thousa nds of chemica ls involved in human metabolism; the endocrine and nervous systems tra nsmit signa ls between dista nt parts of the orga nism; etc.

Simila r interdependence exists in a cel l where the plasma membra ne segregates the cel l from the interstitiu m and other cel ls; various orga nel les perform assigned functions such as

DNA tra nscription, RNA translation, protein folding, protein degradation, energy tra nsfer, etc. In the body and in the cel l the plethora of activities ca nnot operate independent of one another but must be bala nced to deliver needed materia ls t o the right location at the right time to su pport life of each cel l and of the orga nism. A system relying o n a family of chemicals cal led ca nnabinoids and the proteins with which they interact and control plays a predominant role in this ba lancing.

Bodies of living orga nisms are in consta nt and continuous action responding both to external influences, e.g., tem peratu re, sou nds, light, odors, tastes, motion, society, food availability, competing orga nisms, commensa l orga nisms, pathogenic orga nisms, etc.

Animal bodies must respond appropriately t o all these external influences and to externalities that the animals must internalize t o provide sustenance.

As an exa mple, cells and the host organisms require food t o fuel their biologic activities.

External material must therefore be internalized. This materia l may include alien organisms, that, like the animal and its cel ls, are capable of reproducing their own genomes. In response to these alien organisms attem pting t o use host bodies t o replicate their foreign genome, large animals, require a high ly coordinated and regu lated immu ne and its associated infla mmatory response to preserve good health and maintain homeostasis. However, when immu ne/inflam matory responses lose ba la nce and fail t o regulate themselves properly the result ca n be acute such as an ana phylactic shock or other allergic response or chronic disease.

Even without invasion from alien orga nisms, the consta nt and continuous stresses on living organisms require compromises in the form of opportunistic responses that optimize the cell's or more prefera bly the orga nism's modu lation of, perha ps even by t urning off or by restoring a slew of pathways in constant interaction to mai ntai n the cel ls homeostasis at a level different from chemica l and energetic equilibrium. Each system cannot be allowed t o ru n maxima lly; e.g., suga r must be su pplied at the proper location in amou nts needed at times of need; tra nsfer RNA (tRNA) with associated amino acids must be delivered to ribosomes to match sequences of messenger RNA (mRNA); ions must be com pa rtmentalized and allowed t o flow when needed for the numerous cel l functions; etc.

The thousa nds of biochemica l reactions required every second to operate our intracellu la r t o support its host organ's systems require signals to rapid ly, almost insta nta neously, switch on and off t o modu late or ba lance the various pathways.

For exa mple, one such system, itself with multi ple pathways requiring their own controls and modulations, is the immune system, which when bala nced maintains vigila nce against invaders and preservers the host organism's functions. But when imbala nced by insufficient immu ne response may cause the orga nism to succu mb t o uncontrol led infection or when imba la nced by hyper-im mune reactions can cause serious self-im posed damage to the host biomolecules, cel ls and possibly result in the organism's demise.

Characteristics typica l of immune system imbala nce may include response inadequate t o kil l or contain the alien substance and/or ina ppropriate response t o non-threatening or norma lly benign stimuli, excitation of immu ne or infla mmatory cel ls resu lting in overproduction of responsive biomolecules or cells including, but not limited to: powerful oxidants (especia lly mitochond ria l reactive oxygen species (ROS), cytokines, chemokines, eicosanoids matrix meta lloproteinases, antibodies, mast cells, etc. Excessive levels of such mediators amplify allergic or infla mmatory responses t o degrees where they become destructive and ca n then be cha racterized as clinical symptoms.

When the interna l systems become im ba lanced, external influence or intervention including, for exa mple, food components such as long chain -3/6 fatty acids, antioxida nts, vita mins, pla nt flavonoids, amines, amides, su lfur compounds, iron supplement, prebiotics and probiotics are potential interventions available to us for reba la ncing or modulating misdirected inflam matory or allergic situations. Macroorganisms, of cou rse, have interna l mecha nisms for maintaining ba la nce. However, these interna l mechanistic paths can become overwhel med, ineffective, misdirected, or unresponsive when externa l stresses are encountered. For exa mple, viruses have adapted t o recognize specific markers on cel ls by binding to these marker proteins as a prelimina ry event in the infectious process. Viral inca pacitation of these proteins can elicit effects independent of the infectious process through which the vira l particle co-opts the cel ls machinery t o propagate the virus. The 1918-19 flu pandemic (Spa nish Flu) in humans resulted in over 20 mil lion deaths, a number of deaths that exceeded those kil led in the just ended World War I (or "Great

War", as it was then known). The high death rate, especial ly affecting healthy youths under age 26, is believed t o have been caused by a cytokine storm, a hyperactive immune response.

The Spa nish Flu virus, like all vira l particles, self-replicates in a cou nterpart host. They must enter cells and com mandeer the host cel l's platforms to fol low vira l instructions for making new copies of the vira l genome and its packaging. To insert its genomic materia l into the host cel l's replication pathways, viruses require the cell to interna lize the viral pa rticle. The virus must get through the target cel l's protective mem bra ne, while leaving the cell healthy so that it can produce additiona l vira l pa rticles. The virus must ca rry a protein that wil l bind t o and activate a protei n on the target cell. The specialized binding requirements for vira l entry into a cell, i.e., the necessity to bind t o a specific "receptor" protein expressed on the cel l mem brane often limits a virus' ability to a si ngle species or closely related species.

When cel ls recognize invaders, one response is suicide, a self-im posed death, often through the process cal led apoptosis. This may occu r before vira l replication thus acting to save the host orga nism o r the virus may have ability esca pe recognition until it has coopted the cell t o make many thousa nds of vira l copies. These viruses have ada pted so that they use later stages of the apoptosis process as an efficient means t o escape the confines of the cel l's plasma mem bra ne. Disintegration of the cel l membra ne ca n effect efficient and timely release of the offspring viral pa rticles. Heathier, younger persons were at high risk because of their robust immune systems lau nching a ful l blown immune response. The youthfu l hea lthfu l response to the flu infection ca used release of invader fighting chemicals in such high proportions that native tissues were destroyed.

Pa rt of the response of infected cel ls is to release chemicals that attract immune system cel ls. Reactive oxygen species (ROS) are non-specific toxic chemica ls released to oxidize

(chemical ly modify) molecu les they come in contact with. Ina ppropriate immune response results in asth ma attacks that can com promise health and is frequently fata l if the hyperactivity is not managed. Hyper-recruitment of immune cel ls and resu lting inflam mation ca n make breathi ng difficult or impossible. Another cou nterproductive response often seen is "specific food allergy", a hyperim mune response t o a specific food or food biomolecule. Specific food allergy is characterized by hyperse nsitization t o normal ly innocuous food proteins, lipoproteins, or other macromolecu le, ca lled the allergen. This reaction requires production of an allergen- specific IgE that binds t o receptors in biomembra nes of basophils and mast cel ls upon recurrent exposure t o the sa me allergen. Macrophages and mast cel ls induce the release of inflam matory mediators, such as COX-2, iNOS, and infla mmatory cytokines. Infla mmatory responses have long been considered associated with the nuclea r factor-ka ppa B (NFKB) signaling pathway.

With respect to food allergies, the gastrointestina l tract, a tract designed t o encou nter outside molecules and microbes, contains the largest reservoir of immune cel ls in the body.

The function of this gastrointestinal mucosa l immune system is to protect the large su rface area of the gastrointestinal tract from invading pathogens and to keep the commensa l microbiota compartmenta lized. The mucosal immune system is divided from the gut lumen by a single layer of colu mnar epithelia l cells, which secrete a number of biochemica ls that contribute t o barrier f unction. These include but are not limited to: mucins, antimicrobia l peptides, trefoil factors, etc. The epithelia l cel ls also transport antibodies, pa rticularly IgA, into the intesti na l lumen where these anti bodies ca n contribute t o barrier f unction by excluding the upta ke of antigens or microbes.

Thousands of allergens have been documented for huma ns, including common ly, poison ivy, dust, shel lfish, gluten, pea nuts, etc. Com mon allergies in cats are against beef, seafood, and dairy products, while in dogs, chicken, beef, dairy products, eggs, wheat, and soy are com mon allergens.

Just with this exa mple of the immune/a llergy system of systems it is obvious that intricate bala ncing is required for optima l interplay between the multi ple interacting and cou nteracting pathways to provide the weapons t o dispatch invaders while sparing toxic effects on the animal's cel ls and systems. One f undamental balancing system that macrobiota have developed for control ling their immune responses involves the cannabinoids. Ca nna binoids, chemica ls that in cel ls are rapid ly synthesized, released and degraded on demand for control ling several immu nity on-off switches including one of our off-switches, corticosteroids, aka glucocorticoids. Exogenous steroids have been used for immune su ppression to cou nteract undesired, bothersome allergic or immune responses. In nature, low levels of corticosteroids are produced and maintained within anima l cel ls to modu late immu ne system and other system responses. These steroid levels are under robust feed back control. When steroid levels are increased, endogenous synthesis virtua lly shuts down. Ca nna binoids and cannabinoid receptors have a role in the on-off switching.

Corticosteroids are common in short term thera pies used by physicians t o tone down the immu ne system. They ra pid ly reduce immune and inflam matory responses for exam ple t o hista mine and t umor necrosis factor. Autoim mune diseases, e.g., arth ritis, are often acutely treated using hefty doses of corticosteroids with massive immu ne system depression as a result. These thera pies however, provide strong negative feed back t o the endogenous synthetic pathways. Abru pt cessations of treatment cause a dangerous shortage of steroids in circu lation which ca n lead to severe com plications, including death.

While the t apering appears necessary, proper bala ncing with ca nna binoids may facilitate the re-ada ptive processes.

Steroids when used in thera py ca n be given by fast acting or long-lasting injection or delivered ora lly. But these steroids often make the recipient anima l irrita ble so must be used with caution, especia lly when child ren may be in contact with the animal.

The two most common oral steroids are pred nisone and pred nisolone. Pred nisone is ha rd for cats to metabolize and must be converted t o pred nisolone in the liver before it wil l work. Therefore, for rapid effect it is more efficient and less stressful to give pred nisolone itself. In less severe and/or less acute crises, ca nnabinoids are via ble su bstitutes. After the crisis is managed by pred nisolone or other corticosteroid, it is advised t o begin incorporating can na binoid acting substa nces as either pa rt of the wea ning process or as su bstitute therapy.

However, in addition t o this t apering issue, steroids have many dangerous side effects.

Injected forms are correlated with dia betes. Steroids also damage the kidneys with extended use. The primary action of steroids is immune system su ppression rapid ly interrupting infla mmatory reaction t o the allergen. But this makes the imm une su ppressed recipient quite prone to infections from any adva ntageous pathogen gaining access t o the body. Steroids also cause gastric and intestinal ulcers and prevent immu nity from forming after vaccinations. While less dramatic than ana bolic steroid injection, activation of CBi and CB2 results in release of epinephrine, corticosteroids, and immu ne cal ming IL-10, while decreasing pro inflam matory IL-2. Steady su pplementation with one or more synthetic o r phyto- cannabinoid has effects that ca n be used t o substitute for chronical ly used corticosteroid immune suppression, but wil l have a more natura l control and fewer side effects.

Can na binoid mediated responses include a general ca lming of local (e.g., derma l, iliac, bowel, gastric, mucosa l, etc.) pro-infla m matory mediators including, but not limited to: myeloperoxidase, CXCL8, IL- Ι β, TNF, etc. Can na bis has also been shown t o su ppress the immune system by activating myeloid-derived su ppressor cel ls (M DSCs). M DSCs may hel p dam pen the hyperactive immune system.

The corticosteroids are distinct from another class of steroids, the ana bolic steroids.

Ana bolic steroids are the steroids used by ath letes for growth and ath letic performa nce.

These, and in fact all ana bolics (steroids o r other ana bolic com pou nds), are in a class associated with serious side effects and must be used sparingly, definitely not in the extreme doses used in the past by athletes. Internationa l sport federations ba n use all ana bolics at all times, during com petition and even during off-season training. By contrast cannabinoids and corticosteroids (aka glucocorticoids) are classified as performa nce enha ncing drugs and are o nly ban ned during competition. Though many ana bolics are ba nned for use in athletic competition and o nly a few are approved for pharmaceutical use in many cases, use in animals may be more accepta ble tha n use in humans.

The corticosteroids are natu ra l hormones generated by specia lized cel ls in the anima l t o tone-down immu ne responses and have been used clinical ly in anima ls and hu mans t o control or even shut down im mune responses. Endocan na binoids act in conjunction with the corticosteroid hormones as part of the corticosteroid pathway, but also exert their influence o n several additiona l immu no-modulatory pathways.

In response t o a viral attack o n one or more cel lu lar receptors, the im mune system em ploys various activating and deactivating pathways for corra lling and/or destroying the alien organism. Normal im mune responses are ba lanced, i.e., the alien is dispatched by kil ling, wal ling off or removal. But more often tha n w e would like perha ps, a hyperactive response t o alien invader such as induced by the Spanish flu, o r an interna l (autoim mune) attack instigated by a misdirected im mune system, results from significa nt imbala nces o r diversions away from hea lthy im munologic o r other metabolic responses. Reba la ncing becomes necessa ry for the organism's su rviva l. An important and ra pid ly responsive control system used to maintai n or reba la nce response t o externa l events relates t o specia l classes of receptors on cel ls and orga nel les and delivery or the biologic signa ls that modu late their activities. A class of modulating biomolecules has been cha racterized as

"endoca nnabinoids". The na me is derived from the receptors active in this system that also being t o products from the ca nna bis pla nt.

These compounds and the proteins responsive t o them have importa nt roles in maintaining homeostasis, especial ly relating to response to smel ls/odors, food inta ke, appetite, and external or internal immunologic or allergic response. The endocan na binoids were recognized as the native biomolecules that employ receptors discovered when investigating biologic responses to compounds originating in pla nts. Original ly two cannabinoid receptors were recognized in humans/mam mals because THC, a psychoactive cannabinoid substance from Cannabis was fou nd t o interact with these proteins. These were dubbed : ca nnabinoid receptor 1 (CBi) and ca nnabinoid receptor 2 (CB2). AEA and 2AG were recognized as predominant endoca nnabinoids binding these receptors. CBi immunoreactive neurons were found in close proximity t o ileal Peyer's patches and were localized in some su bmucosa l blood vessels. However, subsequent discoveries have revea led other endobiologic com pounds also binding these receptors and the additiona l receptors which interact with AEA and 2AG and the additiona l recognized com pou nds with endoca nnabinoid activity. Homologs of human CBi and CB2 receptors have been fou nd in virtua lly every anima l and even in plant chloroplast membra nes. Most mammals tested com prise homologues for the additiona lly discovered canna binoid receptors. For pu rposes of this discussion, the human protein designation is used.

Activation of CB2 is general ly anti-infla mmatory, for exam ple, involved in reduction of

N F-KB, AP-1 and inflam matory mediators. CB2 is prima rily expressed on su bsets on immu ne cel ls and several leu kocyte lines of the hematopoietic su bsystem (macrophages, both B and

T lymphocytes), seconda ry lymphoid tissues such as spleen, tonsils, Peyer's patches,

Lym phatic ganglia, microglia and hepatic myofibroblastic cel ls. CB2 activation is a helpfu l pathway for turning down the immune system after an infectious disease is resolved.

Two rather specific ca nnabinoid receptors, CBi and CB2, have been identified and are targeted by numerous exogenous and endogenous ca nna binoid liga nds. Activation of mast cel l CB2 has direct anti-infla mmatory effects, causing decreased release of pro- inflam matory mediators by these cel ls. Activation of CBi o n bronchia l nerve endings has bronchodilator effects acting on the airway smooth muscle with benefits for treating airway hyperreactivity and asthma. Pha rmacologic interference using endoca nna binoid inhibitors reduces pain and inflam mation. This is mediated at least by CBi and CB2. Activation of CBi in cerebral blood vessels has shown beneficia l anti-inflam matory/a nti-ischemic effects.

G PR55 and CBi receptors modulate each other's signa ling properties. GPR55 forms heteromers with another 7x tra nsmem bra ne spa nni ng/G PCR which then interacts with CBi.

G PR55-CB1 heterodimer acts as a modified can na binoid receptor that cells form t o modulate activities in response t o exogenous ca nna binoid. This plasma mem brane response is independent of can na binoid effects o n interna l orga nelles including, but not limited to: mitochondria, peroxisomes, endoplasmic reticulum, golgi, etc.

CBi and CB2 are both expressed o n Mast Cells (MC) and CB2 is o n Eosinophil (Eo) membra nes. CBi and CB2 have demonstrated anti-inflam matory effects on MCs. CBi downregulates M C degra nulation, and CB2 down regu lates pro-infla mmatory mediator release. Antagonizing CBi o n the MCs stimulates degranulation and increases cell num bers without affecting M C proliferation. CBi activation of bronchial nerve endings has bronchodilatory effects and therefore proves t o be beneficia l in asth matic response thera py. 2AG and the synthetic selective agonist JWH-133 induce Eo chemotaxis, shape change, ad hesion production of reactive oxygen species and increase in CDllb expression, via CB2 activation Mast cells are multifu nctional bone marrow-derived cells residing in mucosa l and con nective tissues and in the nervous system. Pa lmitoyletha nolamide (PEA) is an endoca nnabinoid especia lly capable of downregu lating M C activation and inflam mation.

AEA is also an effective endogenous agonist for the central ca nna binoid receptor CBi o n

MCs. PEA activity may be t hrough CB2 and other ca nnabinoid receptors. PEA and AEA bind t o CB2 but AEA may be more effective when bou nd t o CBi. This provides evidence that PEA and/or its derivatives may be used t o provide anti-inflam matory therapeutic strategies specifica lly targeted at MCs.

The endoca nna binoid system (ECS) is an im porta nt lipid based signa ling and immunomodulator system. Lipophilic com pou nds, those that can readily cross plasma membra nes are prime activators of these endoca nna binoid pathways. Research relating t o medical uses of marijua na and traditiona l medicines has shown that at least compounds that bind CBi and CB2 pa rticipate in modulating many physiological responses including, but not limited to: appetite, respiration, meta bolism, infla mmation, allergy, pain, neurotransmission, etc. The ECS is com prised of G-protein cou pled receptors (G PCRs) including, but not limited t o human: CBi, CB2, TRPVi, TRPV2, TRPV3, TRPV4, TRPAi, TRPM 8,

G PR55, GPR118, etc. and the animal homologues.

The native ca nna binoid receptor ligands aka "endoca nnabinoids" are classica lly represented by arachidonyletha nola mide (a na nda mide, AEA) and 2-arachidonoylglycerol

(2AG). Tissue levels of endocan na binoids are maintained by the ba lance between biosynthesis (e.g., phospholipase D and diacylglycerol lipase-dependent and other pathways), cel lula r uptake and degradation by enzymes principal ly, but not limited to: fatty acid amide hydrolase (FAAH) and/or monoacylglycerol lipases (MAG L). Since the discovery of CBi and CB2 GPCRs such as GPRi8, GPR55, GPR g and the TRPs have been recognized as members of the ca nna binoid family.

Exogenous AEA treatment effectively suppresses inflam matory para meters, including, but not limited to: footpad swel ling, d raining LN cell proliferation, histopathological cel l infiltration and tissue injury. AEA decreases the induction and num bers of proinflam matory

IFN-γ and IL-17 producing cel ls and increases IL-10 production. IL-10 acts in part through direct induction of severa l different microRNAs that target proinfla mmatory cytokines.

Can na binoid supplementation also induces popu lations of im munosu ppressive cel ls including myeloid derived su ppressor cel ls and regu latory T cel ls.

IL-10 was first recognized as an inhibitory factor secreted by Th2 cells that inhibited the secretion of cytokines by Thl cells. Can na binoids through interaction with one o r more cannabinoid receptor increase expression of IL-10. IL-10 signa ling is im porta nt for inhibition of Thl7 mediated infla m mation.

Two nota ble cata bolic enzymes, fatty acid amide hyd rolase (FAAH) and monoglycerol lipase (MAGL), are involved in the breakdown of ana nda mide and 2AG, respectively. Simply put, less FAAH and MAG L mea ns more AEA and 2AG. So inhibitors of these catabolic enzymes, for exam ple, by nutmeg extracts, raise the levels of AEA and 2AG t o genera lly boost can nabinoid receptor signa ling. FAAH and MAGL inhibition therefore ca n be effective in reducing o r managing pain, anxiety, hypertension and various inflam matory conditions. The "ca nna binoid" (a term indicating ca nna bis-like activity) com pou nds have diverse effects, including most notably, some psychoactive effects became known as phytoca nnabinoids based on their relation to com pou nds found in the ca nna bis genus. The endo/phyto-ca nnabinoids include but are not limited to: N-acyletha nolami(n/d)es which include N-a rachidonoyletha nola mine (better known as ana nda mide or more simply AEA),

N-pal mitoyletha nola mine (PEA), N-linoleoylethanolamide (LEA) and N-oleoyletha nolamine

(OEA). Since living orga nisms sha re many com mon metabolic paths and features many mammalian endoca nna binoids ca n be fou nd in other species, including pla nt species. For exam ple, OEA and LEA are in cocoa. Black truffles when grown under certain circu msta nces contain high levels of AEA.

Adhesion molecu les are another important target for infla mmatory responses, such as asth ma attack and the ca lming influences of can nabinoid com pounds. They are an essentia l com ponent for leukocyte-endothelia l interactions at the inflamed site for leukocyte tethering, rolling and ad hesion t o the endotheliu m. Inactivation of adhesion molecu les is associated with increased allergic/im mune response. As pa rt of the body's response to inflam matory attack, can na binoids induce expression of ad hesion molecu les which have been bou nd, for exam ple, ICAM-1, VCAM-1, are up-regulated on endothelial cel ls during ocu la r infla mmation and CDH R3 is induced and upregu lated in response to binding by RV-C.

Can na binoids have been shown to promote expression of these and other adhesion molecules in vitro.

More than 160 types of common cold viruses, aka rhi noviruses (RVs) are classified into the three species (A, B, and C) of enteroviruses within the family picornaviridae. Viruses belonging t o the RV-C species were only recently differentiated in 2006. These viruses are not cu ltura ble using sta nda rd tissue-cultu re techniques.

Now RV-Cs have taken on highlighted clinica l interest because of their involvement in severe illnesses requiring hospitalization in infa nts and child ren compared with the RV-A or

RV-B. The interaction of RV-C with receptive cel ls is high ly correlated with acute exacerbations of asth ma.

Recent data reveal that the RV-C receptor is distinct from the intercellu la r ad hesion molecule 1 (ICAM-1) that had previously been identified as the primary RV binding target and from the low-density lipoprotein receptor (LDLR) family members that bind RV-A and RV-B. Both ICAM-1 and HDCR3 act as vira l receptors, but they have primary beneficial roles for the cel l. Ad herin proteins hel p orga nize cel ls into orga ns and tissues and control ion binding and tra nsmembrane gradients, such as control ling the Ca++ binding and tra nsmembra ne potentia l gradient.

Cadherins are a family of ad hesion molecu les that mediate Ca++-dependent cel l-cel l adhesion in the solid tissues of multi-cel lula r organisms. They also modu late a variety of other processes including cel l pola rization and migration. Cad herin-mediated cel l-cell j unctions are formed by dimerization between extracellu la r domains of identical cad herin molecules that are located on the mem bra nes of the adjoi ning cel ls. Stability of the adhesive junctions is enhanced by binding of the intracellula r cad herin domain with the actin cytoskeleton. Several different isoforms of most cad herins exist and are distributed in a tissue-specific man ner throughout most orga nisms. In vitro, cel ls containing different cadherins tend t o segregate, while those that expressing sa me cad herin isoforms tend t o aggregate together.

Cadherin-related family mem ber 3 (CDH R3) is a human mem ber of cadherin family of tra nsmembra ne proteins. Cadherins are cel l-cel l ad hesion proteins requiring ca lciu m ions

(Ca ++) for adhesion. They are highly conserved in and across species. CDH R3's specific functions for the cel l and orga nism are unknown. Cadherins in genera l have a significant extracel lular domain that is responsible for cel l-cel l interactions. The extracel lular portion has repeated conserved sequences for bindi ng Ca ++, e.g., -Asp-Arg-G lu-, -Asp-Xxx-Asp- and -

Asp Xxx-Asn-Asp-Ala-Pro-Xxx-Phe-. A transmembra ne portion of the molecule anchors the receptor molecule t o the plasma membra ne. A short intracellu lar domain is responsi ble for the cadherin's intracel lu lar signaling. The Ca++ ions are essentia l for maintaining the three- dimensiona l structu re allowing cad herins t o tra nsbind between cel ls and for internalizing protease recognition sites.

CDH R3 is expressed in a variety of tissues including, but not limited to: lu ng, liver, kid ney, pa ncreas, thyroid, ad rena l, smal l and large intestine, smooth and skeleta l muscle, thymus, centra l nervous system, pa ncreas, marrow, etc. It is especia lly prominent in activity in in lung tissue bronchia l epitheliu m, and during mucociliary differentiation in airway epithelial cel ls. Withi n a cel l mem bra ne cad herins form cis-dimers (latera l align ment).

Identica l cadherins o n adjacent cel ls form tra ns-di mers. Though it is not believed that the physiological reason for the CDH R3 or any other plasma membra ne protein lies in its ability to bind rhinovirus (RV), this receptor is a prima ry recognition site for the virus t o attach and gain entry into the cel l. RVs are pathogens responsible for the com mon cold. Two specific types, RV-A and RV-C are a major agent of hospita lized infections in you ng child ren, especia lly those with asthma. As dog pa rks become more popu la r, the interaction and close contact between animals wil l likely increase transmission of these types of viral diseases.

Cadherin receptor domains 1 and 2 may be key t o virus interactions. The glycosylation,

pa rticula rly at N i 8 6, may be a contributory liga nd facilitator. The conservation across species, especia lly including more recently diverging genuses and species strongly su pports the concept that thera pies wil l have simila r effects in related classes like the mam mals.

A human thera peutic antibody, Rituxima b, an anti-CD20 monoclona l anti body used in hu mans t o treat relapsed or refractory non-Hodgkin's lym phoma, has been used in dogs but Rituximab lacks sufficient affinity for action on the ca nine targeted B-cells. The asth matic etiology involved with human CDCR3 includes the compou nd prostagla ndi n D2 etha nola mide, a meta bolite of the endogenous ca nna binoid, AEA.

Therapies involving CDH R3 ca n take multiple or com bined paths. The virus initia lly decreases CDH R3 activity when it binds the receptor. This bindi ng can lead to asth matic sym ptoms, for exam ple. However, the virus ca n also induce tra nscription and expression of the cadherin thereby making more protein availa ble to act in its capacity t o ca lm immune responses. Although the full pathway used by the hu man cadherin CDH R3 t o restrain inflam matory activities is not esta blished, the conversion of AEA t o prostaglandi ns (PG) including, but not limited to: D2, E2, F2, G2, H2, 12, J2, etc. antagonizes the cad herin inflam mation ca lming functions. H2 is readily converted to D2, E2, F2, 12, Fl , and throm boxanes. D2 is a major prostaglandin produced by mast cel ls and binds to the receptors PTGDR (DPI) and CRTH 2 (DP2). This recruits Th2 cel ls, eosinophils, and basophils leading t o an infla mmatory response. D2 is a critical com ponent in development of allergic disease responses such as asthma and therefore is of prime interest. E2/F2, 12/ Fl and throm boxanes are separate production bra nch offshoots from H2 that ca n com pete with

D2 production. E2 is importa nt for labor/delivery and bone resorption. F2 is stimulated by oxytocin/pitocin and drives la bor forwa rd. Both E2 and D2 can com pete for the predominant F2 receptor. 12 (a ka prostacyclin) is an intermediate in Fla synthesis and is an anti-clotting agent and vasodilator in its own right. H2 is mostly known for its major intermediate status as a source for the other PGs and t hrom boxanes. Oxytocin also has an effect t o increase AEA synthesis thereby hel ping t o maintai n ba lance throughout multiple systems within an anima l's body.

The cad herin anti-infla mmatory activity ca n also be maintained by using means t o decrease D2 etha nola mide production. Several paths are availa ble here. 1) the COX enzymes responsible for creation of D2 ca n be inhibited with NSAI DS and other COX inhibitors. 2) Brea kdown of AEA can be control led by inhibiti ng FAAH. 3) An engineered virus or a vira l capsule without its genome ca n bind cadheri ns t o induce expression. And 4) an anti-cad herin antibody, antibody fragment, or other binding agents ca n be used as an inductive agent. When using an inductive agent, t o avoid an initial drop in cad herin modulation of the immune response, one of the other strategies may be advantageous.

These strategies may be repeated and/or cycled as appropriate, for exa mple, the vira l pa rticle may be intranasa lly administered one or more times, e.g., weekly, monthly, quarterly, bia nnual ly, annua lly, etc., with continuous inhibitor ad ministration by oral means. The oral dose may be increased arou nd the time of the inducement.

AEA meta bolizes t o Prostaglandin D2 ethanola mide through lipoxygenase and cyclooxygenase catalyzed reaction. Maintaini ng AEA and like compounds at effective levels and preventing meta bolism to ha rmful products is one means for facilitating ca nna binoids' ba lancing functions.

URB597 inhibits FAAH, the pri nciple enzyme involved in degrading the lipid molecule

AEA into its arachidonoyl and ethanola mide com ponents. FAAH is a significant step in the pathway for creating prostagla ndin etha nolamide com pou nds including D2 etha nola mide.

Inhibiting FAAH raises natural AEA levels and leads t o long-term can na binoid receptor activation and pain relief. URB937, is another p-hydroxyphenyl-O-arylca rbamate that targets FAAH. FAAH is also responsi ble for the metabolism of other fatty acid amides e.g.,

N-oleoyletha nolamine (OEA) and N-pa lmitoylethanolamine (PEA). FAAH inhibition maintains or increases tissue levels of ana nda mide in vivo. FAAH inhibitors decrease pain in rodent models of OA

COX-2 is involved in the D2 etha nola mide synthetic pathway following FAAH activity to provide both ethanola mide and su bstrate for D2 synthesis. There is also evidence that COX

2 may act directly on AEA in the absence of FAAH catabolism. COX-2 inhibition can serve as an alternative t o FAAH inhibition t o preserve the anti-a llergic effects downstrea m of CDH R3 and may also act in conjunction in a pa ra llel or seria l treatment.

FAAH inhibitors are known in the art. Exa mples include but are not limited to: AM374,

ARN2508, BIA 10-2474, BMS-469908, CAY-10402, JNJ-245, JNJ-1661010, JNJ-28833155, JNJ-

40413269, JNJ-42119779, JNJ-42165279, LY-2183240, Can na bidiol, M K-3168, MK-4409,

M M-433593, OL-92, OL-135, PF-622, PF-750, PF-3845, PF-04457845, PF-04862853, RN-450,

SA-47, SA-73, SSR-411298, ST-4068, TK-25, URB524, URB597 (KDS-4103), URB694, URB937,

VER-156084, V-158866, AM3506, AM6701, CAY10435, CAY10499, IDFP, JJ KK-048, JNJ-

40355003, JNJ-5003, JW618, JW651, JZL184, JZL195, JZP-372A,KM L29, MAFP,

M JN110,M L30, N-a rachidonoyl maleimide, OL-135, OL92, PF-04457845, SA-57, ST4070,

URB880, URB937, etc.

COX inhibitors are numerous and known in the art. Several are recognized as efficient inhibitors of COX-1, others are more efficient inhibiting COX-2. Many inhibit both COX-1 and COX-2 or their selectivities are not wel l-established. COX-1 inhi bitors include but are not limited to: indomethacin, M K-886, resveratrol, cis-resveratrol, aspirin, COX-1 inhibitor

II, loga nin, tenidap, SC560, FR 122047 hyd roch loride, valeryl salicylate, FR122047 hydrate, ibu profen (favors COX-1), TFAP, etc. While COX-2 inhibitors include but are not limited to:

6-methoxy-2-na phthylacetic acid, meloxicam, APHS, etodolac, meloxicam, meloxicam sodiu m salt, N-(4-aceta midophenyl)indomethacin amide, N-(2-phenylethyl)indomethacin amide, N-(3-pyridyl)indomethacin amide, indomethaci n heptyl ester, SC236, etc. And no n specific or those without clea r specificity include but are not limited to: COX sulinac, su lindac su lfide, pravadoline, na proxen, na proxen sodium salt, meclofenamate sodiu m, ibu propfen, S-ibuprofen, piroxicam, ketoprofen, S-ketoprofen, R-ibuprofen, Ebselen, ETYA, diclofenac, diclofenac diethyla mine, flu rbiprofen, fexofenadine, Pterostil bene, Pteroca rpus marsupium, 9,12-octadecadiynoic acid, Ketorolac (tromethamine sa lt), NO-indomethacin,

S-flurbiprofen, seda nolide, green tea extract (e.g., epicatechin), licofelone, lornoxica m, rac ibu profen-d3, ampirxicam, za ltoprofen, 7-(trifluoromethyl)lH-indole-2,3-dione, aceclofenac, acetylsalicylic acid-d4, S-ibu profen lysinate, loxoprofen, CAY10589, ZLJ-6, isoica m, dipyrone, YS121, M EG (mercaptoethylguanidine), etc.

Managing allergic reactions in mam mals is a difficu lt endeavor since the pool of possible allergens is immense and testing usi ng skin patch or other com mon tests protocols requires considera ble patient pa rticipation and can be difficult to manage in child ren especial ly in many pets. Managing by toni ng down or preventing continued allergic or inflam matory responses at an early com mon stage in the pathway before significa nt sym ptoms accrue is desired. Preventing inactivation or removal of proteins that statica lly su ppress immu ne reactions ca n be an importa nt aspect of this management.

The CDH R3 receptor is high ly conserved throughout the animal kingdom. HDCR3 when present operates to tone-down immune responses. But, when inactivated massive allergic and/or genera l immense responses ca n result. The cadherin proteins with their com mon viral receptor pathways are only one exam ple of severa l importa nt proteins in pathways for managing allergic and immune responses. When control of any one or more of these is com promised thereby removing normal constraints, allergy or perha ps an asth matic attack results.

Maintaining AEA activity and preventing its meta bolism to damaging inflam matory su bstances is a powerfu l tool. COX inhibition ca n limit prostaglandin D2 ethanolamide formation. A selective COX inhibitor is one approach when constraints are preferred or when other COX-1 or COX-2 pathways are favora bly spa red. The CDH R3 downstrea m effects can also be maintained with FAAH inhibition. In many exa mples both COX inhibition and FAAH inhibition are used.

Conceptual ly the FAAH and COX inhibitors may be used interchangea bly, with one su bstituted for the other or they may be used together for additive or synergistic effect.

Actual selection is based on any desired factor, including, but not limited to: taste tolera nce, cost, solu bility, bioavaila bility, regu latory burden, color, consu mer accepta nce, etc.

EXAM PLE 1

An anima l, e.g., ca nine, feline or equine, receives su pplements that maintain cadherin downstrea m activity. These supplements may be in smal l doses in frequent treats or on a timed schedule. The supplements inhibit downstrea m cadherin activity breakdown and thus maintain the strength of cad herin immune and inflam mation management. COX, FAAH and/or MAGL inhibitors may be used in conju nction with or as alternatives to ad ministering one or more can na binoid com pou nds t o the recipient anima l.

Cadherins

Cadherins like the hu man CDH R3 are a family of ad hesion molecu les that mediate Ca++- dependent cel l-cel l adhesion in all solid tissues of the anima l and which modulate a wide variety of processes including cel l pola rization and migration. Cadherin-mediated cel l-cel l j unctions are formed by interaction between extracellu la r domains of identical cad herins, which are located on the mem branes of the neigh bori ng cel ls. The sta bility of these adhesive junctions is ensu red by binding of the intracel lu lar cadherin domain with the actin cytoskeleton. There are a num ber of different isoforms distributed in a tissue-specific manner in a wide variety of orga nisms. Cel ls containing different cad herins tend to segregate in vitro, while those that contain the sa me cadherins tend to preferentia lly aggregate together. This observation is lin ked to the finding that cad herin expression causes morphologica l changes involving the positional segregation of cel ls into layers, suggesting they may play an importa nt role in the sorting of different cel l types during morphogenesis, histogenesis and regeneration. They may also be involved in the regulation of tight and gap j unctions, and in the control of intercel lula r spacing. Cad herins are evolutiona ry related t o the desmogleins which are component of intercel lu la r desmosome j unctions involved in the interaction of plaque proteins.

Structu ra lly, cadherins com prise a number of domains: classica lly, these include a signal sequence; a propeptide of around 130 residues; a single tra nsmembra ne domain and five tandemly repeated extracel lu lar cadherin domains, 4 of which are cad herin repeats, and the fifth contains 4 conserved cysteines and a N-termina l cytoplasmic domain. Proteins are designated as mem bers of the broadly defined cadherin family if they have one or more cadherin repeats. A cadherin repeat is an independently folding sequence of approximately

110 amino acids that contains motifs with the conserved sequences DRE, DXN DNAPXF, and

DXD. Crystal structu res have revealed that multiple cadherin domains form Ca++-dependent rod-like structures with a conserved Ca++-binding pocket at the domain-domain interface. Cad herins depend on ca lciu m for their f unction: calciu m ions bind t o specific residues in each cadherin repeat t o ensure its proper folding, to confer rigidity upon the extracel lular domain and is essentia l for cad herin adhesive function and for protection against protease digestion.

Prostagla ndin D2 etha nolamide (PGD2-EA) is a bioactive lipid produced by the sequentia l meta bolism of ana nda mide (a rachidonoyl etha nola mide) by cyclooxygenase

(COX) enzymes, in particu lar by COX-2, and PG D synthase. The biosynthesis of PGD2-EA from AEA is also increased when AEA meta bolism is dimi nished by deletion of fatty acid amide hyd rolase in experimenta l anima ls. PG D2-EA is inactive against recom binant prostanoid receptors, including the D prosta noid receptor. It increases the frequency of miniature inhibitory postsyna ptic currents in prima ry cultu red hippocam pa l neurons, an effect which is the opposite of that induced by AEA. PG D2-EA also induces apoptosis in colorecta l ca rcinoma cel l lines. Loss of the human cadherin CDH R3 correlates with increased infla mmatory PGD2 activity. Preventing or minimizing the anti-inflam matory deficit caused by cad herin loss ca n restore the systems to the pre-infectious attack status.

The human CDH R3 is a mem ber of a cadherin family of tra nsmem bra ne proteins that is high ly expressed in hu man lu ng tissue, bronchial epithelium, and during mucociliary differentiation in hu man airway epithelia l cel ls in vitro. Members of this family interact with like cel ls through ca lcium-dependent interactions. Cad herins on the sa me cel l surface self- associate into cis-dimers (sideways or latera l dimers). Cel l adhesion holding cel ls together uses interactions between identica l cad heri ns on neigh bori ng cel l surfaces to form tra nsdimers. Modeling of the CDH R3-virus com plex shows a proba ble binding site for monomers and dimers in a region of the RV-C15 ca psid, a site that is highly conserved among different RV-C types. The docking exercise further suggests that receptor domains 1

and 2 may be key to virus interactions, and that glycosylation, pa rticula rly at Asni 8 6, may have some involvement. Such models of proteins and their interactions will help guide studies using mutationa l ana lysis t o accurately map virus binding domains in CDH R3.

Expression of CDH R3 increases RV-C bindi ng and enables re plication in host cel ls. Hu man

CDH R3 thus is a functiona l receptor for RV-C.

A la rge portion of the response t o RV-C attack relate to down-regulation of the HDCR3 viral receptor. Presumably, the vira l receptor has another purpose and in fact this plasma membra ne protein and other cad herins and other adhesive proteins work through endoca nnabinoids to among other functions ba la nce allergic and immune responses.

HDCR3 is not alone in these responses. The entire cadherin family likely sha res similar regulatory paths in cells. The endocan nabinoids therefore would be expected t o have major involvement in a wide variety of cel l interactions especia lly with respect t o allergic and other immune system reactions.

Phytochemicals (substa nces found in pla nts or derivatives of the pla nt chemicals) or the pla nts themselves, have been recognized t o possess biological activities in traditional medical practices. Severa l classes of com pou nds with simila rities in structure and/or activities to the THC purported active ingredient of the marijua na source pla nt have been identified. These are available in severa l pla nts outside the Cannabis genus and can be, cultured (e.g., t hrough selective breeding or genetic engineering), extracted, purified or synthesized chemical ly de novo or from derivatives. Such compounds including, but not limited to:

Cannabigerol class: can na bigerolic acid (CBGA) (antibiotic); can na bigerolic acid

monomethylether (CBGAM); ca nna bigerol (CBG) (antibiotic, antifungal, ant i

inflammatory, ana lgesic); Can na bigerol monomethylether (CBG M); can nabigerovarinic

acid (CBGVA); Can nabigerovarin (CBGV).

Cannabichromene class: Cannabichromenic acid (CBCA); Cannabichromene (CBC)

(antibiotic, antifungal, anti-inflammatory, analgesic); Ca nnabichromevarinic acid (CBCVA);

Ca nna bich romeva rin (CBCV); Ca nna bidiolic acid (CBDA) (a ntibiotic); Ca nna bidiol (CBD)

((antioxidant, anxiolytic, antispasmodic, anti-inflammatory, analgesic); can na bidiol

monomethylether (CBDM); ca nnabidiol C4 (CBD-C4); ca nnabidivarinic acid (CBDVA);

ca nna bidiva ri n (CBDV); ca nna bidiorcol (CBD-C1); A -tetra hydrocan na binolic acid A

(THCA-A); A -tetra hydroca nnabinolic acid B (THCA-B); 6a,10a-tra ns-6a,7,8,10a-

tetrahydro-6,6,9- trimethyl-3-pentyl-6H-dibenzo[b,d] pyra n-l-ol, (∆ 9

tetrahydrocanna bino THC) (analgesic, antioxidant, antiemetic, anti-infla mmation); ∆9-

tetrahydrocanna binolic acid-C4 (THCA-C4); A -tetrahydroca nna binol-C4 (THC-C4); ∆ 9-

tetrahydrocanna biva ri nic acid (THCVA); A -tetrahydroca nnabivarinic (THCV); A7-cis-

isotetra hyd roca nnabiva ri n; A -tetrahydroca nna biorcolic acid (THCA-C1);

tetrahydrocanna biorcol (THC-C1). ∆ -tetrahydrocannabinol class: ∆ -tetra hydrocan na binolic acid (∆ -TCA); ∆ -

tetrahydrocanna binol (A -THC).

Cannabicyclol class: ca nna bicyclol (CBL); ca nnabicyclolicacid (CBLA);

ca nna bicyclova rin (CBLV).

Cannabieson class: canna biesoic acid A (CBEA-A); ca nnabiesoic acid B (CBEA-B);

ca nna bieson (CBE).

Cannabinol and cannabinodiol class: canna binolic acid (CBNA); ca nnabinol (CBN );

ca nna binol methylether (CBN M); can na binol-C4 (CBN-C4); ca nna biva rin (CBV);

ca nna binol-C2 (CBN-C2); ca nnabiorcol (CBN-C1); ca nnabinodiol (CBN D);

ca nna binidiva rin (CBDV).

Cannabitriol class: ca nna bitriol (CBT); 10-Ethoxy-9-hydroxy- A-6a-

tetrahydrocanna binol (10-EH DT); 8,9-dihydroxy-delta-6a-tetrahydrocan na binol (8,9-

DHDT); ca nnabitriolva rin (CBTV); ethoxy-ca nnabitriolvarin (CBTVE).

Miscellaneous class: dehydroca nna bifuran (DCBF); can na bifu ra n (CBF);

ca nna bich roma non (CBCN); can na bicitra n (CBT); 10-oxo-A-6a-tetrahydrocan na binol

(OTHC); A -cis-tetra hydrocan na binol (cis-THC); 3,4,5,6-tetra hydro-7-hydroxy-a-a-2-

trimethyl-9-n-propyl-2,6-methano-2H-l-benzoxocin-5-methanol (2H-iso-H HCV);

ca nna biripsol (CBR); Trihyd roxy-A -tetra hydroca nnabinol (triOH-THC).

LEA, PEA and OEA wil l bind t o one o r more of the endogenous can na binoid receptors, but they are also im portant because they maintain AEA activity through their inhibition of the FAAH enzyme that is responsible for degrading AEA. N-a lkylamides exert selective effects on the CB2, and have been shown t o exert anti-infla mmatory effects simila r t o AEA. Echinacea contains multi ple N-a lkylamides that have mimetic effects.

Phytoa lka nes, another class of chemica l compounds fou nd in various pla nts, also have demonstrated ca nna binolic modulation traits, e.g., n -a lka nes ra nging from Cg t o C3g, 2- methyl-, 3-methyl-, and some dimethyl alkanes are com mon in spices such as curcu min.

The major alka ne present in an essentia l oil obtained by extraction and steam distil lation was the n-C2g alkane nonacosa ne (55.8 and 10.7%, respectively). Other abunda nt alkanes were heptacosa ne, 2,6-dimethyltetradeca ne, pentacosane, hexacosa ne, and hentriaconta ne. Cu rcu in reduces liver fibrosis by modu lating ca nna binoid receptor tra nsmission.

In general, many pla nt species, especia lly those used for spices have anti-a llergy/a nti- inflam matory activities. E.g., nutmeg interacts with the endoca nnabinoid system by inhibiting certain key enzymes that cata bolize (break down) the two main endoca nnabinoids, ana nda mide and 2AG.

β -ca ryophyllene, a phytoca nnabinoid, and/or its oxides act as ful l agonists of the CB2- receptor where they exert anti-infla mmatory and ana lgesic effects that are mediated through CB2, but not CBi. Another phytocan na binoid, sa lvinori n A, from the plant species

Salvia divinorum extract is a terpenoid that interacts with a can na binoid receptor, not yet characterized that appa rently forms only in inflam matory conditions. This uncharacterized receptor also acts as a κ-opioid receptor. Many sages produce simila r compounds with some activity, but whose activities have not been fol lowed in detail t o identify receptor interactions. Myrcene is a major constituent of the essential oil of hops and appears to be related t o opioid "high" possibly by agonizing opioid receptors or possibly by antagonizing opioid degradation. Plant sources are hops, verba na and ca nnabis. Myrcene is also fou nd in lemongrass, thyme and mango. Echinacea contains multiple N-a lkylamides that have cannabinoid mimetic effects.

The Helichrysum umbraculigerum, aka wool ly umbrel la Helichrysum or kerriekruie in

Afrikaa ns, is a fast growing peren nial herb with a strong mood-stabilizi ng and ant i depressa nt effect due to high concentrations of ca nna bigerol (CBG). Liverwort contains large amounts of perrottetinenic acid, a THC, mimetic that binds CBi. The cacao pla nt has endoca nnabinoid activity by deactivating the FAAH enzyme thereby maintaining AEA levels and levels of similarly active fatty acid derived molecules. FAAH inhibition com bines anti- inflam matory effects of several N-acyletha nolamines while it targets additiona l receptors such as TRPV1 and peroxisome proliferator activated receptors.

URB597 is a potent and selective FAAH inhibitor. Inhibiting the FAAH enzyme, a principle degradative enzyme and one involved in synthetic pathways for infla mmatory prostagla ndins, maintains beneficia l ca nnabinoid levels while reducing adverse effects from breakdown products. Flavonoids are one of the largest nutrient families known and include over 6,000 already-identified family mem bers. Many flavonoid classes com prise chemical mem bers that have been tested and found t o work with the canna binoid anti-im mune and ant- allergic systems. At least 20 of these flavonoid compou nds, including, but not limited to: apigenin, quercetin, can nflavin A and can nflavin B, β -sitosterol, vitexin, isovitexin, kaem pferol, luteolin and orientin have been identified in the can na bis plant. Most if not all of these flavonoids are not exclusive to Cannabis also produced and ha rvesta ble/extracta ble from other pla nts. Flavonoids are known for their antioxida nt and anti-inflam matory health benefits, as wel l as their contribution of vibra nt color t o the many of the foods we eat (the blue in blueberries or the red in raspberries).

Perrottetinenic acid, a phyto- or synthesized compound similar t o THC appears t o act through CBi with effects simila r t o AEA.

Ginger has anti-inflam matory properties without many of the side effects of synthetic pharmaceuticals. Ginger comprises several powerfu l anti-oxida nts and at least one phyto- cannabinoid that reacts with same receptors as ca psaicin (pepper), gingerol. Ginger com prises potent com pou nds that are efficacious agonists of the VRl receptor. The activity of specific gingerols depends on the length of the ca rbon chain, which also determines hydrophobicity (pa rtitioning between the lipid mem bra ne and internal or external aqueous environ ments). Increasing the num ber of ca rbons from 6 to 8 and the hydrophobicity index from 1.90 to 2.88 in the tra nsition from [6]-gingerol to [8]-gingerol increases by 10-fold the potency for inducing tra ns-plasma membra ne cu rrents (ion fluxes).

Turmeric contains the fou r major curcu minoids: curcumin, demethoxycurcu min, bisdemethoxycurcu min, and cyclocurcumin. One or several of these curcumins may be used as a supplement to mollify the body's norma l inflam matory responses. The polyphenols tra ns-resveratrol and cu rcumin selectively bind human CBi canna binoid receptors with na nomolar affinities and function as antagonists/inverse agonists. Curcu min, whose active moiety: diferuloylmethane, is a well-known polyphenol molecule that is an active taste constituent of the spice turmeric (Curcuma longa). The crude spice has been used for dieta ry and medicina l purposes for severa l centuries. Cu rcu min regulates various signa li ng molecules including several infla mmatory molecules, cytokines and chemokines, adhesion molecules, transcription factors, enzymes, protein kinases, protein reductases, ca rrier proteins, cell survival proteins, cel l-cycle regu latory proteins, drug resista nce proteins, growth factors, receptors, DNA, RNA, and meta l ions. These stem from cu rcumin's ability to bind CBi with na nomolar affinity and micromolar affinity with CB2. Cu rcumin shares structu ra l motifs with severa l ca nnabinoid receptor liga nds.

Trans-resveratrol receptor shares cha racteristics with can na binoid receptors. The affinities of tra ns-arachidins, tra ns-resveratrol, and tra ns-piceata nnol for CBi and CB2 are different in that tra ns-resveratrol and analogs bind CBi, while isoprenylated tra ns- resveratrol derivatives tAl and tA3 bind CB2. The affinity of tra ns-resveratrol and tra ns- piceata nnol for CB2 is 5- t o 10-fold lower tha n for CBi. All compounds except tA3 exhibit ~2- t o ~10-fold selectively for binding CBi relative to CB2.

Magnolol, a biphenyl neoligna n from Magnolia officinalis, magnolol acts as a partia l agonist for CB2, while honokiol is less potent but has full agonistic activity at CBi and antagonistic properties at CB2. Malyngamide B binds both CBi and CB2, with moderate potencies as an agonist anti-infla mmatory com pound. While many ca nna binoids su pport

µ Μ nitric oxide (NO) production, magnolol inhibits NO production with an IC5 ~6.2 .

Sa binene from severa l diverse pla nts, includi ng, but not limited to: Norway spruce, black pepper, basil, Myristica fragrans (the world's main source of nutmeg), etc. Sa binene is optical ly active with (+) and (-) ena ntiomers. Sa binene is also responsible for the unique flavor and aroma of marjoram. Sabinene is also present in other spicy spices like carda mom and cloves.

Sciadonic acid from the seeds of a coniferous pla nt, Sciadopitys verticillata (um brel la pine) exhibits can na bimimetic activity by increasing intracellular Ca 2+ levels in cel ls expressing CBi.

Isobutylamide and dodeca-2E,4E-dienoic acid isobutyla mide, have been isolated from

Echinacea purpurea and Echinacea angustifolia. Chemical ly, these alkyla mides show structu ra l similarity with AEA and bind CB2 more potently tha n the endogenous cannabinoids with the values (CB2 approximately 60 nM; and CBi > 1500 nM) and act as ful l agonist on CB2 in the nanomolar ra nge. Interactions of alkylamides with CB2 is shown by immunomodulatory effects of Echinacea prepa rations or intact Echinacea. The Echinacea alkylamides, includi ng, but not limited to: those above and dodeca-2E,4E,8Z,10Z-tetraenoic acid alkylamides exhibit relevant can na binoid receptors binding affinity with a tertiary alkylamide, l-[(2E,4E,8Z)-tetradecatrienoyl] piperidine, having the most potent bindi ng

µΜ µΜ affinity t o both CBi and CB2 with values of 0.8 and 0.16 , respectively. It demonstrates CB2 selectivity with a CBi/CB 2 affinity = ~5. Alkyla mides: dodeca-2E,4E- dienoic acid isobutyla mide, tetradeca-2E,4E-dienoic acid isobutyla mide, tetradeca-

2E,4E,8Z-trienoic acid isobutylamide, and l-[(2E,4E,8Z)-tetradecatrienoyl] piperidine have great affinities for CB2 and much lower affinities for opioid receptors.

β-Caryophyl lene is a volatile sesquiterpene fou nd in essential oils of severa l pla nts including, but not limited to: cloves, oregano, cinna mon, black pepper, hem p, rosema ry, and hops. It is used in foods, cosmetics, and fragrances as a preservative, additive, and flavoring agent. It is approved by severa l food and flavor regulatory agencies including

United States Food and Drug Administration (FDA) for its use as a food addit ive β-

β caryophyl lene binds CB2. It has a peppery, woody and/or spicy smel l -caryophyl lene exerts potent can na bimimetic anti-inflam matory effects in mice.

The flax plant makes ca nnabidiol (CBD) and a mixture of simila r compou nds that have demonstrated anti-infla mmatory effect. Ca nna bich romene (CBC) and some related com pounds are found in Chinese rhododend ron. Ajulemic acid is a synthesized non- psychoactive ca nnabinoid that has also now been fou nd in sma ll qua ntities in severa l pla nts. Ajulemic acid has demonstrated anti-al lergic/anti-al lergic ca pacities. N-

Isobutyla mides com pounds found in the electric daisy have can na binolic activity simila r t o severa l other ca nna binolic amides (e.g., AEA) and like them has ca pacity t o regu late pain sensation and infla mmation.

Other phyto-com pou nds or derivatives include but are not limited to: abinene, - pinene, 4,8-dimethyl-l,7-nonadien-4-ol, 2-hydroxy-4-methyl-valeric, acid methyl ester, octanal, O-cymene, euca lyptol, -phella ndrene, cis-sabinene, hydroxide, myrcenol, terpinen-4-ol, a-terpineol, β-thujene, ς-terpinene, trans-a-ocimene, ca rveol, β-citra l, guanidine, gera niol, bornyl, acetate, β-pi nene, thymol, geranic, acid methyl ester, a-terpi nyl acetate, d-limonene, eugenol, geranyl acetate, dihydrocarvyl acetate, a-ylangene, cis- dodec-5-enal, 3-phenyl-2-propenoic, acid methyl ester, β-elemene, c, vanil lin, epoxy-a- terpenyl acetate, buta noic, acid 2-methyl-, 3,7-dimethyl-2,6-octadienyl ester, l-methyl-4-

(l-acetoxy-l-methylethyl)-cyclohex-2-enol, l,2,3,4,4a,5,6,8a-octa hydro-4a,8-dimethyl-2-( l - methylethenyl)-, [2r-(2a,4aa,8aa)]-na phthalene, p-mentha-l(7),8-dien-2-ol, ς-muurolene hydroxy-a-terpenyl acetate, nerolidol, gera nyl bromide, (-)-a-pa nasinsen, pyrocatechol, ς - elemene, 9,10-dehyd ro-isolongifolene, a-ca lacorene, cis-verbenol acetic, acid, 1-methyl-l-

(4-methyl-5-oxo-cyclohex-3-enyl)ethyl ester, alloa romadendrene, z,z-2,6-dimethyl-3,5,7- octatriene-2-ol, 4-epi-cu bedol, 2-oxa bicyclo[2.2.2]octan-6-ol, 1,3,3-trimethyl-acetate, patchoula ne, farnesol, ca ryophyl lene oxide, cis-lanceol, ledene oxide-(ii), farnesol acetate,

6-epi-shyobunol, falca rinol, phytol, aromadend rene oxide-(2), heptacosane, longipi nene, epoxide, hentriacontane, deca methyl-cyclopentasiloxane, geranyl, isobutyr, hexamethyl- cyclotrisiloxa ne, 1-docosene, tetratetraconta ne, dodecamethyl-cyclohexasiloxa ne, etc.

A hexane or simila r extract of a ca rda mom, e.g., Elettaria repens, is rich in polyphenols, flavonoids, and terpenoids. The crude extract com prising one or more of these compounds can be used with ca nna binolic effect or may be further fractionated for improved taste, color, smel l efficacy, etc. A su pplement comprising E. repens is a potent antioxida nt, for macromolecules such as DNA, protein and lipid damage protective properties and also effective against ca rrageena n-induced acute infla mmation and paw edema in rats. f . repens administration down-regulates ca rrageen induced increase in cytokines such as

COX-2, IL-6, and TNF-a. E. repens exerts antioxida nt effects by restoring SOD, cata lase, GSH levels and as a result inhibits lipid peroxidation.

Ca nna binoid agonists and antagonists have been synthesized and may be availa ble for modulati ng the immune system through their ca nna binolic activities.

Catechins general ly possess moderate affinities for CBi with less efficacious binding to

CB2.

R-WI N 55,212-2 is a synthetic can na binoid that strongly inhibits the interleukin-1 (IL-1) induction of the adhesion molecules intercel lular adhesion molecu le-1 (ICAM-1) and vascula r cell ad hesion molecu le-1 (VCAM-1) and the chemokine IL-8.

CBi and CB2 ca nna binoid receptors are induced in response to hepatic inju ry.

Hepatic infla mmation is linked t o hepatic fibrosis in models of fibrogenesis.

Kupffer cells are crucia l and promote activation of hepatic stellate cel ls (HSCs).

Activated T lymphocytes and neutrophils also contribute to infla mmatory

microenviron ment leading to HSC activation and fibrogenesis. Ku pffer cells are

shown t o express high CB2 mRNA which is known t o mediate anti-inflam matory effect by su ppression of TNF- and IFN-γ and stimulate anti-infla mmatory cytokines

such as IL-I 0 and also inhibit macrophage migration at sites of infla mmation leading

t o anti-fibrogenic effects of endocan na binoids in the liver. The selective CB2 receptor

agonists JWH 133 and HU-308 have also been shown t o decrease TNF-a, ICAM-1, and

VCAM-1 expression in human liver si nusoida l endothelia l cel ls (HLSECs) expressing

CB2 receptors and thus decreased ad hesion of hu man neutrophils t o HLSECs, thus

depicting a role for CB2 receptor in endothelial cell activation and endothelia l-

infla mmatory cell interactions (Rajesh et al., 2008).

While synthetic ca nna binoids shou ld be used with ca re in frequency and volume of dosing, one cha racteristic of the ca nna binolic systems is that they are fantastic self- regulators. For exa mple, exogenous AEA and simila r phyto-com pou nds that bind endogenous receptors set in motion pathways t o reba lance ad restore can na binoid meta bolisms including related pathways for inducing receptors synthetic enzymes and even the degradative enzymes. Smal l frequent doses ca n be all the orga nism requires for su perbly ba lanced ca nna binolic controls.

Native, phytomimetic, and/or synthetic can na binoids can be directly ad ministered t o the recipient that may benefit from ca nnabinolic reba la ncing by any suita ble means. For exam ple, they may be de livered oral ly, buccal ly, su bli ngual ly, nasal ly, vagina lly, recta lly, tra nsdermal , ocu larly, as a vapor, etc. For example, suitable formats incl ude but are not limited to: a bucca l gel, spray, lozenge, drop ca psule, paste, etc., as a nasa l spray, d rop, lozenge, etc. as an edi ble su pplement o r food additive, for exam ple as d rops o r in pet treats o r hu man snacks, etc., a suppository, a skin patch, eye d rops, im plant, etc. There is no restriction o n suita ble packaging. Another option involves pro-can na binolic com pou nds, com pounds meta bolized by the orga nism t o become can na binoids which are also suita ble as com positions for ad ministering o r delivering the active su bsta nce.

Both -6 and -3 Essential Fatty Acids (EFAs) are two groups of poly-u nsaturated fatty acids (PU FAs) required for the production of endoca nnabinoids and ca nna binoid receptors.

Mam mals must consume both types of these EFAs because the body ca nnot synthesize them in amounts required for good hea lt h -3 PU FAs are general ly anti-i nfla m matory, while -6 PU FAs are often proinflam matory. Given that -3 acids and endoca nnabinoids share simila r benefits, they may often be com bined in a su pplemental com position for use n accordance with this invention.

A deficiency in -3 PU FA causes CBi t o u ncou ple from its effector G proteins, essentia lly disa bling them, -3 consum ption u pregulates CBi and CB2 expression, along with increased levels of endoca nnabinoid synthesis enzymes. Foods including, but not limited to: flax, hem p, and chia seeds, along with walnuts, are excel lent vegetaria n sources of J - 3 PU FAS. The -3 PU FA in these foods is a-linolenic acid, which is converted into the more synthetica lly usefu l longer-chain -3 PU FA com pounds eicosa pentaenoic acid ( EPA) and docosa hexaenoic acid (DHA) t o synthesize many other com pou nds.

-3 PU FAs include but are not limited to: hexadecatrienoic acid (HTA), a-linolenic acid

(ALA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), heneicosa pentaenoic acid (HPA), docosapentaenoic acid

(DPA), clu pa nodonic acid, docosa hexaenoic acid (DHA), tetracosa pentaenoic acid, tetracosa hexaenoic acid (nisinic acid), etc.

Ha plosa mate derivatives are the first natural ly derived ca nna binomimetic com pound belonging t o steroid family. They represent another new chemica l class of can na binoid receptor liga nds. This group of steroids includes but is not limited to: ha plosa mate A and ha plosa mate B.

Ha plosa mate A and desu lfoha plosa mate have opposite effects. Haplosa mate A has strong affinity for CBi. Desulfoha plosa mate has higher affinity for CB2. The 7- monoacetylated derivative of ha plosa mate A exhibits affinity t o both CBi and CB2 cannabinoid receptors in com pa rison t o its pa rent com pound. However, acetylation at C-4 o r dialdehyde derivative resu lts in the loss of affinity o n both CBi and CB2.

Eu phol has potent immu nomodu lation a nd anti-inflam mation effects. CB2 plays a predominant role in this. The antihyperalgesic effect of eu phol is simila r t o the effects caused by ACEA, a CBi agonist, and JWH-133, a CB2 agonist.

l^-glycyrrhetinic acid and its diastereomer 18a-GA are triterpenoid saponins from the roots of Glycyrrhiza glabra L , popularly known as "licorice". They are genera lly used as natu ra l sweeteners and flavoring additives in food and have been fou nd in traditional medicines pu rported t o possess antimicrobia l, anticancer, and anti-inflam matory properties. The inhibitory activities of licorice extract i involve a dose-dependent decrease in intracellu la r Ca 2+ levels.

Aliquirtin, gla bridin, and 18a-glycyrrhetinic acid also exhibit inhibitory activity against

Ca 2+ flux induced by AEA, whereas l^-glycyrrhetinic acid has stronger potency evidenced by more tha n 90% inhibition in responses t o CBi agonist.

The oxylipin, 3-hyd roxyarachidonic acid (3( R)-H ETE), is an intermediate of the β - oxidation of arachidonic acid and has an importa nt role in the life cycle of fungi. T

Clostridia affect the gut: Acting t hrough several immune cells and cytokines, the bacteria can prevent pea nut proteins that can cause allergic reactions from gaining access t o the bloodstream. Clostridia, a gut bacterium, in some cases protects against food allergies. By inducing immune responses that prevent food allergens from enteri ng the bloodstrea m, Clostridia minimizes allergen exposu re and prevents sensitization - a key step in the development of food allergies. Genetic ana lysis reveals that Clostridia causes immune cel ls to produce high levels of interleukin-22 (IL-22), a signa li ng molecule known t o decrease the permea bility of the intestinal li ning. Ca nna binoids may be su pplemented t o aid this effect.

Mam mals have their own endocan na binoids. But many can na binoid substa nces, the phytoca nnabinoids, are found in plants. Ca nna binoid su bstances are found t hroughout the pla nt and animal kingdoms. Ca nna binoid receptors are ubiquitously present in most euka ryotes, being present in chloroplast mem bra nes of pla nts and in nuclea r and mitochondrial mem branes of other euka ryotes.

CBi and TRPVi are active in mitochond ria l mem bra nes where the ca nna binolic pathways act to ba lance distribution and activities of mitochondrial proteins and mitochondrial meta bolism itself. In severe cases, the ca nnabinoid receptors in the nuclea r membra ne and in mitochondrial mem bra nes are importa nt mediators in apoptotic cel l death.

Another class of compou nds with wide systemic meta bolic effects comprises corticosteroids or glucocorticoids. While immune system imbala nces can occur throughout an organism's lifespan, corticosteroid pathways tend t o decline in efficiency as anima ls age and their mitochond ria become burdened by previous meta bolic com promises that accumulate over time.

One additional importa nt factor involved in the present invention is that as the animals age androgenic influences of endogenous hormone, especia lly testosterone, continuously wanes. While high prolonged su pplementation with this class of steroids suffers from serious side-effects, these steroids are natura l compou nds and when present in appropriate concentrations can augment other mecha nisms for optimizing healthfu l living.

In the blood seru m of mam mals, testosterone exists primarily bound t o a protein, typical ly albumin or sex hormone bindi ng protein. Unbou nd testosterone is referred t o as

"free testosterone". The term "total testosterone" refers t o the tota l amou nt of testosterone in the blood seru m, that is, the com bined amou nt of protein-bou nd testosterone and free testosterone. The typical half-life of "testosterone" in the blood serum ranges from 10 t o 100 minutes. While many of these steroids and steroid mimetics are not presently approved for human as thera peutic compounds, several may be made available in the form of su pplements to humans and other mam mals.

Testosterone, a prima ry ana bolic steroid, is meta bolized into dihydrotestosterone in the body by way of the 5-al pha reductase (5AR) enzyme (this means that dihyd rotestosterone is a meta bolite of testosterone), and furthermore, na nd rolone is a byproduct of the aromatization (conversion) of testosterone into estrogen. With this knowledge, it then sta nds t o reason that testosterone quite litera lly is the origin of all ana bolic steroids. Without testosterone, DHT and na ndrolone wou ld not even exist, and therefore without the existence of DHT and na nd rolone, their individua l derivatives and ana logues would also not exist.

Testosterone itself is the principal male sex hormone. Hormones are defined and classified as chemical messengers of the hu man body, which means that hormones are what carry messages t o different cel ls and tissues in the body to tel l those cel ls and tissues what t o do (grow muscle tissue, heal and repair, manufacture importa nt com ponents, perform a specific job, etc.). Without hormones of all different types, all functions within the huma n body wil l proceed unregulated and out of control. How much testosterone the average male produces is dependent on many different factors, which include: individual genetics, age, lifestyle ha bits, nutritional habits, and activity levels. On average, it has been determined that the media n level of testosterone production among 30 yea r old human

~150-175 lb. males is between 50 - 70 mg weekly. Where any given individua l might la nd within that ra nge is dependent o n the aforementioned factors. It is com mon knowledge that the most prominent effects of the hormone testosterone appear and are experienced during pu berty, which is evidenced by an increase in testosterone production and secretion, and wil l typica lly reach the highest endogenous levels at this point in any given man's life. This significant increase in testosterone serves to im pa rt very importa nt physiologica l changes of the male body. Testosterone governs many different functions within the body. The natu re of hormones in the circulation is to govern systemic functions remotely around the body, and testosterone is no exception t o this. Dosing ca n be based o n the blood levels of the intended recipient, their weight, the chemical natu re of the su pplement (bioavailability, ha lf-life, pa rtitioning in body com pa rtments, bindi ng t o proteins, etc.) t o maintain the animal at an androgen level approximating or prefera bly exceeding by about 1.5, 2, 2.5 or 3 times the previous average levels.

Androgens such as testosterone and DHT bind to androgen receptors (ARs) in cells. The resulting androgen-receptor com plex regu lates gonadotropin secretion and spermatogenesis. The and rogen-receptor com plex is responsible also for external vinilization and for most and rogen actions during sexua l maturation and adult life. DHT is an especia lly potent and rogen because it binds with greater affinity t o and rogen receptors than testosterone does. Testosterone production in intact mamma ls is stimulated by luteinizing hormone (LH). It is understood that follicle stimu lating hormone (FSH) stimu lates testosterone production also. Testosterone concentrations in the blood seru m are regu lated in pa rt by a negative-feedback pathway in which testosterone inhibits the formation and/or secretion of luteinizi ng hormone-releasing hormone (LH RH). LH RH acts to stimu late secretion of LH by the pituita ry gla nd. Testosterone acts also by regu lating the sensitivity of the pituita ry gla nd t o LH RH .

Taking dogs, aka ca nines, as an exa mple, the present invention provides improved health and longevity for the anima l com ponent of the relationships huma ns are finding more and more significant. Mai ntai ning a pet's wel l-being ca n su pport oxytocin levels in a hu man owner. Oxytocin is one of the natural inducers of AEA synthetic pathways. Thus, improving pet's activities that lead t o oxytocin release in the human owner's body ca n have a beneficia l side-effect of su pplementing can nabinoid production and circulating levels in the huma n owner(s).

On top of this, animals exhibit la rge differences in their mitochondria and mitochondrial activities. By optimizing energy meta bolism t hrough patient specific monitoring and improvement in mitochond rial metabol ism, the vita lity effects observed through androgen ba la ncing may be further enha nced. Accordingly, the invention prefera bly includes as alternative approaches wherein in conjunction with and rogen ba lancing as an anti-aging measu re that optimizes activities and/or in conjunction with system reba la ncing by enha ncing can na binoid activities, additiona l improvement may be obtained by also optimizing mitochondria l activity, metabolism and performance.

Com mon diseases in the aging dog include: arth ritis, which reduces activity levels and may make the animal more irritable or reclusive; obesity, which ca n acerbate arthritis and other diseases such as cardiomyopathy and usua lly reduces anima l activity levels; joint dysplasia, which reduces anima l comfort and activity; gum disease; dia betes; blindness of various etiologies; dementia; and other diseases of aging familiar in humans. Meta bolic functions may be impaired, for exa mple, adipose tissue may experience accelerated or location improper deposition and/or aberrant utilization, glucose metabolism and meta bolism of other suga rs may be altered though diabetic effects and com pensati ng meta bolic shifts.

For exam ple, in humans both free testosterone and tota l testosterone have been documented in their decline as a male ages. Up t o their fifties, human males essential ly maintain total testosterone with about a 25% drop in free testosterone from about the age of thirty to about fifty. In the ensuing years both tota l and free testosterone continue t o decline until about the age of eighty the levels are only about ha lf the levels previous t o age fifty. While there are differences in effects of aging between mammals, in genera l testosterone levels decline with age as the anima l's vita lity also declines. As an approximation, 25% su pplementation may be used as augmentation begin ning at approximately age 5 in dogs and age 7 in cats. The supplemented amounts wil l depend on the and rogen com pound chosen and its com pa rison in activity to testosterone. Advised ly testosterone levels wil l continue to be monitored with additiona l su pplementation as

Testosterone activity lessens. Evidence is building that age related reduced testosterone levels in human males, and thus in other mam mals, may be related t o growth of pot bel lies and possi bly, hea rt attacks, strokes, osteoporosis, clinica l depression and some presentations of Alzheimer's disease.

A body of evidence relating to human fema les suggests that testosterone levels may be importa nt factors with regard to depression, activity level and genera l sense of wel l- being. There is also evidence that in hu man females a testosterone su pplement may improve activity levels and maintai n a lea ner body. Low testosterone levels in human fema les have been associated with lack of motivation and a sense of fatigue. The com mon weight gain and increased adipose tissue deposition in women starting approximately 10 years prior to menopause coincides with a com mon ly observed decreased level of circulating testosterone. This suggests an importa nt com ponent of the present invention relating to maintaining testosterone bala nce wil l benefit both male and female mammals, including, but not limited to: canines, equines and felines.

Importance of Balancing (controlling) Androgens in Circulation

Although it is reported that thousa nds of and rogenic hormones have been made, for exam ple t o achieve and rogenic effect but to avoid detection by sports monitoring organizations, "testosterone" is used as an exa mple t hroughout this discussion since testosterone is an inexpensive and commonly reported and rogen that has been used and abused by male and fema le huma ns. As testosterone replacement or testosterone level augmentation raises testosterone levels up t o or possibly slightly exceeding previous norma l range it has a high success rate of alleviating many conditions associated with aging that have been fou nd t o compromise hu man and anima l health and genera l wel l-being.

Testosterone and ana logues have successful ly treated or managed fema le breast cancer, hereditary angioedema, anemia, multiple muscle wasting diseases including HIV/AI DS, severe burns, acute and chronic wou nds, general ca loric wasting, muscu la r atrophy, osteoporosis, male infertility, adolescent growth failure, osteoporosis, female libido problems, Turner and Klinefelter Syndrome, menopause, chronic dysfu nctiona l uterine bleeding (menorrhagia), endometriosis, and many others. Recent reports suggest that testosterone has an import effect in strengthening connective tissues such as liga ments, for exam ple the anterior cruciate ligament (ACL) in the knee. Actual ACL strength has been measured in anima ls with a conclusion that exposu re t o the and rogenic hormone somehow makes the tissue less prone to ruptu re during stretching. Su pporting this testosterone effect on at least the ACL is the perplexing high incidence of ACL tears in girl's knees well in excess of their pa rticipation in stressful sports.

These vastly different effects associated with testosterone in both males and females suggest that an appropriate amount of circu lating and rogen is importa nt for genera l health and wel l-being.

Thus, these and other findings suggest that maintaining an optimized testosterone level as the anima l ages can resu lt in improved vigor, reduced inju ry, and greater activity and possi bilities for socia l interaction. Management of circulating testosterone also has the possible effect of preventing or reducing inju ry, such as muscle or joint inju ry, and ca n thereby appea r as an anti-aging agent to maintain a higher level of activity availa ble to the anima l and to the animal 's hu man com pa nion(s).

While testosterone level management and supplementation where warra nted have proved successful in improving specific health effects all over the body, ad ministration has been ca reful ly control led withi n the medical commu nity t o avoid misuse and deleterious effects that ca n be associated with elevated testosterone levels that exceed safety limits.

Popu la r accepta nce of testosterone bala nce in the body may suffer from reports of overuse and abuse of supplements in huma n males who may have obtained testosterone for una pproved and especial ly for ineffective treatments. For exam ple, the growth of novel disease states such as erectile dysfu nction (ED), the expense of prescriba ble ED pharmaceuticals, and claims on the internet touting androgenic com pounds such as testosterone and testosterone mimetics as effective treatments coincides with a 2000% increase in testosterone sales happening in the United States from about 1990 t o about

2002. It is also widely accepted that testosterone, and the then more difficu lt to detect design androgenic com pou nds, were used in Olym pic and other high level sporting com petitions because of the desira ble effects on physica l performa nce. In the more genera l population several occupations have been prone t o testosterone overuse and abuse. For exam ple, police officers, security gua rds and bou ncers, having become aware of testosterone's profou nd efficacy have made use of androgens to improve at least their perceived on-job performa nce and genera l performa nce in life situations. Such stories may interfere with easy availability of su pplementa l steroid com pounds for use in animals. In some insta nces a veterina ria n prescription may be necessa ry t o obtain the compound as a su pplement.

Proper Androgen Levels Can Have Anti-aging Effect, but Misuse is Dangerous

The observation that as testosterone levels decrease during aging and that testosterone is believed t o enhance muscle development suggests that the occu rrences are not pu rely coincidence. In fact, muscle tissue expresses androgen receptor (AR) protein so it wou ld be understood that testosterone would influence muscle metabolism. Supporting evidence that testosterone su pplementation or replacement increases muscle fiber protein synthesis and that plu ri potent stem cells ca pa ble of differentiating into muscle fiber cel ls have high levels of A R expression suggests a causal relationshi p exists. Accordingly,

Supplementing and rogen, e.g., testosterone t o an aging anima l may maintain or build muscle mass. Better muscle mass is associated with lower incidences of dia betes so the benefits of testosterone bala ncing would be expected t o cascade t hrough many orga ns and tissues. But at lower levels of activity while testosterone bala nce may produce profou nd benefits an even greater improvement is possible if mitochondria l optimization is partnered with the ba la ncing. Not intending to disparage the invention approach wherein anima l health and relationships are augmented by testosterone bala ncing, the invention recognizes that the augmentation ca n be amplified by 1) maintaini ng or optimizing mitochondrial performance as part of the intervention; and/or 2) by taking adva ntage of cannabinoid com pounds t o facilitate bala ncing throughout additiona l systems. On the other ha nd, allowing mitochond ria l impairment or other systemic im ba lances t o degrade benefits of androgen balance would be seen as slowing or limiting benefits of the bala ncing itself. In fact, relating to aging, some believe that oxidative stress of mitochondria may have a major role in age related energy deficit.

Androgenic com pou nd abusers have contributed to testosterone's and other androgenic hormones' shocking disparagement in general news media t hrough reports of sometimes violent activities and severe health outcomes such as brain tumor, but perha ps pa rtly related t o pu blicity from these mainstrea m press warnings about and rogenic use and

"over manliness", abuse continues in a significant segment of the population. Though serious abuse may present long term problems for the individua l and society, society in genera l ca n understa nd that the abuse is a resu lt of testosterone's positive effects.

While some desired effects, for exa mple, increased muscle mass in body builders and other professiona l ath letes, may be val ued for their immediate effects, long term effects, for exa mple use over decades, has been shown to increase propensity for hea rt attack and stroke. The length of ad ministration and the expected remaining lifespan of the individual should be considered before enha ncing androgen in the bloodstrea m.

Other noted effects include elevated LDL and higher LDL/H DL ratio, increased blood pressure, increased ca ncer, for exa mple, brain and liver, and difficulty in movements that may be caused by excess tissue deposition. Androgen abuse is also associated with testicula r wasting or atrophy which in humans may o r may not be desired depending on one's desires for fatherhood. In neutered dogs, this of cou rse wou ld not be a releva nt concern.

Most of these recognized problems ca n be avoided or minimized sim ply by managing testosterone blood levels to levels more preva lent in normal animals or limiting administration t o older anima ls with for exam ple an expected remaini ng lifespan of about a decade or less. For example, the irrita bility, aggressive behaviors, rage, violence, delusions, manic eating, etc., appear t o be associated with abuse of and rogens that involves massive dosing regimens; liver disease and tumor events appea r associated with long term administration of moderate t o high doses.

The present invention seeks t o avoid these problems by optiona lly providing systems wide reba lancing tools in the form of ca nnabinolic augmentator su pplements or facilitators and by monitoring, either through behaviora l observation, or more preferably by measuring blood, sa liva, urine, or skin androgen or and rogenic activity. Even minor undesired elevation above a targeted amou nt, perha ps resulti ng from meta bolic differences, change in food, or a mistake in dosing or formu lation can be properly corrected. Long term effects seen over decades may not be a problem at all in shorter lived species. But age may be considered as a factor. Proper Androgen Balance is not for Amateurs

The natural testosterone molecule is poorly available to a mamma l's circu lation when it is delivered by oral administration and absorbed across the intestinal wal l into the hepatic portal system. Liver metabolizes most ingested testosterone before it ca n enter genera l circulation. An attem pt t o surmou nt this obstacle by alkylating (methylating) the C-

17a position of the molecu le has been essentia lly aba ndoned for human use because of toxic effects on the liver. Testosterone undeca noate is not modified at the C-17a position and appears t o avoid this toxicity issue perha ps because its absorption is not through the porta l system.

Due to the efficiency of the mam malian digestive system in brea king down foodstuffs t o simpler molecules delivering la rge amou nts of testosterone t hrough the gastro-intesti na l track, including the hepatic porta l system most, but not 100% of an intact lipid like the fat- soluble hormones will reach general circulation. However, since the digestive process is not

100% efficient (a smal l percentage of la rge molecu les wil l bypass or escape the degradative process) after giving a la rge dose a smal l but effective amou nt of delivered testosterone wil l enter genera l circulation. Since digestive efficiencies vary greatly between individua ls, frequent monitoring of circulating levels to mainta in proper ba la nce is highly recommended.

To avoid the chemical brea kdown and filtering pathways that have evolved for digesting natu ra l environ mental feeds and possible toxins, testosterone ca n be bou nd, packaged or complexed in a less natura l man ner t o enha nce absorption of the active molecule, through a non-porta l pathway, for exam ple, through the lym ph system.

Complexing testosterone with a form of sex hormone binding globulin (SH BG), which carries the hydrophobic (lipid based) hormone in the circulatory system may be one important mea ns for delivering testosterone through the general circulation. Liposomes and other hydrophobic ca rrier systems are possible delivery agents. A coating or packaging that protects the testosterone ca rrier from gastric acid and enzymes may be designed for remova l in the smal l intestine to permit testosterone t o be ca rried into the lymph system.

Another mea ns for avoiding hepatic-portal absorption is have the hormone absorbed into the circu lation before it encou nters the porta l pathway. Su blingua l or buccal delivery wou ld accomplish this feat. Most dog owners would dou bt that their pet wou ld retain a pel let o simila r item under its tongue. However, extensive or prolonged exposure t o the mouth endothelial tissues for upta ke very early in the Gl track, well before action by stomach acid or possible sequestering into the portal system, is easily accom plished by exploiting the chewing behavior of canines. Dogs, for exam ple, will spend unbelieva ble time and effort chewing raw hide or scented or flavored dog toys. Thus, one com position that might be used in practicing the present invention is a hormonal compound com plexed or packaged in a chew toy. Incorporating testosterone in a chew toy which is facilitated by testosterone's lipophilicity is an effective mea ns for effecting prolonged exposu re through the gums and other early Gl tissues. Direct su pplementation using an and rogen or testosterone molecule in food is not without its downsides. Testosterone in its native state or in chemica lly modified form has positive and negative consequences from use.

Accordingly, use of the com positions is preferably in conju nction with repeated monitoring of androgen, e.g., testosterone, bala nce t o minimize or avoid undesired effects while benefiting from the desired effects.

Circulating testosterone may be increased to a degree using compounds such as vita mins t o stimu late production or to inhibit brea kdown. For exam ple, vita min D, has been shown to protect the liver from viral and chemical toxicity. Accordingly, vita min may be co administered with an and rogen t o hel p protect the liver from toxic response to the androgen. Vita min D has a second beneficial attri bute in that it is lipophilic as are the cholesterol derived sex hormones such as androgens like testosterone.

Vita min D can serve as a lipid ca rrier for other lipid molecules such as testosterone.

When co-administered with testosterone Vitamin D both serves as a delivery vehicle until the SH BG and testosterone are able to associate. The testosterone and rogen is circu lating t o find its target(s) and the vitamin D can migrate t o the liver t o exert its protective effect there. Other lipid vitamins, such as vitamin A, vitam in Eand/or vitamin K may also serve as lipid ca rriers t o hold lipophilic and rogen in circulation until it is able t o be gathered by circulating SBHG.

So in addition t o ora l su pplementation with and rogen, such as testosterone, testosterone bala nce ca n benefit from the presence of lipid vitamins and from inducing expression of SBHG using one or more means known in the art. Sub-derma l identity chips are popu la r with pet owners in the United States and are growing in popu larity worldwide. This illustrates that pet owners are receptive to "foreign" bodies being inserted into their anima ls. Similarly, severa l forms of fema le birth control in hu mans make use of an impla nted rod or stick that slowly dispenses a sex hormone. This accepta nce suggests that many pet owners may welcome androgen su pplementation in this manner to avoid risks, for exam ple of hepatic toxicity. Such device implanted in an anima l might use any of the availa ble delivery options. Shorter lasting implant (several months) might use an osmotic pu mping mecha nism. Another form of implant might use control led solu bility or diffusion where the and rogen is pa rt of a slowly dissolving matrix or is incorporated within a barrier that controls and rogen diffusion into the bloodstrea m. Such implanted devices wil l help ensure better hormonal ba lancing because of the required visits t o the veterinary clinic where a tech nician or veterinarian ca n assay circu lating androgen and refresh the impla nt.

These extensive effects of the anabolic steroids, though beneficia l in la rge often resu lt in wel l-known side effects, some of which are mentioned above. When ad ministering ana bolic steroids or other meta bolism altering com pou nds, systems and su bsystems and their cel l suffer imbala nces. Coordinating such ana bolic thera pies with a supplemented cannabinoid thera py ca n maximize benefits with reduced side effect issues.

Caution is Warranted Because of Testosterone's Wide Effects, but Benefits are

Immense

Testosterone and other androgenic com pou nds have historica lly been misused or abused because of their profou nd effects in multi ple locations throughout the body, especial ly in muscles and sex organs.

Testosterone activity is mediated trough androgen receptors that are fou nd in a multitude of tissues t hroughout the body. To function the testosterone molecule crosses the cell membra ne and binds to an intracel lu lar receptor (AR) present in the cytosol of many cells. The testosterone-receptor com plex then migrates into the nucleus where it can bind specific deoxyribonucleic acid (DNA) segments t o control gene expression by activating synthesis of specific messenger ribonucleic acid (m RNA) segment molecules to increase tra nscription (copying the targeted DNA) and processing the copy to inaugurate protein synthesis controlled by the targeted segment of DNA; which, for exa mple, in muscle cel ls, may increase production of the proteins actin and myosin.

After this tra nscription/tra nslation process is com plete, the testosterone-receptor com plex dissociates and the receptor is recycled along with the hormone to repeat this process multiple times. Androgenic receptors, including some responsive to testosterone meta bolic products or meta bolites such as dihydroxytestosterone (DHT) have been observed throughout the body in various tissues including, but not limited to: skin, scal p, prostate, thyroid, muscle fiber cells, muscle stem cel ls, pancreas, bladder, bone marrow, stromal cel ls, endothelia l cel ls, macrophages, myeloblasts, myelocytes, neutrophils, megakaryocytes, cornea l cel ls, lens cel ls, iris cel ls, cil lia ry body cel ls, adrena l cells and adipose (fat) cel ls. A casual observer should understa nd that testosterone activity would in all likelihood be releva nt on many organs and tissues throughout the body.

Accordingly, the present invention recognizes that decreased testosterone levels such as those occurring during the aging process may result in diminished or su boptima l function of at least one and proba bly many organ systems in the body. As a resu lt control led restoration of testosterone presence and activity can have profound beneficial effect with regard t o multi ple physiologic functions. Improving at least one of these f unctions, and prefera bly several ca n result in a genera l improvement in the animal's physiology and wel l- being. En ha ncing mitochond ria l meta bolism and/or providi ng can na binolic active or activating com pou nds ca n su pport the androgen augmentation effects.

Administration of testosterone t o restore normal physiologica l levels can hel p to restore t o a more youthful state and improve the function of many of the different systems where testosterone's effects on the cellu la r level are accom plished. This includes, for exam ple, action in the bone marrow that increases red blood cell count, which tra nslates t o increased endu ra nce, improvement in energy, wel l-being, and restoration of muscle mass.

There are various studies that have determined where, on average, testosterone levels should be in males according to various age grou ps. Genera lly, testosterone in huma n males declines about 1% per year from the late thirties. For anima ls, the decline may be steeper depending on size, species and lifespa n, and wil l genera lly occur at a younger but still at a midd le age. Osteoarth ritis and hip dysplasia are especia lly com mon and problematic in larger dog breeds and larger dogs in genera l. Dogs wil l reduce activity level and avoid some previous activities to hide the sym ptoms or t o avoid associated pain. Aging is also associated with a genera l lethargy that can be a resu lt of or mask other diseases such as a failing hea rt, painful joints, decreased muscle tone, arth ritis, etc. and may be a factor in weight gain that can cause or exacerbate other disorders. Increased dysplasia and obesity have been observed to have increased occurrence in canines that have been spayed or neutered.

While the benefits, in most cases, necessity of spaying or neutering are profou nd, the procedure does remove a major sou rce of and rogenic hormone, testosterone and its meta bolites, from the anima l's physiology. While other organs such as the adrena l produce androgens, often the amou nt decreases as the anima l ages and becomes insufficient for optimizi ng anima l activity and hea lth. Simila r concerns prevail in cats, but may be less noticed. Vigila nce is advised.

While larger dogs appea r more prone to hip dysplasia, the outcome is observed in smal ler dogs also. Orthopedic Fou ndation for Animals reports that the top 20 breeds exhibiting dysplasia were: bul ldog, pug, dogue de bordeaux, nea polita n mastiff, otterhou nd, St. Berna rd, boerboel clu mber spa niel, black Russia n terrier, Sussex spa niel, cane corso, basset hound, fila brasileiro, Argentine, dogo, perro de presa cana rio, American bulldog, Norfol k terrier, Maine coon cat, boykin spaniel, and French bulldog. Clearly this phenomenon is a concern for sma ll as wel l as large canines. This is not as frequent a concern in cats, but the general ly teachings are stil l applicable.

Testosterone is the main male sex hormone, predominantly synthesized in the testes by Leydig cells (95%). In huma n males, for exa mple, a smal l amount of testosterone is produced by adrena ls (5%). Classic effects of testosterone include the androgen effects su pporting-the growth and development of sex orga ns, the formation of stereotypica l domina nt male behavior (aggressive, attack behavior, territoria l or harem protection, and other undesired behaviors), ana bolic functions (mai ntaining muscle mass includi ng myoca rdiocytes), stimu lation of the synthesis of orga n (specific proteins in kidneys, liver, sebaceous and sweat gla nds in anima ls that have them, maintaini ng bone density, hematopoiesis (stimulation of eryth ropoietin generation in kidney and stimulation of erythropoiesis in the bone marrow). Androgens include, for exam ple, l^-hydroxya nd rost-4-en-3-one, commonly known as testosterone, and dihydrotestosterone (DHT), a meta bolite of testosterone. Testosterone is a natural ly occu rring and rogen which is secreted in males and, t o a much lesser extent, in fema les. In males, testosterone and DHT are responsible for normal growth and development of the male sex orga ns and for maintena nce of seconda ry sex cha racteristics.

In females, testosterone and DHT are believed to be importa nt for norma l growth, sexual desire, and sexua l function. In addition, and rogens promote retention of nitrogen, sodium, potassium, and phosphorus, and decrease the urinary excretion of calcium. Androgens have been reported t o also genera lly increase protein ana bolism, decrease protein catabolism, and stimulate the production of red blood cells.

Com mon sym ptoms of androgen deficiency that may be of specific concern t o pet owners are blood pressu re fluctuations, cardialgia, psycho-emotional disorders (irritability, decreased overal l health and performance), decreased memory and attention, insom nia, depression, somatic disorders (reduction of muscle mass and strength, increase of adipose tissue amount, bone loss, viscera l obesity and thin ning of skin. Several studies have shown that a decrease of testosterone concentration results in increased deposition of fat cel ls in various locations resulting in degeneration of the smooth muscle cel ls. While most research in this area has been reported with huma n males as target test su bjects, effects are widespread and affect mamma ls in genera l and both male and female individuals.

Most pets and farm and companion anima ls are spayed or neutered as popu lation control and to avoid undesired behaviors associated with the hormones that drive or control sexual activity, including mate attraction, and other undesired behaviors.

The benefits are deemed t o vastly overcompensate for the changes associated with the spaying or neutering. For exam ple, very few farmers maintain a bul l; they are dangerous and difficu lt t o control; and especial ly for dairy herds, artificial insemination produces more relia ble timing and product. In pets, male dogs and cats become easier t o manage and less aggressive, more homebou nd, less prone t o testicula r cancer; fema les are less prone to breast cancer, wil l not have repeated heat cycles attracting nuisa nce male cal lers and more frequent urination, even indoors, associated with heat to signa l receptivity for males. Neutered males are less likely to w ander in search of fema les and less likely t o mark territory around and within you r house. Controlling or Balancing Levels of Circulating Androgen to Optimize Long-Term

Health

A tradeoff that huma ns have accepted is that as spayed or neutered animals age, androgenic hormonal su pport such as provided by testosterone drops off. [Even in intact male and female anima ls androgenic su pport declines with agi ng.] While in male anima ls the testes wou ld produce the predominant sha re of androgenic hormone, the feedback mecha nisms within the body of a younger animal com pensate quite adequately t o maintain a genera l state of hea lth.

But as the creatures age, testosterone activity fal ls off regardless of the anima l's sex or gonada l status. This trend is smal l but noticeable and has genera lly been accepted as a pa rt of the agi ng process.

While the declines in animal health are expected and accepted as pa rt of a norma l aging process, the diminished performa nce, comfort and hea lth of the animals ca n be slowed by persons practicing the present invention.

In regular practice of medicine, often medica l intervention is compromised because a patient's metabolism is weakened because of intrinsic or extrinsic factors or because the thera py itself wil l cha nge normal cel l metabolism. Recognizing the wide distribution of androgen receptors t hroughout the body multiple effects are expected in many different organs and tissues. Accordingly, the ful l beneficia l effect of the medica l therapy is limited by one or more other cel l function, in particula r cell energy meta bolism.

Optimizing Energy Metabolism in Conjunction with Androgen Balance Promises Even

More Superior Anti-Aging Benefits

Mam malia n cel ls are euka ryotic cel ls and therefore, like eukaryotic cel ls general ly, they rely on their mitochondria to produce adenosine tri phosphate (ATP). In each mitochondrion at the mitochond rial inner mem bra ne, electrons from NADH and succinate are tra nsported by the Electron Tra nsport Chain (ETC) to oxygen, which, when it accepts the electrons, is reduced t o com bine with hyd rogen t o make water. Along the way the ETC com prises severa l donor and receptor enzymes in series, eventua lly depositing the electrons with an oxygen. Passing electrons from donor t o acceptor releases energy in the form of a proton (H+ across the mitochondria l membra ne. This ion flux has the potentia l to do work. This meta bolic process is known as oxidative phosphorylation and results in production of adenosi ne triphosphate, aka, ATP. The mitochondrion is importa nt t o cel l meta bolism and su rviva l. Detailed descriptions are known or can be fou nd in the art.

Thus, the mitochondrion orga nelle is essentia l for healthy cel ls and therefore for healthy anima l life. ATP, an essentia l molecule for energy meta bolism within the cel l is prima rily generated by mitochond ria. Processes such as ada ptive thermogenesis, ion homeostasis, immune responses, production of reactive oxygen species, and progra mmed cel l death (a poptosis) are some of the more complex processes that also require appropriate ATP synthesis and transport. Mitochondria contai n their own DNA (mtDNA), which serves as a tem plate for 13 mitochond ria l proteins, 2 ribosoma l RNAs (rRNAs), and

22 transfer RNAs (tRNAs). However, the mitochondrion ca nnot function as a distinct and independent organel le. Replication, tra nscription, tra nslation, and repair of mtDNA require proteins encoded by nuclear DNA (nDNA) of the hosting cel l. When the host cell is su b- optima l, perha ps from androgen shortage, mitochondrial meta bolism wou ld be expected to be com promised.

Modern mitochondria have many simila rities to some modern prokaryotes, even though they have diverged significa ntly from the early proka ryotes since the ancient sym biotic event. For exam ple, the inner mitochondrial mem bra ne contains electron tra nsport proteins like the plasma membra ne of prokaryotes, and mitochondria also have their own proka ryote-like circu lar genome. But one difference is that these orga nelles are thought t o have "lost" most of the genes once ca rried by their prokaryotic ancestor.

Although present-day mitochond ria do synthesize a few of their own proteins, a vast majority of the proteins they require to maintain the host cel l are now encoded in the nuclea r genome of the host.

While androgen bala nce holds promise for vast improvement in animal liveliness, an additiona l manipulation wherein after or during and rogen ba la ncing mitochondria l function is also improved holds further promise for optimizing anima l general liveli ness and more fulfil ling interaction with others.

Thus, the present invention relates an ora lly ingestible, anima l life enhancing product t o be administered by a human t o an anima l t o optimize human anima l relationshi ps, and/or the animal's comfort, longevity and/or qua lity of life. Importance of Hormonal Influence to Balance Physiology in Aging Mammals

Though there is variance among breeds of dogs, in genera l diminished androgenic influences become appa rent between four and eight years of age. Some effects are seen in larger dogs at earlier ages. Some early effects, such as the pu ppy wildness, which though cute often invokes glee in huma ns as they pass and the anima l becomes more predicta ble.

These may be related t o androgenic stimula nts and it will be discretiona ry whether to begin treating these dogs at this early period or to begin treatment at a stage where animal comfort may be a la rger factor. Cats, though not as varia ble in size, have simila r concerns.

Mam malia n bodies, like those of dogs, cats, rabbits, etc., have interna l mea ns of messaging. Blood flow can be increased or decreased t o an area or orga n. Nerves sense what is ha ppening at different locations within the body and then transmit information to the central nervous system where multi ple inputs are analyzed and coordinated to initiate an output. The output could be neu rotra nsmitter secretion causing a nerve impulse sending instructions t o another location in the body. Another very importa nt mea ns of interna l com mutation is the endocrine system which uses hormones as signa ling agents. Hormones are chemica ls just as neu rotransmitters, but hormones have effect dista nt from the place of release.

Hormones are chemical messengers used to transfer information through the bloodstrea m from one part of the body, genera lly an endocrine gla nd, to the body in genera l or to a specific target orga n that has a receptor capable of binding or receiving the hormone. Target organs have specialized receptors that gather information that has been tra nsferred from the circulatory system by hormones. An exa mple of a target orga n is the uterus, which is stimulated by the circulating hormone estrogen t o develop uterine glands.

Hormone production-for exa mple, testosterone, estrogen, and progesterone-is regulated by another hormone secreting endocrine gland, the pituitary, at the base of the brain.

Prohormones are building block chemicals used t o produce the hormone. In genera l, the blood levels of sex steroid prohormones are not regulated by any substa nce. Instead, prohormones are genera lly availa ble to assist in the production of hormones, which then act as chemical messengers to other target orga ns. These prohormones are essentia l building blocks for production of the respective hormones and may themselves be at levels insufficient for optima l hormone production. Providing functioning hormone eliminates the problem that may stem from insufficient prohormone. In some hormonal pathways, a hormone may be meta bolized t o an inactive prohormonal state that may be recruited when needed to produce active hormone.

The invention has a goa l of administering to the anima l a non-toxic, effective amount of a composition com prising an androgenic hormone such as testosterone, or a pharmaceutical ly acceptable salt or meta bolite thereof. Hormone level or activity fol lowing administration of the composition t o the anima l is evaluated. The active ingredient may be bou nd to complexed with or incorporated in a ca rrier t o facilitate ad ministration and possibly t o control bioavaila bility. The composition is re-administered t o the subject as needed to maintai n a desired level of circulating hormone or observed activities.

Co-administering such hormone with can nabinoid active su bsta nce t o assist the body in reba la ncing the hormone effects is an especial ly favored aspect of practicing this invention.

Definitions

In genera l words in this description will have a mea ning as used in American English.

The fol lowing list is provided as additiona l guida nce.

ADP - adenosine diphosphate. Higher ADP levels are often associated with higher respiratory activity.

ATP - adenosine triphosphate, a primary molecule involved in energy storage, tra nsport and release.

Biogenesis - a synthetic process occurring as part of meta bolism in a livi ng organism.

Cel lu lar metabolism - set of chemical reactions that occu rs in living orga nisms t o maintain life. Metabolism includes both ana bolism and cata bolism as wel l as multiple pathways that maintain life functions within a cel l or organism. There is no real count of an actual number of meta bolic pathways. With branches and cycles within major pathways and pathways sometimes only active in specific cel l types and sometimes only at select times, counti ng an actua l num ber wou ld be arbitrary. However, the skilled artisa n appreciates that the tota l num ber of pathways, including su bpaths num bers in the thousa nds. The internet is an available resou rce t o study classes of pathways or individual pathways. See e.g., www.itsokaytobesmart.com, though there are many web pages available relating to metabolic pathways.

Clinica l improvement - An observa ble improvement in at least one factor in a patient's quality of life.

Coenzyme Q (CoQio) - aka: ubiquinone or ubidecarenone. An oil-solu ble, vitamin-like su bstance is present in mitochondria. CoQio is part of the electron transport chain pa rticipating in aerobic cel lu la r respiration to form ATP. CoQio is especia lly significa nt because of its respiratory functions and because cholesterol inhibitors, such as stati ns ca n also inhibit synthesis of CoQio precursors.

Desmin - An intermediate fila ment (IF) protein expressed in striated and smooth muscle tissues and is one of the earliest known muscle-specific genes to be expressed during cardiac and skeleta l muscle development. Desmin is seen as controlling mitochondrial f unction by interaction with myofibrils and interacting with the cytoskeleton t o affect positioning within a cell.

ETC - electron tra nsport chain which is used t o ha rvest energy for use in meta bolism.

Kcnq2 - a member of the kcnq family of proteins which act as ion chan nels control ling potassium (K) flux across mem branes. Potassium gradients ca n control electrical potential across a membrane and therefore ca n be involved with electrica l signa ling within and between cel ls. A potassiu m gradient can also control flux of other ions.

kif5b and kif5b- a gene encoding the protein and the encoded a heavy chain portion of kif5 protein working t hrough microtu bules t o effect appropriate distribution of mitochondria within a cel l. Mitochondria are not its only ca rgo; the protein is also associated with lysozyme and endocytic vessel distribution and is an essentia l com ponent for distribution of many proteins within a cel l. Neurons also express related proteins encoded by kif5a and kif5c.

Mitochondria l integrity - Mitochond ria l integrity is known as a control ling factor in apoptosis, cel l control led self-destruction. Integrity may be com prised by events including, but not limited to: mem bra ne permeability cha nges, altered exposure of membra ne proteins, changed expression of the mitochondria l genome.

Mitochondria l protei n - a protein encoded by or used within a mitochond rion. Mitochondria l su pportive su bsta nce - a chemical that cha nges mitochond ria l activity t o benefit at least one aspect of cel lula r meta bolism.

mtDNA - dou ble-stranded DNA fou nd exclusively in mitochondria that in most euka ryotes is a circula r molecu le. A single mitochondrion may include multiple copies of this circular mtDNA molecu le.

Optimization - As used herein, optimization has the genera l meaning of a process leading t o an improved outcome. Optimization wil l genera lly incorporate at least one facet of enha ncement of num ber, outcome function or the like. In some uses optimization may refer t o maximizing a component or process or a selected grou p of com ponents and/or processes. More loosely optimization is used to mea n improvement, even if a greater improvement might be obtaina ble. Many factors and outcomes, including but not limited to: effect on other processes, availability of an instrument, com ponent or professiona l, cost, location, patient's wishes and government regulation may be factors in the optimization procedure and ultimate decisions made to determine a level of optimization.

Optimization for one patient often wil l differ from optimization for another patient, but each patient wil l have im provement. Optimization may often involve im proving one or more outcomes in concert with a possi ble worsening of another com ponent of process.

Optimizing - The process of optimization. Optimization or the process is considered as a goal or a work in progress approaching an optimal or best outcome. Thus optimization may vary with time.

Orga nic - a com pou nd containing carbon. A molecu le having ca rbon and at least one other element.

Plectin - A protein fou nd in several isoforms that is ubiquitous in the cytoskeleton of most mamma lia n cel ls. Plectin lin ks actin microfila ments, microtu bules and intermediate fila ments (IF) together. Plectin also appea rs outside the cell in the extracel lu lar linkages between cel ls.

Restore - t o bri ng something t o or towa rds a previous condition, a norma l condition or an improved condition. The condition may be defi ned as a number or concentration, a rate of activity, a structure, or any observa ble or measura ble process or product of meta bolism. Vimentin - Viml F, an intermediate fila ment protein that is involved in distribution, motility and anchoring of mitochondria. Vimenti n ca n work with dyneins and actin- dependent myosins within the cel l t o deliver and anchor mitochondria close to where meta bolic requirements are high.

The Mitochond rion: Opti mization Target 1

Mitochondria, one of the organel les fou nd in most euka ryotic cells are often ca lled the

" powerhouse" or " battery" of the cel l. A eukaryotic cell typica lly has multi ple mitochondria, the num ber being higher in cel ls with higher meta bolisms. The molecule adenosine triphosphate (ATP) functions as a predomina nt energy ca rrier in the cell. Eukaryotic cel ls derive the majority of their ATP from biochemical processes ca rried out by their mitochondria. Withi n the cel l mitochondria also tend to be fou nd in regions with higher activities. Each cel l has mechanisms t o control mitochond ria l synthesis and degradation and by bala ncing these mecha nisms ca n control the num ber of mitochondria and metabolic rate of the cell. Cel ls also control movement of mitochond ria so that their substrates and products can be efficiently delivered. Assisting the cel ls and organism containing the cel ls t o optimize these activities wil l be fou nd valuable in optimizing thera peutic outcomes.

These biochemica l processes ca rried out by mitochondria include, but are not limited t o the fol lowing importa nt cycles: i) the citric acid cycle (the trica rboxylic acid cycle, or

Krebs's cycle), generating reduced nicotina mide adenine dinucleotide (NADH + H+) from oxidized nicotina mide adenine dinucleotide (NAD+), and ii) oxidative phosphorylation, during which NADH + H+ is oxidized back to NAD+. (The citric acid cycle also reduces flavin adenine dinucleotide, or FAD, to FADH2; FADH2 also participates in oxidative phosphorylation. )

The respiratory chain of a mitochondrion is located in the inner mitochond ria l membra ne and consists of five multimeric protein com plexes: Com plex I; (approximately 44 su bunits), Com plex II (approximately 4 subu nits), Complex III (a pproximately 11 su bunits),

Complex IV (approximately 13 su bunits) and Com plex V (approximately 16 units). (The reported number of su bunits is given as approximate because the counts are different in different reports due t o improving scientific understa ndi ng. ) The respiratory chain also requires two smal l electron carriers, ubiqui none (coenzyme (¾ 0 ) and cytoch rome c. ATP synthesis involves two coordinated processes: 1) electrons are tra nsported horizontal ly from com plexes I and II t o coenzyme Q t o Complex III to cytoch rome c t o

Complex IV, and ultimately to the fina l electron acceptor, molecular oxygen, thereby producing water. At the same time, protons are pumped "vertica lly" across the mitochondrial inner mem brane (i.e., from the matrix to the inter membrane space) by com plexes I, II, II and IV. ATP is generated by the influx of these protons back into the mitochondrial matrix t hrough com plex V (mitochondrial ATP synthase). The energy released as these electrons traverse the complexes is used to generate a proton gradient across the inner mem bra ne of the mitochondrion, which results in stored potential energy in the form of an electrochemica l potential across the inner mem bra ne.

In this process, Com plex I (NADH dehyd rogenase, also ca lled NADH :u biquinone oxidoreductase) removes two electrons from NADH and tra nsfers them t o a lipid-soluble carrier, ubiquinone. The reduced product, ubiqui nol, is free t o diffuse within the membra ne.

At the sa me time, Com plex I moves four protons (H+) across the mem bra ne, producing a proton gradient. Com plex I is one of the main sites at which premature electron leakage t o oxygen occu rs, thus being one of main sites of production of one harmful free radica l cal led superoxide.

Com plex II (succinate dehydrogenase) funnels additional electrons into the quinone pool by removing electrons from succinate and tra nsferring them (via FAD) to the quinone pool. Com plex II consists of fou r protein subu nits: SDHA, SDH B, SDHC, and SDH D. Other electron donors (e.g., fatty acids and glycerol 3-phosphate) also fun nel electrons into the quinone pool (via FAD), again without producing a proton gradient.

Com plex III (cytoch rome b/c com plex) removes two electrons from QH2 and tra nsfers them to two molecu les of cytochrome c, the water-solu ble electron carrier located between the mem bra nes. As part of this process, it moves two protons across the membra ne, producing a proton gradient (in total 4 protons: 2 protons are tra nslocated and

2 protons are released from ubiquinol). When electron tra nsfer is hindered (e.g., by a high membra ne potentia l, poi nt mutations or by respiratory inhibitors such as antimycin A),

Complex III can leak electrons to oxygen resu lting in the formation of superoxide, a highly- toxic oxidative species, which appea rs in the pathology of many diseases and is seen in aging.

Com plex IV (cytochrome c oxidase) removes fou r electrons from four molecules of cytochrome c and tra nsfers them t o molecu la r oxygen (0 2), producing two molecu les of + water (H20). At the sa me time, it moves fou r protons (H ) across the mem brane, producing a proton gradient.

Com plex V (mitochond rial ATP synthetase) which is not directly associated with

Complexes I, II, III and IV uses the energy stored by the electrochemical proton gradient to convert ADP into ATP.

McCormack et al. (2012) cha racterized one facet of mitochondria l disease as follows:

Mitochond ria l respiratory chain disease is an increasingly wel l-recognized, but

notoriously heterogeneous, grou p of multisystemic energy deficiency disorders. Its

extensive heterogeneity has presented a su bsta ntia l obstacle for esta blishing a

definitive genetic diagnosis and clear pathogenic understanding in individual

patients with suspected mitochond ria l disease. While known genetic causes of

"classica l" mitochondria l DNA (mtDNA) - based disease syndromes have been

readily diagnosable, the overwhel ming majority of patients with clinica l and/or

biochemical evidence of suspected mitochondrial disease have had no identifiable

genetic etiology for their debilitating or letha l disease. McCormick et al. 2012

To date about 103 genes encoding mitochondrial proteins have been identified in hu mans (MitoCa rta hu man inventory, Broad Institute). It is expected that most mam malian genomes wil l be quite simila r. Mitochond rial dysfunction ca n arise from a mutation in one of these genes (causing a primary mitochond ria l disorder) or from an outside influence on mitochondria (causing a secondary mitochondria l disorder). Mutations in 228 protein- encoding nDNA genes and 13 mtDNA genes have been li nked t o a huma n disorder with no reason to dou bt that most mam mals wou ld not have similar evolutiona ry issues. The involvement of the activity of these genes in disorders emphasizes that optimizing function of any of these where they are found deficient ca n improve medica l thera py.

Mitochondria l DNA is more prone to mutation effects in that the mitochondrion has a high rate of replication and lacks a DNA repair pathway in the organel le. The high level of active oxygens and the resultant oxidative stress also proba bly contri bute to a relatively rapid mtDNA mutation rate. Thus, control of mtDNA mutation and control of mutated mtDNA can be importa nt targets for optimization.

The present invention may target any one or more of these genes, control of these genes, expression products of these in optimization.

Com mon pha rmaceutica l drugs such as amiodarone, bigua nides, ha loperidol, statins, val proic acid, zidovudine, anesthetics, anti biotics, chemotherapeutic agents, and even

NSAI DS like aspirin (acetylsalicylic acid) have been observed t o affect tota l mitochondrial function. Given the multiple actions of drugs and their specificities for on and off target action, many drugs may lead more frequently to adverse reactions and side effects in patients with mitochond rial disorders tha n in otherwise healthy persons.

A recent sea rch of Wikipedia (https://en.wikipedia.org/wiki/Mitochondria l_disease) accessed July 7, 2015 and again Ju ly 26, 2016 found the teaching:

Mitochondria l diseases are sometimes (a bout 15% of the time) used by

mutations in the mtDNA that affect mitochond rial function. Other causes of

mitochond ria l disease are mutations in genes of the nDNA, whose gene

products are imported into the Mitochondria (Mitochondria l proteins) as wel l

as acquired mitochond ria l conditions. Mitochond ria l diseases take on unique

cha racteristics both because of the way the diseases are often inherited and

because mitochondria are so critica l to cel l function. The su bclass of these

diseases that have neuromuscu lar disease sym ptoms are often cal led a

mitochond ria l myopathy.

Mitochondria l Mem bra nes as structure

As previously mentioned, mitochond ria contain two mem branes. The outer mitochondrial mem brane encom passes the inner membra ne, with a smal l intermem bra ne space in between. The outer membra ne has many protein-based pores that can allow the passage of sim ple ions and molecu les as large as a smal l protein. In contrast, the inner membra ne has much more restricted permea bility. It is more like the plasma mem brane of a cell. The inner mem bra ne anchors proteins involved in electron tra nsport and ATP synthesis. This mem brane surrou nds the mitochond ria l matrix (the innermost com pa rtment within the mitochondrion), where the citric acid cycle produces the electrons that travel from one protein com plex t o the next along the inner mem brane. At the end of the ETC, the fina l electron acceptor is oxygen which ultimately forms water (H20). At the sa me time, the electron transport chain produces ATP. ADP (adenosine diphosphate) is phosphorylated t o ATP (adenosine (tri phosphate). (This is why the process is cal led oxidative phosphorylation.)

Du ring electron tra nsport, the participati ng protei n com plexes release protons from the matrix t o the intermem bra ne space. This creates a concentration gradient of protons that another protein complex, Com plex V, ATP synthase, uses t o power synthesis of the energy carrier molecule ATP.

Although the mitochond rion has its own mtDNA, a vast majority of mitochondria l proteins are synthesized from nuclea r genes (the DNA within another cel l organel le, the cell nucleus) and transported into the mitochond ria. These include, but are not limited t o the enzymes required for the citric acid cycle, the proteins involved in DNA replication and tra nscription, and ribosomal proteins. The protein com plexes of the respiratory chain are a mixture of proteins encoded by mitochond ria l genes and proteins encoded by nuclea r genes. Proteins in both the outer and inner mitochondria l membra nes hel p tra nsport newly synthesized, unfolded proteins from the cytoplasm into the matrix, where folding ensues.

Genetic Factors of Mitochond rial Proteins

Both nuclea r and mitochond rial genes have been associated with disease by correlation with genetic mutation.

All 13 of the proteins encoded by the mitochondria l genome: MTND1, MTND2,

MTND3, MTND4, MTND4L, MTND5, MTND6, MTCYB, MTCOl, MTC02, MTC03, MTATP6 and MTATP8, have mutations associated with disease. These proteins are general ly found at mitochondria l inner mem branes.

Nuclear genes encoding mitochondrial proteins (most likely fou nd associated with or bou nd for the mitochondria l outer membra ne) whose mutation has been lin ked t o mitochondrial disease include but are not limited to: ARMS2, BCL2, CPT1A, DNM1L, GCK,

GK, KIF1B, MAO A, PINK1. Nuclear genes encoding mitochondrial proteins (most likely fou nd associated with or bou nd for the mitochondria l inter membra ne space) whose mutation has been lin ked t o mitochondrial disease include but are not limited to: AK2, DIABLO, GATM, GFER, HTRA2,

PANK2 and PPOX.

Nuclear genes encoding mitochondrial proteins (most likely fou nd associated with or bou nd for the mitochondria l inner membra ne) whose mutation has been lin ked to mitochondrial disease include but are not limited to: ABCB7, ACADVL, ADCK3, AGK, ATP5E,

C12orf62, COX4I2, COX6B1, CPT2, CRAT, CYCS, CYP11A1, CYP11B1, CYP11B2, CYP24A1,

CYP27A1, CYP27B1, DHODH, DNAJC19, FASTKD2, GPD2, HADHA, HADHB, HCCS, L2HGDH,

MMAA, MPV1 7, NDUFA1, NDUFA2, NDUFA9, NDUFA10, NDUFA11, NDUFA12, NDUFA13,

NDUFB3, NDUFB9, NDUFVl, NDUFV2, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6,

NDUFS7, NDUFS8, OPA1, OPA3, PDSS1, SDHA, SDHB, SDHC, SDHD, SLC25A3, SLC25A4,

SLC25A12, SLC25A13, SLC25A15, SLC25A19, SLC25A20, SLC25A22, SLC25A38, SPG7, TIMM8,

UCP1, UCP2, UCP3, UQCRB and UQCRQ.

Nuclear genes encoding mitochondrial proteins (most likely fou nd in or bound for the mitochondrial matrix) whose mutation has been lin ked t o mitochond ria l disease include but are not limited to: AARS2, ACAD8, ACAD9, ACADM, ACADS, ACADSB, ACAT1, ALAS2,

ALDH2, ALDH4A1, ALDH6A1, AMI, ATPAF2, AUH, BCAT2, BCKDHA, BCKDHB, BCS1L,

C8orf38, C10orf2, C12orf65, C20orf7, COA5, COX10, COX15, CPS1, D2HGDH, DARS2, DBT,

DECR1, DGUOK, DLD, DLAT, DMGDH, ETFA, ETFB, ETFDH, FOXRED1, FH, GCDH, GCSH,

GFM1, GLUD1 , HADH, HARS2, HIBCH, HMGCS2, HMGCL, HSD17B10, HSPD1, IDH2, IDH3B,

ISCU, IVD, KARS, MCCC1, MCCC2, MCEE, ME2, MRPS16, MRPS22, MTFMT, MTPAP, MUT,

NAGS, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NUBPL, OAT, OGDH, OTC, OXCT1, PC,

PCCA, PCCB, PCK2, PDHAl, PDHB, PDHX, PDPl, POLG, POLG2, PYCRl, RARS2, RMRP, SARDH,

SARS2, SCOl, SC02, SDHAF1, SDHAF2, SOD2, SUCLA2, SUCLG1, SURF1, TACOl, TK2,

TMEM70, TRMU, TSFM, TTC19, TUFM, UNG, XPNPEP3 and, YARS2.

Nuclear genes encoding mitochondrial proteins (but proteins that are also fou nd in other places in the cel l) whose mutation has been linked t o mitochondria l disease include but are not limited to: AIFM1, AKAP10, AMACR, APTX, BAX, BOLA3, CYB5R3, ETHE1, FXN,

GDAPl, HKl, HLCS, LRPPRC, LRRK2, MFN2„ M LYCD„ NFUl, PARK2, PARK7, SACS, SPG20 and

WWOX. Nuclear genes encoding mitochondrial proteins (but whose specific loca lization within the mitochond rion is still to be elucidated) whose mutation has been linked to mitochondrial disease include but are not limited to: GLRX5, HOGA1, MMAB, M M A DH

PDSS2, AFG3L2, COQ2, COQ6, COQ9, GLD PNKD, PUS1, REEP1, STAR and TMEM126A.

Functions of these genes and their products are known in the art. A listing of these genes and other information ca n be fou nd, for exa mple, in NEJ M 2012; 366:1132-41,

Supplementary Appendix, and is not repeated here.

Mitochondria l genes in general undergo post-translationa l modification. Accordingly, in the optimization process, embodiments of the present invention may modify any aspect of these genes, including but not limited to: any function associated with the gene, integrity of the gene itself, tra nscription, and all the factors including expression and post- tra nslational modification and movement within the cel l.

Since genetics underlie life functions, genes that do not encode a protein fou nd in mitochondria can also be of extreme importance in optimized cel l meta bolism. For exam ple, as discussed below the Position of mitochondria withi n cel ls is dependent on many proteins. The genes encoding these proteins can also be important in optimization.

Mitochondria are the major source of metabolic energy, and they regu late intracel lular calciu m levels and sequester apoptotic factors.

Mgml and Opa 1 are involved in regulating cristae structu re. Mgm l pa rticipates in

ATPsynthase oligimerization.

Mitochondria are not just cell powerhouses producing ATP. They also are essentia l for other facets of cell functions required for meta bolism. Cel l metabolism is accom plished by thousa nds of enzymes. Many of these enzymes require metals for proper activity and to form coordination complexes. Iron su lfu r clusters (ISVC), essential for iron homeostasis in the cell, are a product of mitochondria. Accordingly, mitochond ria through this contribution t o iron control, are necessary for many oxidation reactions, including, but not limited to: oxidative phosphorylation, pyrimidine/pu rine meta bolism, the tricarboxylic acid cycle, acontinase activity, DNA repair, NTH Ll activity, heme synthesis, ferrochelatase function, ISC synthesis enzymes (N BP35 and CFD1). Meta l containing enzymes, of which iron containing oxidation/reduction enzymes are common, are importa nt for scavenging active oxygens. For exa mple: FtMt is an importa nt nuclear encoded mitochondrial protein that sequesters iron in mitochond ria and makes it available when needed. Mdm33 is importa nt for inner membra ne fission. Proton pu mping is cou pled to ATP synthesis through FiF ATP synthase.

Biochemicals

As observable from both Figures 1 and 2 and from reading this text, many biochemica ls are essential or beneficia l for proper cell meta bolism. Depending on the contribution of the biochemical to the cel l processes, the biochemical, may serve, for exam ple, as a chemica l su bstrate, a ca rrier, a structural member, a signa l modifying activity of other biochemica ls, etc. Cha nging location or activity of one may affect utilization of several others. Although not all of these intertwining pathways are mentioned in detail herein, any one or com bination of the meta bolic biochemicals and/or the biochemica l enzymes processing them can be proper targets for optimization.

Targets, including, but not limited to:

Riboflavin (B2)

L-Creatine

CoQio

L-arginine

L-carnitine

Vita min C

Cyclosporin A

Manga nese

Magnesium

Ca rnosine

Vita min E

Resveratrol

Alpha lipoic acid

Folinic acid Dichloroacetate

Succinate

Prostagla ndins (PG) - specific to the PG and tissue may show positive/negative effect; e.g., PGA, PGA2, PGB, PG B2, PGC, PG D, PG D2, PG E, PGEi, PGE 2, PG E3, PGF , PG F , PG F2 ,

PG F3 , PGG, PGH, PG H2, PG I, PGJ, PG K, and related biomolecules, including, but not limited to: prostacyclins, throm boxanes, prosta noic acid, 2- Arachidonoylglycerol, etc.

NSAI DS - aspiri n - COX1 and COX2 inhibitors

Melatonin

Cocaine

Ampheta mine

AZT and similar antivira l compou nds

Mitophagic o r mitophagic inhibitory com pou nds: incl uding, but not limited to: isoborneol, piperine, tetra methylpyrazine, and astaxanthin

Glutathione

β-ca rotene and other carotenoids

and as further described below, to provide exa m ples of optimization processing, are deliverable t o cel ls and ca n be used in optimization as discussed in this application.

Some representative com pounds and their im portance

Riboflavin

Riboflavin (vitamin B2) works with the other B vita mins. It is im portant for body growth and red blood cel l production and hel ps in releasing energy from carbohydrates.

L-creatine

Creatine is a natural ly-occu rring amino acid (protein building block) found in meat and fish, and also made in the liver, kid neys, and pa ncreas. It is converted into creatine phosphate o r phosphocreatine and stored in the muscles, where it is used for energy.

Du ring high-intensity, short-duration exercise, such as lifting weights o r sprinting, phosphocreatine is converted into ATP. CoQio

There are two major factors that lead to deficiency of CoQi : reduced biosynthesis, and increased utilization by the body. Biosynthesis is the major sou rce of CoQi . Biosynthesis requires at least 12 genes, and mutations in many of them are known to cause CoQ deficiency. CoQio levels ca n also be affected by other genetic defects (such as mutations of mitochondrial DNA, ETFDH, APTX, FXN, and BRAF, genes that are not directly related t o the

CoQio biosynthetic process)

Toxicity is not usual ly observed with high doses of CoQi . A daily dosage up to 3600 mg was fou nd to be tolerated by hea lthy as wel l as unhealthy persons. However, some adverse effects, largely gastrointestinal, are reported with very high inta kes.

L-arginine

Arginine can be made by most mam mals. However, normal biosynthetic pathways, produce insufficient amounts of argi nine so some must stil l be consumed through diet.

Arginine is the immediate precursor of nitric oxide (NO), urea, ornithi ne, and agmatine.

Arginine is also a necessary precu rsor for the synthesis of creatine and other cell com ponent biochemicals. The enzyme, arginase, is found in mitochondria l membra nes and here contributes t o proper function of the urea cycle. The metal, manganese, is also important for mitochond rial activity at least through its participation in arginine meta bolism.

L-carnitine

Ca rnitine is involved in the tra nsport of acyl-coenzyme A across the mitochond rial membra ne to be used in mitochond ria l β-oxidation.

Vitamin C

Vita min C reduces the exercise-induced expression of key transcription factors involved in mitochondria l biogenesis. These factors include peroxisome proliferator- activated receptor co-activator 1, nuclea r respiratory factor 1, and mitochondrial tra nscription factor A. Vita min C also prevented the exercise-induced expression of cytochrome C (a marker of mitochond rial content) and of the antioxidant enzymes su peroxide dismutase and glutathione peroxidase. Vitamin C is an antioxidant, that along with resveratrol and alpha-lipoic acid reduces excessive reactive oxygen species production by the mitochondria. Manga nese is also importa nt here as vitamin Cworks with manga nese su peroxide dismutase.

Cyclosporin A

Cyclosporin A, an immune su ppressant, interferes with the mitochondria l permeability tra nsition pore and therefore has been found effective in protecting against oxidative stress in for exa mple, stress inducing ischemia and reperfusion. Cyclosporin A ca n improve meta bolism in some insta nces by slowing or blocking cell apoptosis.

Manganese

Manga nese plays an essentia l role in the mitochond rial antioxida nt: manga nese su peroxide dismutase. Without adequate manga nese, su peroxide dismutase activity wil l be insufficient, and therefore can resu lt in sub-optimal mitochondrial activity and cel lu lar meta bolism.

Magnesium

Magnesium is importa nt for proper calciu m meta bolism and f unction as a cofactor with many enzymes. Magnesium also appears especial ly important for mitochondrial biogenesis.

Zinc

Zinc is importa nt in mitochondria l activity, for exam ple, zinc can affect ATP production rates.

Carnosine

Ca rnosine is a potent scavenger of free radica ls

Vitamin E

Vita min E is a protecta nt against mitochond rial mem bra ne peroxidation and therefore can be an im portant factor in maintaining mitochond rial activity and cel lula r meta bolism.

Resveratrol

Resveratrol is a potent antioxida nt with appa rent involvement in mitochondria l biogenesis. Resveratrol acts through AM PK and SI RT1 and is involved in PGC-la. Alpha-lipoic acid

Alpha-lipoic acid is associated with rejuvenation and replacement of damaged mitochondria. This renewa l becomes more prevalent as mitochondria age.

Folinic acid

Folinic acid is a factor in mitochondrial oxidative stress and has been associated with mitochondrial dysfunction in autism spectrum.

Dichloroacetate (DCA)

DCA stimu lates oxidative phosphorylation by inhibiting pyruvate dehyd rogenase kinase. DCA has been investigated as a possible therapy in some ca ncers. DCA may also exert effects in the endoca nnabinolic system as a weak inverse agonist of CB2.

Succinate

Succinate is an intermediate in the trica rboxylic acid cycle (making ATP), and pa rticipates in inflam matory signaling. Succinate dehydrogenase pa rticipates in electron tra nsport as part of mitochondrial "Com plex M".

Prostaglandins (PG)

Ca lcium ion controls binding of many PGs to mitochondria thereby modifying many aspects of mitochondrial function. NSAI DS have been associated with decou pling activity in mitochondria.

NSAIDS - aspirin - COX1 and COX2 inhibitors

NSAI DS are active in control ling mitochond rial Com plex I. NSAI DS may also alter mitochondrial mem brane permeability by opening the mitochond ria l permeability tra nsition pore that allows sma ll molecu les up t o 1.5 kDa easier passage across the mitochondrial mem brane.

Melatonin

Melatonin demonstrates cel l protectant activity though slowi ng apoptosis as it controls activity of aged or oxidatively stressed mitochond ria involvement in leading the cel l down the apoptotic pathway. Cocaine

The anesthetic, cocaine, has been observed as modifying Com plex I activity in mitochondria.

Amphetamine

The stimu lant class of amphetamines, are inhibitors or norma l mitochond rial meta bolism and appea r t o increase oxidative stress.

AZT and similar antiviral compounds

AZT is mitochond ria lly active by increasing active oxygen generation, interacting with respiratory chain enzymes and damaging mtDNA. Thus optimization of mitochondria l function is a specia l need when drugs of this type are used.

Mitophagic or mitophagic inhibitory com pou nds: includi ng, but not limited to: isoborneol, piperine, tetra methylpyrazine, and astaxanthin.

Mitophagy is importa nt for recycling of mitochondria and controlling position and number of mitochond ria. Either slowing or accelerating mitophagy may be importa nt for optimizi ng meta bolism in a pa rticula r cell or individua l.

Glutathione

Increased glutathione is known t o protect mitochond ria and the cel l against damaging effects of the oxidative moieties produced in mitochondria such as: su peroxide anion

* radica l O , hydrogen peroxide, H20 2, and the extremely reactive hydroxyl radica l HO.

Increasing intracel lu lar glutathione content is possible by several methods including, but not limited to: su pplying precu rsors for glutathione synthesis, e.g., N-acetylcysteine; increasing CoA, for exam ple, by supplying its precu rsor pa ntothenic acid; making cu rcu min

(a spice) available t o the cel l; and the analgesic drug flu pirtine. Since glutathione is seen t o increase throughout the cel l, the antioxida nt protection is not limited t o the mitochond ria.

β-carotene

β -ca rotene, lycopene, lutein, astaxanthin and zeaxanthin are popula r ca rotenoids.

These biochemica ls demonstrate antioxidation properties. These tend t o be lipophilic and thus often are found partitioned in mem bra nes. So at high concentrations they may disorga nize normal mem brane structure. Cautious treatment with one or more ca rotenoids can protect membra nes against oxidative stress by inhibiting mitochondria l active oxygen production. At least in some cel ls carotenoids increase mitochondria l f unction while limiting active oxygen generation. Cell su rviva l can be improved. If the cel l whose hea lth is improved is, for exam ple, a cancer cel l, then sometimes reduced carotenoids may be adva ntageous. Optimization here and with other modifications wil l depend on the disease, the individual and the cel l and cel l function targeted.

M ITOCHON DRIAL STRUCTU RE and POSITION ING

As more has been lea rned about mitochondria it is appa rent they are dyna mic organel les. From the earliest citing of the mitochondrion over a half century ago we now understand that mitochond ria l sha pe and size are highly variable. Shape and size is control led by fusion and fission processes. We can also observe that mitochondria are actively tra nsported in cells depending o n energy needs within the cell. More mitochondria become situated in areas with higher energy needs, including, but not limited to: active growth cones, presynaptic sites and postsyna ptic sites. Also, the internal structure of mitochondria can cha nge in response t o their physiological state.

Shape. Length, shape, size and num ber of mitochondria are controlled by fusion and fission. Fusion wil l general ly resu lt in fewer, larger and more spherica l mitochond ria.

Whereas high fission cel ls general ly have more mitochondria that are smal ler and rod shaped.

Outer sha pe is not the sole sha pe criterion. Mitochond ria also have internal structure

(e.g., shape of cristae). The cristae are regions of the inner mem bra ne more dista nt

(internal) from the outer membra ne. Cristae are formed by interna l foldi ng of the inner membra ne. The different portions of the inner mem brane have different f unctions. For exam ple, cristae are richer in oxidative phosphorylation machinery are more prevalent in cristae while tra nsport facilitators are more preva lent in the inner membra ne regions apposite the outer mem bra ne. Not su rprisingly, the density and length of cristae are control led according to the cel l's needs and the needs of specific location within the cel l.

Location. One factor control ling mitochondria l movement is its mem brane potentia l.

Higher potential favors movement away from the cell nucleus or main cel l body towards the periphery. Lower potential (possibly damaged mitochond ria) migrate towa rds the cel l center (possibly for destruction). Signa ls such as a nerve growth factor (NGF) gradient act to recruit mitochondria to higher concentrations of NGF. These types of factors may be used as a piece of an optimization process t o recruit mitochond ria t o t argeted sites. Blocking nerve growth factor activity has been associated with bone cell necrosis.

Within the cel l, mitochondria use the cytoskeleton as a guide t o destination and for tra nsportation.

Mitochondria are now known t o migrate t hroughout cells, t o fuse, and t o divide as mitochondrial activity is regu lated according to the cel l's needs. The dyna mic mitochondrial processes ena ble mitochond rial recruitment on dema nd to the changing more active su bcel lular com pa rtments. Fusion processes as cel ls converge upon one another and merge facilitates content excha nge between mitochond ria and is a com ponent of mitochondrial shape control. Stem cel ls which can fuse with endogenous cel ls may be involved in rescuing cel ls with damaged or otherwise dysfunctiona l mitochond ria.

Movement is also important for mitochond ria l communication with the cytosol and mitochondrial quality control. With these activities mitochondria readily ada pt t o changes in cel lula r requirements and therefore ca n respond t o physiologica l or environmenta l imperatives. When mitochondria l dyna mics becomes disrupted, cel lula r dysfu nction ensues. Accordingly, optimization of cel lula r meta bolism may involve modifying mitochondrial dyna mics.

Optimization may thus involve consideration of the num ber of mitochond ria, location of mitochondria, size of mitochondria, size and sha pe, interna l structu re of mitochondria in addition t o chemical factors that may more specifical ly modify one or more mitochond ria l function. Optimization of mitochondrial activity can be a valua ble addition over and above the benefits obtained from ba lancing circulating androgen. Su pplementation with cannabinoid active substa nces ca n facilitate the cells' and the orga nisms mitochondria l rebalancing.

Supplementing Levels of Androgen to Achieve Balance

As a side to the present invention, ora l com positions, absorba ble or meta boliza ble as the desired hormone ca n be incorporated into an anima l's regu la r diet. Prohormones include dehyd roepia nd rosterone (DH EA), pregnenolone, androstenedione and/or androstenediol.

The ora l composition may comprise the hormone itself or a suita ble prohormone and may be delivered by any suita ble means, including, but not limited to: as a tooth paste, a smal l treat, a food formu lation, a prescription food product, a chew toy, etc.

The invention also provides methods of making the ora l com position for enha ncing hu man animal or anima l-a nimal interaction, or si mply animal health comfort and well-being by incorporating the hormone into one or more delivery devices.

One such device might be a toy, for exam ple a dog toy sha ped as a bone, a ring, a smal l anima l, etc. Such device ca n be made in bul k using any conventiona l procedures, but for most accurate control of dosing for a specific anima l may be produced in whole or in pa rt using tech niques com monly referenced as 3-D printing.

The 3-D printing procedure wou ld incorporate a matrix suita ble to maintain the anima l's interest and print within this matrix, at least a portion of the toy with the hormone at the desired and exquisitely control led concentration.

The matrix may start as a form produced using more bul k production processes and may be enha nced with one or more therapeutic areas such as a coating, a fil ler, a layer, etc., that com prises the hormone at the precisely determined dosing.

Non-ora l delivery methods are availa ble: for exam ple, impla nta ble devices simila r in concept to identity chips or to birth control sticks or rods used by human females.

Rationale and Process

The present invention is based in part on the insight that administering one or more androgenic hormones or prohormones t o general ly hea lthy appea ring anima ls can increase their overall hea lth and beneficial interactions with nea rby huma ns. In addition, though not as readily observable, achieving an optima l level of circu lating hormone may be associated with an increased qua lity of life, possibly t hrough enhancement of the immune system's ability to defend against bacteria and viruses, t o resist cancer, to enhance the circulatory system, and/or to ameliorate undesired stress-responses. Co-ad ministration of com pounds active in the can na binolic systems ca n fine-tu ne and facilitate such administrations. Testosterone, since it is wel l studied and readily available is a preferred hormone to be used for control ling circu lating and rogenic hormone level and hormonal activity, though in some cases prohormones may have adva ntages. Known prohormones that are com mercia lly availa ble include: DHEA, pregnenolone, and rostenedione, and androstenediol.

The compositions used in the present invention are prefera bly formulated and control la bly ad ministered t o an animal to induce desired effects without also inducing undesired side effects, such as undesired ana bolic or androgenic effects, in that animal.

Dose wil l depend on the initia l status of circulating hormone in the anima l, on the active ingredient and its activity within the anima l, on the size of the anima l, the frequency of dosing and the rate at which an animal wou ld metabolize the active ingredient(s) of the com position. Thus suita ble unit doses may ra nge from about: 0.01 mg t o 500 mg, e.g., 0.01 mg, 0.05 mg,. 0.07 mg„ 0.1 mg„ 0.15 mg, 0.2 mg. 0.5 mg, 1.0 mg, 2 mg, 3 mg, 5 mg, 7 mg,

10 mg, 20 mg, 25 mg, 30 mg, 50 mg, 75 mg, 100 mg, 120 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. Depending on the route of delivery, the anima l's size, the anima l's age, the anima l's gender, the specific composition, etc. other ranges may be releva nt, for exa mple, 10 mg - 200 mg, 12.5 mg t o 150 mg, 15 mg-100 mg,

20 mg-75 mg, 20 mg -50 mg, or 50 mg - 100 mg.

Sa lts, esters, metabolites, protein bou nd, glycosylated, or matrixed formats of delivery a can be used in the composition, provided they are converted in vitro or in vivo to an active form. The com position may com prise hormone or pro-hormone that is bound, covalently or non-cova lently t o a non-hormona l substance.

The composition may optiona lly include additiona l vita mins or minerals and scents or flavorings or flavor enha ncers to render the com position more accepta ble to the administeri ng huma n and/or to the animal. For exam ple, beef, elk, chicken, sal mon and/or other scent or flavor appea ling t o dogs, cats or other pets may be incorporated, a protein binder and/or a vitamin such as one of the B vita mins, e.g., B6 might be added as it or they might be fou nd to hel p sta bilize hormone level.

The composition may be made available in one or more formats including, but not limited to: a capsule, a tablet, a ca plet, a liquid beverage, a powder, a liquid or powder beverage additive, a gel, a ready-to-eat food, either moist or dry, a chu nk, a ba r, a toy of desired sha pe and size. These wil l depend on the dosage required and accepta bility t o the anima l and ad ministering human.

A com position of the present invention may further comprise natural and/or artificial flavoring com ponents, dyes or other coloring additives, preservatives and other conventiona l food su pplement additives known in the art to increase pa latability, storage options, etc.

The time and dosage amount administered wil l vary from anima l to animal and wil l be influenced by the age of the su bject, and therefore may be adjusted as the animal ages. It is believed that general ly, the you nger the animal, the earlier resu lts wil l be apparent with a smal ler dosage amount needed t o achieve optimal results. As the anima l ages, the com position wil l have t o be ad ministered perhaps more frequently and in la rger dosages for the animal to experience optimal results.

The form of the ora l composition can be any suita ble form that comprises the active ingredient and allows delivery t o the select animal . For exam ple, prefera bly an anima l has been under a veterina ria n's ca re and is genera l good healt h however, the anima l is aging and ca n benefit from receiving a thera peutic intervention that while not strictly necessary for life is beneficia l to the animal and its hu man interactions though optimizing health, for exam ple, by staving off or diminishing arthritis, other bone issues, such as dysplasia, lessening obesity problems and other issues seen in aging animals, such as dia betes, letha rgy, pain, etc.

Although the and rogen in the oral com position may vary, the method of delivery is also an importa nt factor. For exam ple, testosterone may be co-ad ministered with an oil, may be admixed in a feed, may be delivered as a toy, etc. The format for delivery is subject t o choice of the animal caretakers and is managea ble in accordance with this invention.

Animals including humans have shown la rge variations in efficiencies of moving testosterone and other androgens from the gastro-intestinal track to circu lation. Given the multiple effects of testosterone su pplementation, most desirable effects being observed with approximately a dou bling or tripli ng of typica l circulating testosterone in a middle aged or older mammal, with more extreme levels risking undesira ble and rogenic consequences, monitoring testosterone delivery and testosterone or testosterone analogue in each individual is highly desired. Controlled and ba lanced delivery of the androgen su pplement shou ld be practiced to provide the best outcomes.

Accordingly, a preferred process in practicing the invention wil l utilize multiple tests performed over time and especial ly whenever feed is changed, perha ps when time of administration is changed, perha ps whenever the anima l cha nges residences, and periodical ly as the anima l increases in age.

Understanding that testosterone effects are found in the many tissues and orga ns expressing And rogen receptor and that depending on activity in each orga n or tissue androgen may be degraded at different rates bala ncing testosterone levels may involve several iterative changes. So after an initia l testosterone level determination and a choice of su pplementation format and dose the animal wil l be supplemented for a period of time t o achieve a new ba la nce. After several weeks t o several months the testosterone levels wil l again be monitored and the dosage or frequency of delivery adjusted to com pensate for interbreed differences, differences in co-administered foodstuffs, and significa ntly factors specific to the specific anima l. The ba la ncing shou ld receive periodic adjustment as endogenous and rogen will be expected t o diminish as the anima l ages and degradation rates of testosterone wil l also fluctuate with age and other factors.

Ca nna binoids may be used seria lly or coincident with corticosteroid or mitochond ria l augmentation or rebala ncing. The skil led artisa n wil l be cogniza nt of the ca nnabinoid involvement in corticosteroid synthesis and release. When administration of one class is varied, the other classes may benefit from dosage or timing adjustment.

Example 2

For exam ple, a five year old ca nine (age dependent on the breed, the animal size, etc.) is evaluated at its annual visit. This visit includes a hormona l profile as well as questioning the dog owner about the animal's activities and genera l health. The veterinarian observes that is common at this age for this type of dog, testosterone levels are continuing to drop and that the dog might benefit from restoring circu lating levels of testosterone or other androgenic hormone in the blood.

The veterinaria n ca lculates a target testosterone level and suggests sim ple oral su pplements that ca n hel p the dog achieve these levels and to thereby pep up the dog, the dog owner and the dog's family.

The owner chooses from a brochure provided by the veterina ria n one of the com positions of the present invention. In fact, the owner here wishes for variety and chooses a relatively ha rd chew toy, a gel format wherein the composition is enca psulated in a soft, bone shaped, gum like format that the owner believes her kids wil l enjoy giving the dog. She also takes a sma ll food packet as a sa mple. This packet has two pouches and a smal l distribution device where a sma ll qua ntifia ble (by counting or volume measu rement) portion (prefera bly slightly color coded for the hu man) can be ad mixed in prescribed proportion with the larger pouch contents to achieve the desired ca loric intake and hormonal su pplement dosage.

Example 3

Another exa mple is a sibling of this dog. But this sibling has additional complications relating to itchy skin. The sibling also receives a fil led bone treat structure wherein the inserted treat com prises a flavored ca nnabinolic active paste. This ca nine also receives five drops of active ca nnabinolic compounds with each of the twice daily feedings. In two days the scratching appea rs t o be reduced and after two weeks the skin appea rs normal. The owner reduces the ca nna binolic delivery t o five drops once per day, but keeps replenishing the fil led bones si nce the pet seemed t o enjoy time spent chewing them.

Additional Benefit - Improving Energy Metabolism

As an additiona l benefit mitochondria l optimization might even more robustly improve the animal's general outlook. Com bing mitochondria l optimization t o opti mize cel lular meta bolism in conju nction with androgen bala ncing is another feature that may further improve outcomes over and above the solely and rogen focused approach.

Optimization of cel lular metabolism through opti mizing any mitochondrial function is desired for improved medica l treatment. Cel lular metabolism ca n be observed by any known method or any method that may become known and is not restricted t o the exam ples discussed herein. However, exa mples are provided as a means t o demonstrate the ubiquity of applications of the present invention and feasibility practicing it.

On a simplistic level mitochond ria l function may be improved by what we might deem

"appropriate nutrition". Therapists and individua ls have historical ly been known to su pplement the diet with vita mins, nutrient and/or cofactors. To date, a methodologic approach t o optimizing metabolism specific to an individual or grou p has not been practiced.

In many patients, more com plete optimization wil l involve sequencing their mtDNA.

The entire mitochond rial genome can be sequenced or select genes or regions might be deemed of greatest importance. Any one or more of the mitochond rial genes are candidates for sequencing. Sequencing is known in the art and can be accom plished by any successful methodology. Regions of particu lar interest including, but not limited to: the D- loop or control region might be sequenced to guide optimization protocols. Sim ply determining total mtDNA in a cel l, tissue or individual may also be a step in optimization.

The mtDNA sequence results may be com bined with genetic sequence information from one or more orga ns or cell types in an individua l. Genomic sequence is one level of information that may be used in isolation or in com bination with mtDNA sequence information for additiona l guida nce in the optimization process. Even more robust information may be obtained, not just from gene expression profiling. This is very usefu l when considering specific orga ns or cell types which by being differentiated cel ls only express a sma ll subset of the full genome. Obtai ning RNA transcription profiles or expression profiles ca n thus be instru menta l in the optimization process. In some circumsta nce ana lyzing proteins as discussed below with specific reference t o blood and other ex vivo biopsy sources, ca n provide some genomic profile information by monitoring the end product of genomic expression. Accordingly, genomic information in isolation or more prefera bly in com bination with clinica l observation and other assays is understood to be a usefu l source of information to use in developing an optimization protocol.

Analysis may involve inhibiting certain mitochondrial functions to assess their performa nce levels. Also on occasion optimizing metabolism may involve mitochond rial inhibition.

Several exa mples of inhibitors are discussed as exa mples.

Electron Transport Chain Inhibitors

ETC inhibitors per se act by binding and blocking a component the electron transport chain. ETC function can also be inhibited by impai ring expression or proper loca lization of one of the com ponent enzymes or ca rriers. Inhibiting or blocking the ETC prevents electrons from being passed from one carrier t o the next and stops oxidation of oxygen and synthesis of ATP. Since bindi ng is involved the inhibitors act specifica lly t o affect a pa rticula r carrier or complex. Bindi ng can be tem porary (reversible) or perma nent (irreversible).

Reversible inhibition may be time or concentration dependent. Irreversible inhibition genera lly results in tota l stoppage of respiration via the blocked pathway. Com petitive inhibition is one form of reversible inhibition. It allows some oxygen consu mption (and ATP synthesis) since a "trickle" of electrons can stil l pass through the blocked site. Although it allows some oxygen consu mption, com petitive inhibition may prevent maintena nce of a chemiosmotic gradient. In this exam ple, the addition of ADP wou ld have no effect on respiration. Some combinations of inhibitors might be used t o seek alternative entry points t o the ETC.

Rotenone

Rotenone is used as an insecticide. It is toxic to wild life and to huma ns as wel l as t o insects. It is a competitive inhibitor of electron transport suita ble for testi ng ability to block respiration via the NADH versus succinate pathway.

Antimycin

Antimycin has been used with combinations of su bstrates including succinate, NADH or glutamate, and the dye TMPD (N,N,N ',N '-tetramethyl-p-phenylenediamine) along with ascorbic acid.

Cya nide

Cya nide is a reversible inhibitor of cytochrome oxidase.

Some mitochond ria have cya nide resista nt pathways. Cya nide causes uncoupling. So in the presence of TM PD a dramatic increase in oxygen consum ption is observa ble.

Malonate

Malonate is a com petitive inhibitor of succinate metabolism.

Uncoupling agents

Uncoupling is where the rate of electron tra nsport is no longer be regulated by the chemiosmotic gradient. The condition is differentiated from electron tra nsport inhibition by the fact that in the latter case, bypassing the block can restore the gradient. In uncou pling, the ETC still f unctions but is ineffective because of dissipation of the chemiosmotic gradient.

2,4-dinitrophenol (DNP)

DN P is a proton ionophore. It binds protons o n one side of a membra ne, and then being fat-solu ble d rifts t o the opposite side where it loses the protons. The proba bility of binding is greatest o n the side of the mem brane with greatest proton concentration, and least o n the side with the lesser concentration. This makes it im possible t o maintain a proton gradient.

DN P demonstrates other effects in addition t o uncou pling. DNP gradual ly inhibits electron tra nsport itself as it incorporates into mitochondrial mem bra nes. In the 1930s DNP was promoted as an effective diet pill. Uncoupling of electron tra nsport from ATP synthesis allows rapid oxidation of Krebs su bstrates and promotes mobilization of carbohyd rates and fats t o maintain normal levels of the Krebs su bsta nces. The energy is lost and measurable as heat.

Ca rbonyl cyanide p-[rifluoromethoxyl]-phenyl-hydrozone (FCCP)

FCCP is an ionophore, completely dissipating the chemiosmotic gradient while leaving the electron transport system unin hibited.

Oligomycin

Oligomycin, blocks ATP synthase by blocking the proton cha nnel. This inhibits oxidative phosphorylation. Oligomycin has no effect o n Complex IV respiration, but blocks Com plex

III respiration com pletely. It therefore has no direct effect o n electron tra nsport o r the chemiosmotic gradient.

Any mitochondrial f unction o r related f unction is a possible t arget for optimization

Cel ls and mitochondria each and col lectively require multi ple meta bolic f unctions for their own su rviva l and su rviva l of the orga nism. In any pa rticu lar cel l o r condition, modifying a specific f unction o r activity o r a select group of meta bolic functions o r mitochondrial activities may be selected for opti mization, in other cells o r conditions, including, for exa m ple, cel ls of a different organ with the sa me individua l or cel ls of a different individua l. Such activities that might be altered associated with the optimization process may include but are not limited to: oxidative phosphorylation, energy versus heat production (efficiency), free radical generation, free radical scavenging, initiation of apoptosis, mtDNA tra nscription, mitochondrial protein tra nslation, post translationa l modification, mitochond rial protein import or translocation, nucleotide tra nslocation, ATP tra nslocation, mitochondrial fission, mitochondria l fusion, Ca++ com pa rtmentalization or homeostasis, steroid biosynthesis, control ling portions of the urea cycle, fatty acid oxidation, the tricarboxylic acid cycle, pyruvate meta bolism, cel lular redox bala nce, synthesis of precursor compounds such as myelin precursors, altering iron meta bolism and of course altering oxygen use and any com ponent or activity of the electron tra nsport chain. [Generation of metabolites t o regu late cel lu la r epigenetics (NAD+) methyl grou p and numerous additiona l meta bolic processes.] The skil led artisan wil l recognize that optimization of any one or more of these may not be relevant for every cel l type.

Depending on the thera py at issue, any of these f unctions or activities or any of the many functions or activities not specifical ly mentioned here, but appropriate to the condition or cel l involved in the treatment, the skilled artisa n will select and optimize releva nt functions and/or activities. To optimize treatment for the individua l, disease status; the individual's history with the disease; the individua l's response t o the disease; the individua l's genetic background (including methylation and other epigenetic control of polynucleic acids or their histones); the individua l's biochemical status for one or more markers, metabolites or su bstrates; and experience such as data from the disease, the individua l or any releva nt group or su bgrou p can be used alone or in combination.

Cel lu lar or mitochondrial morphology; e.g., size, num ber, location, shape, ca n be used t o assess mitochondria l function. One mea ns hel pfu l in this analysis is FACS (fluorescence activated cell sorting). This technology is several decades old and therefore has seen development of a variety of fluorescent markers t o indicate location, size, membra ne potentials, including mitochond ria l mem bra ne potentia ls inside a cel l. FACS is one technique availa ble t o assess deficits in mitochond ria l form and/or f unction. Observi ng a facet of mitochondrial f unction that may be improved ca n be used t o then select one or more optimizing strategies. Optional ly, selected strategies can be tested in cel ls using repeated FACS, t o refine and to further improve and optimize strategy.

Analysis of an individua l or a group or class of individua ls for norma lization or validation ca n be directed explicitly at reactions ca rried out by mitochond ria. However, this often may require a bioassay, removal of tissue from an individua l for ex vivo analysis. And since the mitochondrion is an essentia l com ponent of euka ryotic cells, pa rticipating in multiple meta bolic pathways, mitochond rial status can be evaluated by secondary o r tertia ry parameters. For exa mple, blood can be used t o monitor mitochondrial hea lth and therefore may be used in the present invention as a materia l for bioassay. Severa l fractions of blood may be used at the discretion of the practitioner. For exa mple, mitochondria themselves can be fou nd in white blood cel ls. Fibroblasts, mesenchyma l stem cel ls, cancerous and/or cancer progenitor are exa m ples of some ra re but observable cel l types that ca n be fou nd in blood. Any cel l found in the blood might be used as a sou rce for nucleic acid t o assay o r sequence a nuclea r o r mitochondria l genome o r a portion thereof.

The blood also ca rries other com ponents, fatty acids, proteins, glycoproteins, lipoproteins, ca rbohydrates (sim ple and com plex), gases (especial ly oxygen and ca rbon dioxide), ketones, hormones, meta bolites, nitrogen com pou nds, active oxygen molecu les, ions (atomic, polyatomic, organic, etc.), amino acids, plasma proteins (such as albumen that may scavenge [bind] d rugs o r other molecu les), cytokines, platelets, molecu les carried from the digestive system o r lu ngs, etc. that may be used t o indicate, tissue, cel l and mitochondrial status. The invention envisages blood as a robust source of information that might be used in the optimization process. Each com ponent may be assayed in its native o r altered form. For exam ple, a modified protein o r nucleic acid ca n be very instructive in determining meta bolic status. In many embodiments monitoring representative com pounds as those discussed above wil l be useful in developing and monitoring optimization. In several em bodiments cytokines, a generic term for interleukins (including, but not limited to: IL-la, IL-lb, ILIRn, IL2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, II-

12, IL12a, IL12b, IL-13, IL-14, 11-15, IL-16, IL-17, IL-17a, IL17b, 11-18, IL-19, IL-20, 11-21, IL-22,

11-23, IL23a, IL-24, 11-25, IL-26, 11-27, 11-28, IL-29, 11-30, 11-31, 11-32, 11-33, 11-34, 11-35, 11-36, 11-37, etc.), interferons (including, but not limited to: IFN-a, IFN-b, IFN-g, etc.), colony stimu lating factors (including, but not limited to: M-CSF GM-CSF, G-CSF, [aka CSF1, CSF2 and CSF3] etc.), tumor necrosis factors (TN FA, Lym photoxin (TN FB/LTA - TNFC/LTB), TNFSF4,

TNFSF5/CD40LG, TNFSF6, TNFSF7, TNFSF8, TNFSF9, TNFSF10, TNFSF11, TNFSF13,

TNFSF13B, EDA, etc.), and growth factors (including, but not limited to: BM P2, BMP4,

BM P6, BM P7, CNTF, CNTF, GPI, LIF, MSTN, NODAL, OSM, THPO, VEGFA, etc. may be assessed t o aid optimization. Many drugs targeting cytokines or cytokine receptors have been developed or are under development. Accordingly, cytokine assays may be especia lly useful in developi ng optimization protocols since tools are available t o modu late effect. Modulation of the endogenous qua ntities produced by an individua l may be an enha ncement tool used in some embodiments. Synthetic compounds antagonizing or agonizing of any assayed su bstance may also be appropriate tools.

Assaying any one blood com ponent might crudely be used t o monitor cel lular and/or mitochondrial performance. However, there is no practical reason to eschew ana lysis of other com ponents provide more directed information t o guide optimization. Assaying multiple aspects can indicate performa nce or changed performa nce t o judge an optimization pathway. For exam ple, t hreshold levels of one or more blood com ponents may indicate a certain level of activity of one or more meta bolic pathway. Beyond sim ple thresholds, ratios of two or more components, by showing relationships, ca n provide more definitive information. Diurna l or other periodic relations may also guide optimization.

Sometimes more complex algorithms getting at multi factor relationships (multiple pathways, seria l pathways or paral lel pathways, different organs, for exa mple). Com puter lea rning or other forms of artificia l intel ligence is now becoming a more accepted process t o determine most effective analysis criteria.

While blood is a great source for a su bsta ntia l number of components or factors that can be assayed, the body has other assaya ble tissues including, but not limited to: cerebra l spina l fluid, lym ph fluid, sa liva, breath, tears, urine, sweat, mucus, gastric and/or intestinal contents, stool, etc. Any one or more of these tissues or components ca n be used individual ly or in conjunction with one or more other source to provide data used in optimization.

Analysis may be accom plished using any accepta ble mea ns such as categorization, pa ra metric statistics, nonparametric statistics, ratio ana lysis, sim ple or complex com pa risons, threshold assays, computer learning, etc.

Analysis may be repeated t o assess degree of optimization and/or t o assist in determining any cha nge or addition to the optimization process. Ana lysis may also be repeated with any changed condition of the treatment recipient. Several repetitions of ana lysis and modified optimization process may be conducted in an iterative fashion. Cel lu lar metabolism o r mitochondrial f unction may be optimized for an individual, even for an individua l during a particu lar season, time of day, sleep-wake cycle, etc.

Optimization may be based o n data col lected from more tha n one individua l. For exam ple, an optimized process may be determined for a select grouping. The skil led artisa n wil l have capa bility t o select an appropriate grou p, based for exa mple o n similarities withi n a grou p.

If data show insignifica nt varia bility pooling is more appropriate.

Groupings may be based o n disease o r stage of disease. Grou pings may be based o n familia l connections o r la rger genetic associations. For exa m ple, grou ps may be categorized from associations including, but not limited to: shared ancestry; sha red country o r region of familia l origin; sha red blood type (possi bly su btypes); A, Al, A2, B, Bl, etc.), sha red Rh factor (possibly considering each o r a combination of Cc, Dd, and Ee), any of the other grouping systems including, but not limited to: ABO, M NS, P, RH, LU„ KEL, LE, FY, JK, Dl, YT,

XG, SC, DO, CO, L, CH, H, XK, GE, CROM, KN, IN, OK, RAPH, JM H, I, GLOB, GIL, RHAg, FORS,

LAN, JR, Vel, CD59; HLA; one or more of the 4 mai n mitochondria l clusters with multiple

DNA lineages; one or more of the 7 core mtDNA lineages (U, X, H, V, T, K, J); one o r more of the nineteen mtDNA groups (A, B, C, D, F, G, H, I, J, K, L, M , N, U, V, W, and X); shared diet; shared eye color; sha red gender; shared body type; simila r height; simila r weight; simila r

BM I o r other biometric.

Genera lly, any assay might be used as pa rt of the cel l optimization process t o assess one o r more components of cel l metabolism and/ o r mitochond ria l activity. Some com mon types include but are not limited to: end point assays, kinetic assays, qualitative, semi- qualitative o r qua ntitative assays, f unctional assays, im munoassays, radio-assays, fluorescent assays, bindi ng assays, enzymatic assays, isotopic assays, mass spectrometry, photo-assays, M RI, PET, cel l sort assays, spectrophotometry, polymerase chain reaction, laser cou pled assays, agglutination assays, tra nsmitta nce, absorba nce, refraction, flow assays, size assays, ion assays, conductivity assays, upta ke assays, secretion assays, mass, gel electrophoresis, transport of: DNA, RNA, protei ns, o r presence o r amount of specific sequences, toxicity assays, via bility assays, chemiluminescent assays, amino acid assays - amino acid ratio assays, ca rbohydrate ana lysis, biomarker assays, etc. Physiologic assessment may also be employed as an indicator of meta bolism in progress. Production of reactive oxygen species, mitochond rial brea kdown products o r sim ply 0 2 consu m ption may be used as indicators of mitochondrial performance and meta bolism Less specific assays ca n also be used to select optimization strategy. For exam ple, fairly routine analysis of a biosubsta nce, e.g., a body fluid (for exa m ple: urine, blood, sweat, cerebra l-spinal fluid, saliva) for one or more commonly seen com ponents (for exa mple: any of the amino acids, glucose or other monomeric com pounds. One or more of the col lagens may be observed to assess initial status and/or to monitor progression of the optimization strategy. For exa mple, condition of the skin might be scored t o cha rt effectiveness of treatment since skin is easily accessible and col lagen is ubiquitous throughout the body's organs. As an exa mple, col lagen V I or a correlated marker might be monitored t o assess

Alzheimer's disease. Col lagen monitoring may also be beneficia l in tracking ca ncer growth and optimized treatment effectiveness. Assaying one or more biosubstance obtained, for exam ple, from natura l elimination or biopsy is considered importa nt to many embodiments of the present invention.

This process of producing and properly distributi ng ATP for proper cel l function is com plex and therefore is sensitive t o cha nges t o the cel l's homeostasis. Accordingly, a necessity for cell survival optimal function and energy meta bolism (as manifest, for exam ple, in ETC, protein or peptide synthesis, signal tra nsduction, mitochondrial f unction, proton gradients and activated phosphates) is easily com promised before the therapy or during therapy that produces other desired effects. Accordingly, cel l surviva l ca n be easily com promised; disru ption t o these processes ca n disru ptively alter anything else, for exam ple, post tra nslationa l modification. Cell ular energy meta bolism needs t o be optimized before or duri ng therapy t o maximize benefit.

As a description emphasizing com plexity, the ETC incorporates t hree of these proton pu m ps known as com plexes I, III and IV. Notably, com plexes I and III cata lyze reactions very close t o equilibrium. Reactions cata lyzed by these complexes are easily reversed and therefore especia lly sensitive to extracel lu la r events.

Com plex II ca n replace complex I, but is not a proton pum p and produces less energy than pathways using com plex I. When com plex II becomes more active, energy metabolism and therefore the cel l becomes less efficient.

Optimization therefore can have many possible pathways. One or more of these may be applied for any individua l. For exa m ple, the mitochondrial genome encodes 37 genes

(16, 569 bp) : 13 polypeptides, 22 tRNAs and 2 ribosoma l RNAs. The polypeptides are constituents of the respiratory-chain complexes: 7 complex I subunits (NADH dehydrogenase), 1 subu nit of com plex II I (u biquinol : cytochrome oxidoreductase), 3 su bunits of com plex IV (cytoch rome c oxidase) and 2 su bunits of com plex V (ATP synthase).

The genes for tRNAs are presented as one-letter sym bols. Mutations in fou r of these tRNA genes are associated with diabetes: those for leuci ne (L), serine (S), lysine (K) and glutamic acid (E) tRNAs.

[http://www. nature.com/natu re/jou rnal/v414/n6865/fig_tab/414807a_Fl. html] . These, since the mitochondria are essential com ponents of euka ryotic cells, interact with the cel lu lar com ponents produced by nuclear genome of the cell (since many pathways in energy production require genes from both).

Exem pla ry donor and acceptor com pou nds in the pathway include the coenzymes nicotina mide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD), yielding

NADH and FADH2. Then in the pathway, subsequent oxidation of these hydrogen acceptors leads to the production of ATP.

Since NADH is a com ponent of the ETC, ETC and the mitochondrion are involved in other groups of pathways, for exa mple reduction of disu lfides. One such disulfide system is the glutathione system, a system essentia l for many tra nsport functions within the cel l and therefore healing and repair.

Even com pounds such as fatty acids by participation in the citric acid cycle affect and/or are affected by any alteration from optimal mitochond ria l function. So obesity or even localized fat deposition would be ca ndidates for improvement through optimization of mitochondrial f unction.

To further high light complexity of the energy system the fol lowing exam ples of molecules involved in energy meta bolism are mentioned: ca rbohydrates, fats, proteins, acetyl-CoA, CoA-SH, c/s-Aconitate, nicotinamide adenine dinucleotide (NAD+), reduced

NAD+ (NADH), flavin adenine dinucleotide (FAD), FADH2, a-ketogluta rate, guanosine diphosphate (GDP), inorga nic phosphate (Pi), gua nosine triphosphate (GTP), adenosine diphosphate (ADP), adenosine tri phosphate (ATP), hydronium and hydride ions, ubiquinone, and the reduced form ubiqui nol, succinate, fumarate, Cytoch rome c, isocitrate, oxalosuccinate, succinyl-CoA, L-malate and citrate. At a first level, every treatment altering any concentration, location, availa bility or enzymes that can use these su bsta nces as su bstrate would alter the energy meta bolism set by the cel l. In genera l, w e should presume the meta bolic ba lance set by the cel l (in the absence of treatment) was optimized for at least one f unction. Restoring proper bala nce therefore shou ld improve the treatment process.

On the downside of cel l regulatory activities, in the past ha lf centu ry or so a class of molecules cal led reactive oxygen species (ROS) has been implicated in multiple disease etiologies. These are volatile oxygen substa nces that can initiate, for exa mple, peroxidation chain reactions and may damage DNA as wel l as other cell com ponents. Com mon diseases such as cardiovascu la r disease and many ca ncers are suspected as having ROS com ponent in their development.

Mitochondria l function, because of its propensity t o oxidize su bstances (chiefly involving oxygen) is therefore implicated in many disease states. Not surprisingly, many treatments for com mon disease wil l compromise mitochond ria l function. Restoration of better hea lth through optimizing energy meta bolism should idea lly become an importa nt com ponent of treatment.

In addition to merely optimizing mitochondrial f unction measured by opti mizing the energy output, mitochondria l function may be optimized to treat or prevent some common disease. As mentioned above optimizing mitochond rial function t o benefit proper glutathione levels can be considered importa nt both for near term hea lth and prevention or management of futu re disease.

Antioxida nts, such as vita mins and red wines have been used generical ly, but genera lly not for specific effect t o promote mitochond rial related hea lth. Optimization of energy meta bolism involves more tha n sim ply adding items t o one's diet. Michael Ristow, in a

2009 study, fou nd indeed that antioxidant supplementation (He used vita mins C and E. ) had no positive effect. In fact, Ristow's studies were interpreted to conclude that antioxida nt su pplement left one wea ker. So sim ply adding a molecule that cou nters an undesired molecu le involved in mitochondria l meta bolism is definitely not an obvious solution for ameliorating disease treatment or progression.

Enzymes, the cata lysts for biologic activity, are importa nt for optimized metabolism.

Several of these enzymes require a metal to com plete their structure. For exa mple, su peroxide dismutases (SODs) essentia l to detoxify active oxygens (like su peroxide), contain either zinc (Zn 2+) and copper (Cu 2+) or manganese (M n2+) as in the mitochond ria l form. These SODs convert superoxide t o peroxide and thereby minimizes production of hydroxyl radica l, the most potent of the oxygen free radicals. But the peroxides produced by SOD are also toxic. Peroxidase is the enzyme that detoxifies peroxides. The best-known mammalian peroxidase is glutathione peroxidase. This enzyme contains a modified amino acid selenocysteine in its reactive center.

This is perha ps understa nda ble using, for exam ple, Nrf2 as an exemplary intracel lula r regulator protein. Nrf2 activity is implicated in regulating a gross or more of gene in the cel l. Optimization of mitochondria l function may affect Nrf2 activity on concomitantly, optimization of mitochondria l function may be addressed t hrough control ling Nrf2.

In concert with the above discussion, we need to remem ber that the mammalia n organisms, including the mitochondria that reside in its cel ls, have evolved over eons. It is only recently that humans have used medicinal sciences t o target invading orga nisms, dysfunctioning orga ns or cel ls, messaging pathways dictating cel l activity, or cells' internal com ponents and functions. While often animals wil l have evolved to improve or optimize natu ra l stresses, these newly manufactu red stresses wil l not be managed by systems that through tria l and error (evolution) have been opti mized t o a degree t o maximize su rviva l of the species. When a disease affects an organism or with good intentions we presu me t o modify one part of the cel l's activities, because of the interrelatedness of the multiple pathways withi n a cel l, w e likely wil l observe secondary and tertia ry or more abstract effects if we look for them. Investigati ng whether such an importa nt com ponent of the cel l, such as the mitochondrion, can have its f unction improved and t aking action t o improve function can be expected t o show great benefits t o the individual .

Mitochondria l function is thus extremely important and cha ngea ble. Any mitochondrial gene or any mitochondria l protein gene, their control mecha nisms and their products or meta bolites should therefore be considered as possible targets in the optimization processes. For exa mple, Slowing M FN 1, M FN 2 or OPA1 ca n seriously reduce respiratory ca pacity. Com bination of multiple modifying schemes sometimes can be quite adva ntageous. For exa mple, generic com ponents, such as li pids (includi ng glycolipids, phospholipids, etc.), substrates, and possi bly indicator substances might be introduced while also increasing mitochond ria l fusion. The fusion aids in more widespread distribution and delivery. When movement is the goal, increasing fission ca n make the mitochondria more mobile and ena ble delivery to cel l periphery. Fission is also a facilitator of apoptosis.

Accordingly, increasing fission events ca n aid treatments where apoptosis is desired and decreasing fission ca n spa re cel l death.

Com bined interventions involving two or more episodes of redirecting /rebala ncing immune/a llergy activity, bala ncing and rogen levels in circu lation improvi ng anima l activity and outlook by optimizing mitochond ria l activities wil l allow even more robust hu man- anima l interaction and better outcomes for the participa nts.

Accordingly, one embodi ment of the invention might include additional assays. These additiona l assays would relate to optimizing mitochondria l and cel lu la r performa nce taking into account the cha nged and improved orga nism and cellu la r activities the resu lt from ba lancing the androgens.

Unless otherwise defined, all technical and scientific terms used herein have the sa me meaning as commonly understood by one of ordina ry skil l in the art to which this invention belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, wil l control. In addition, the materia ls, methods, and exam ples are illustrative only and not intended t o be limiting. Although for sim plicity in drafting the claims below are drafted in a man ner where each dependent claim specifica lly asserts dependent status with only a si ngle claim, the reader is put on notice that for pu rpose of disclosure every claim that references a preceding claim also implicitly is understood to have alternate dependency t o all claims ultimately depending from the same claim or claims.

Of cou rse the reader wil l recognize that this implicit understa nding wil l not be stretched ridicu lously t o the extent that a claim might depend from itself. For exa mple, claim 22 which explicitly references claim 2 and no other claim is interpreted as disclosing reference t o claims 2-32 (and claim 1 t hrough claim 2); claim 22 which is referenced in claims 23 and 24 is interpreted as disclosing reference t o other codependency claims but not claims 23 and 24 which themselves reference claim 22. Other featu res and adva ntages of the invention will be appa rent from the fol lowing detailed description and claims. Claims

1. A com position for improving a non-hu man anima l's well-being com prising an ora lly or

su bcutaneously ad ministra ble su bsta nce containing at least one dosage selected from the

group consisting of: a mitochond ria l booster, an androgen hormone and a prohormone,

said dosage selected t o optimize at least one physiologic f unction in a selected mammal.

2. The com position of claim 1 f urther com prising a com pound having o r su pporting

ca nna binolic activity.

3. The com position of claim 2, comprising an endoca nna binoid.

4. The com position of claim 2, wherein said activity is effected through a G-protein

coupled receptor.

5. The com position of claim 2, wherein said activity is effected through a receptor

selected from the grou p consisting of: CBi, CB2, TRPVi, TRPV2, TRPV3, TRPV4, TRPAi,

TRPMs, GPRis, GPRng, GPR55 and GPRn8.

6. The com position of claim 2, comprising a phytoca nna binoid.

7. The com position of claim 2, comprising a synthetic ca nnabinoid.

8. The com position of claim 2 com prising a can na binoid selected from the grou p

consisting of: AEA, 2AG, PEA, OEA and LEA.

9. The com position of claim 2 com prising a can na binoid selected from the grou p

consisting of: URB597, URB937, AM374, ARN 2508, BIA 10-2474, BMS-469908, CAY-10402,

JNJ-245, JNJ-1661010, JNJ-28833155, JNJ-40413269, JNJ-42119779, JNJ-42165279, LY-

2183240, Ca nna bidiol, M K-3168, M K-4409, M M-433593, OL-92, OL-135, PF-622, PF-750,

PF-3845, PF-04457845, PF-04862853, RN-450, SA-47, SA-73, SSR-411298, ST-4068, TK-25,

URB524, URB597 (KDS-4103), URB694, URB937, VER-156084, V-158866, AM3506,

AM6701, CAY10435, CAY10499, IDFP, JJ KK-048, JNJ-40355003, JNJ-5003, JW618, JW651,

JZL184, JZL195, JZP-372A,KM L29, MAFP, M JN110,M L30, N-a rachidonoyl maleimide, OL-

135, OL92, PF-04457845, SA-57, ST4070, URB880, URB937, indomethacin, M K-886,

resveratrol, cis-resveratrol, aspirin, COX-1 inhi bitor II, loga nin, tenida p, SC560, FR 122047 hydrochloride, valeryl sa licylate, FR122047 hydrate, ibu profen, TFAP, 6-methoxy-2-

na phthylacetic acid, meloxicam, APHS, etodolac, meloxicam, meloxica m sodiu m sa lt, N-(4-

aceta midophenyl)indomethacin amide, N-(2-phenylethyl)indomethacin amide, N-(3-

pyridyl)indomethacin amide,indomethacin heptyl ester, SC236, sulinac, sulindac sulfide,

pravadoline, naproxen, naproxen sodiu m sa lt, meclofenamate sodiu m, ibu propfen, S-

ibu profen, piroxicam, ketoprofen, S-ketoprofen, R-i buprofen, Ebselen, ETYA, diclofenac,

diclofenac diethyla mine, flurbiprofen, fexofenadine, Pterostil bene, Pterocarpus

marsupiu m, 9,12-octadecadiynoic acid, Ketorolac (trometha mine sa lt), NO-indomethacin,

S-flu rbiprofen, seda nolide, green tea extract (e.g., epicatechin), licofelone, lornoxicam, rac

ibu profen-d3, ampirxicam, zaltoprofen, 7-(trifluoromethyl)lH-indole-2,3-dione,

aceclofenac, acetylsa licylic acid-d4, S-ibu profen lysinate, loxoprofen, CAY10589, ZLJ-6,

isoicam, dipyrone, YS121 and M EG (merca ptoethylgua nidine).

10. The com position of claim 2 com prising a can na binoid that is mem ber of a class

selected from the grou p consisting of: can na bigerol class, cannabichromene class,

ca nna bicyclol class, A -tetra hydroca nnabinol class, ca nnabieson class, ca nnabinol and

ca nna binodiol class, can na bitriol class and miscellaneous class.

11. The com position of claim 2 com prising a can na binoid selected from the grou p

consisting of: CBGA, CBGAM, CBG, CBG M; CBGVA and CBGV.

12. The com position of claim 2 com prising a can na binoid selected from the grou p

consisting of: CBCA, CBC, CBCVA, CBCV, CBDA, CBD, CBDM, CBD-C4, CBDVA, CBDV, CBD-

CI, THCA-A, THCA-B, 6a,10a-trans-6a,7,8,10a-tetra hydro-6,6,9- trimethyl-3-pentyl-6H-

dibenzo[b,d] pyra n-l-ol, THC,) THCA-C4, THC-C4, THCVA, THCV, A7-cis-isotetra hydro-

ca nna biva rin, THCA-C1 and THC-C1.

13. The com position of claim 2 com prising a can na binoid selected from the grou p

consisting of: A -TCA and A -THC.

14. The com position of claim 2 com prising a can na binoid selected from the grou p

consisting of: CBL, CBLA and CBLV. 15. The com position of claim 2 com prising a can na binoid selected from the grou p

consisting of: CBEA-A, CBEA-B and CBE.

16. The com position of claim 2 com prising a can na binoid selected from the grou p

consisting of: CBNA, CBN, CBN M , CBN-C4, CBV, CBN-C2, CBN-C1), CBN D and CBDV.

17. The com position of claim 2 com prising a can na binoid selected from the grou p

consisting of: CBT, 10-EH DT, 8,9-DH DT, CBTV and CBTVE.

18. The com position of claim 2 com prising a can na binoid selected from the grou p

consisting of: DCBF, CBF, CBCN, CBT, OTHC, cis-THC, 2H-iso-H HCV, CBR and triOH-THC.

19. The composition of claim 2 comprising a compound selected from the group consisting of:

an FAAH inhibitor, R-WI N 55,212-2 and an MAGL inhibitor.

20. The composition of claim 2 comprising an EFA.

21. The composition of claim 2 comprising a fatty acid selected from the group consisting of:

oxytocin, -3 fatty acid and -6 fatty acid.

22. The composition of claim 2 comprising a compound selected from the group consisting of:

N-a lkylamides, phytoa lkanes, n-a lka nes, N-acyletha nolamines, flavonoids, cu rcu minoids,

polyphenols, biphenyl neolignans, sesquiterpenes, N-lsobutylamides and p-

hydroxy phenyl-O-arylca rba mates.

23. The com position of claim 22 com prising an alka ne wherein said alkane has a number

of carbons selected from the grou p consisting of: 9, 10, 11, 12, 13, 14,15,16,17, 18, 19, 20,

21, 22,23, 24, 25,26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 and 39.

24. The com position of claim 22 com prising an alka ne wherein said alkane comprises one

o r more sidegroups selected from the group consisti ng of: 2-methyl-, 3-methyl-, and

dimethyl.

25. The com position of claim 2 com prising an alkane selected from the grou p consisting

of: nonacosa ne, heptacosa ne, 2,6-dimethyltetradecane, pentacosa ne, hexacosane, and

hentriaconta ne. 26. The com position of claim 2 com prising materia l derived from a pla nt selected from

the group consisting of: Echinacea, Echinacea purpurea, Echinacea angustifolia,

curcurmin, Salvia divinorum, sage, lemon grass, hops, verba na, Cannabis, thyme, mango,

Helichrysum umbraculigerum liverwort, cacao, ginger, t umeric, Curcuma Ionga, Magnolia

officinalis, Norway spruce, black pepper, basil, Myristica fragrans, cloves, Sciadopitys

verticillata, oregano, cinnamon, black pepper, hemp, rosema ry, flax and Elettaria repens.

27. The com position of claim 2 com prising a material selected from the group consisting

of: β -caryophyl lene, a β -ca ryophyl lene oxide, sa lvi norin A, myrcene, perrottetinenic acid,

apigenin, quercetin, ca nnflavin A, ca nnflavin B, β -sitosterol, vitexin, isovitexin,

kaem pferol, luteolin, orientin, a gingerol, ca psaicin, curcumin, demethoxycu rcu min,

bisdemethoxycurcumin, cyclocu rcu min, trans-resveratrol, diferuloyl methane, tra ns-

arachidins, tra ns-piceata nnol, isoprenylated trans-resveratrol derivatives, sciadonic acid

magnolol, honokiol, malynga mide B, (+) sabinene, (-) sa binene, Isobutylamide, dodeca-

2E,4E-dienoic acid isobutyla mide, dodeca-2E,4E,8Z,10Z-tetraenoic acid alkylamide, 1-

[(2E,4E,8Z)-tetradecatrienoyl] piperidine, β -caryophyl lene and aju lemic acid

28. The com position of claim 2 wherein said compound com prises antioxida nt activity. 29. The com position of claim 2 wherein said compound com prises a pla nt sou rced

composition selected from the grou p consisting of: abinene, a-pinene, 4,8-dimethyl-l,7-

nonadien-4-ol, 2-hydroxy-4-methyl-va leric, acid, methyl, ester, octanal, O-cymene,

euca lyptol, -phella ndrene, cis-sa binene, hyd roxide, myrcenol, terpi nen-4-ol, a-terpineol,

β-thujene, ς-terpinene, tra ns-a-ocimene, carveol, β-citral, guanidine, geraniol, bornyl,

acetate, β-pinene, thymol, geranic, acid, methyl, ester, a-terpinyl, acetate, d-limonene,

eugenol, gera nyl, acetate, dihydroca rvyl, acetate, -ylangene, cis-dodec-5-enal, 3-phenyl-

2-propenoic, acid, methyl, ester, β-elemene, c, vanillin, epoxy-a-terpenyl, acetate,

butanoic, acid, 2-methyl-, 3,7-dimethyl-2,6-octadienyl, ester, l-methyl-4-(l-acetoxy-l-

methylethyl)-cyclohex-2-enol, 1,2,3,4,4a,5,6,8a-octahydro-4a,8-dimethyl-2-(l-

methylethenyl)-, [2r-(2a,4aa,8aa)]-naphtha lene, p-mentha-l(7),8-dien-2-ol, ς-muurolene,

hydroxy-a-terpenyl, acetate, nerolidol, geranyl, bromide, (-)-a-panasinsen, pyrocatechol,

ς-elemene, 9,10-dehyd ro-isolongifolene, a-calacorene, cis-verbenol, acetic, acid, 1-

methyl-l-(4-methyl-5-oxo-cyclohex-3-enyl)ethyl, ester, alloa romadendrene, z,z-2,6-

dimethyl-3,5,7-octatriene-2-ol, 4-epi-cubedol, 2-oxabicyclo[2.2.2]octan-6-ol, 1,3,3-

trimethyl-acetate, patchoulane, farnesol, ca ryophyl lene, oxide, cis-la nceol, ledene, oxide-

(ii), farnesol, acetate, 6-epi-shyobu nol, falcarinol, phytol, aromadend rene, oxide-(2),

heptacosane, longi pinene, epoxide, hentriaconta ne, deca methyl-cyclopentasiloxa ne,

gera nyl, isobutyr, hexa methyl-cyclotrisiloxane, 1-docosene, tetratetraconta ne and

dodeca methyl-cyclohexasiloxa ne.

30. A com position comprising a mitochondrial meta bolic modifier in com bination with a

compound having or su pporting ca nna binolic activity.

31. The com position of claim 30 wherein said modifier is selected from the group

consisting of: Riboflavin (B2), L-Creatine, CoQio, L-a rginine, L-carnitine, vita min C,

cyclosporin A, manganese, magnesium, carnosine, vitamin E, resveratrol, a-lipoic acid,

folinic acid, dichloroacetate, succinate, prostagla ndi ns (PG) prostacyclins, t hrom boxanes,

prosta noic acid, 2- arachidonoylglycerol and glutathione.

32. The com position of claim 30 wherein said com pou nd having or su pporting

ca nna binolic activity interacts with the pathway of a receptor selected from the group consisting of: CBi, CB2, TRPVi, TRPV2, TRPV3, TRPV4, TRPAi, TRPM 8, GPRi8, GPRn9, GPR55 and GPRng.

33. A method for improving hu man emotiona l and/or meta bolic well-being com prising

increasing can na binoid synthesis in said human t hrough a targeted mani pu lation of a

hu man-anima l relationship.

34. The method of claim 33, wherein said targeted manipulation com prises ad ministering

t o a pet or other hu man associate at least one com pound selected from the grou p

consisting of: a com pound having or su pporting ca nnabinolic activity, a compound having

or supporti ng ana bolic steroid activity and a com pound comprising a mitochondria l

metabolic modifier.

35. The com position of claim 1, comprising testosterone.

36. The com position of claim 1, wherein the physiologic function is selected from the

group consisting of: suga r meta bolism, joint hea lth, bone density, blood pressure and

ca loric inta ke.

37. The com position according t o claim 1 wherein the com position is formatted as a gel,

a powder, a toy, a liquid, a food supplement, a moist food, a dry food, a sma ll treat or a

solidified matrix.

38. The method according t o claim 1 wherein a 3-D printer is used t o control dosing of

the hormone or prohormone.

39. The com position according t o claim 37 wherein the food com prises a plu rality of

packagings, wherein at least a first packaging contains active ingredient for admixing to at

least a second package contents.

40. The com position according t o claim 37 comprising a toy, wherein the toy is a

chewable substance.

41. The com position according t o claim 40 wherein the chewa ble su bsta nce is sha ped in a

form selected from the grou p consisting of: a doggie bone, a dinosau r, a cat, a mouse, a

squirrel, a rodent, a ring, a fist, a bow and a bal l. 42. The com position according t o claim 37, comprisi ng a gel.

43. The com position according t o claim 42 wherein the gel is incorporated into a dog toy.

44. The com position according t o claim 1 wherein said at least one physiologic function is

selected from the grou p consisting of: adipose meta bolism, ca rdiac performa nce, glucose

utilization, circu lation, genera l nervous system activation or activity, hormona l secretion,

sa lt (electrolyte) ba la nce, function of a pa rticula r tissue or orga n system, mem brane

tra nsport across the mem brane of one or more cel l types, muscle activity, maintained

muscle mass, 0 2 consum ption, skin health and visua l abilities.

45. The com position according t o claim 1 wherein the optimization of said at least one

physiologic function has a result that improves at least one life factor selected from the

group consisting of: general sense of wel l-being, clinica l depression, fatigue sensation,

athletic activity, positive interaction with another organism, motivation, liveliness and

healing rate.

46. The com position according t o claim 1 further comprising at least one promoter of

mitochondria l meta bolism.

47. The com position according t o claim 46 wherein the facet of mitochond ria l

metabolism that is promoted is selected from the grou p consisti ng of: oxidative

phosphorylation, cou pling efficiency (energy versus heat production), free radical

generation, free radical scavenging, initiation of apoptosis, mtDNA tra nscription, mtDNA

maintena nce, generation of reactive oxygen species, control ling DNA acetylation,

control ling DNA methylation, histone modification, mitochondria l protein translation,

post translational modification or mitochond rial proteins, mitochond ria l protein import or

tra nslocation, ion import, ion homeostasis, nucleotide translocation, ATP translocation,

mitochondria l fission, mitochondria l fusion, Ca ++ com pa rtmentalization or homeostasis,

steroid biosynthesis, a component of the urea cycle, fatty acid oxidation, a component of

the trica rboxylic acid cycle, pyruvate meta bolism, cellular redox ba la nce, synthesis of

precursor com pou nds for a mitochond ria l function or activity, iron meta bolism, oxygen

metabolism and any com ponent or activity of the electron tra nsport chain. 48. The com position according t o claim 1 further comprising a substance selected from

the group consisting of: Riboflavin (B2), L-Creatine, CoQio, L-a rginine, L-carnitine, vita min

C, cyclosporin A, manga nese, magnesiu m, carnosine, vita min E, resveratrol, a-lipoic acid,

folinic acid, dichloroacetate, succinate, prostagla ndi ns (PG) prostacyclins, t hrom boxanes,

prosta noic acid, 2- arachidonoylglycerol and glutathione.

49. The com position according t o claim 1 wherein the su bsta nce is com plexed by

covalent or non-cova lent bonding with non-hormona l or non-prohormona l material.

50. The com position according t o claim 1 wherein the su bsta nce further com prises at

least one lipophilic vita min.

51. The com position according t o claim 50 wherein the at least one lipophilic vitamin is

selected from the grou p consisting of: vita min A, vitamin D, vitamin Eand vita min K.

52. The com position according t o claim 1 wherein the su bsta nce is ad ministered usi ng a

device impla nted su b-derma lly in the non-huma n animal.

53. The com position according t o claim 52 wherein the com position is prepa red using a

3D printing method.

54. A method for improving a non-hu man anima l's wel l-being com prising: delivering to a

selected non-hu man animal a dosage of androgen hormone or prohormone selected to

improve at least one physiologic function in the selected animal.

55. The method according t o claim 54 wherein:

a) testosterone level is assessed in a non-huma n animal selected for possible benefit;

b) an amount of testosterone is selected to increase circulating testosterone t o a desired

level and t o improve at least one facet of the select anima l's physiology;

c) at least one com position is prepa red, said composition com prising testosterone in an

amount that taking into account the frequency and volume of said com position is

designed t o administer the amou nt selected in b); and

d) administering said at least one com position in accorda nce with the volu me and

frequency of c). 56. The method according t o claim 54 wherein said at least one physiologic function is

selected from the grou p consisting of: adipose meta bolism, ca rdiac performa nce, glucose

utilization, circu lation, genera l nervous system activation or activity, hormona l secretion,

sa lt (electrolyte) ba la nce, function of a pa rticula r tissue or orga n system, mem brane

tra nsport across the mem brane of one or more cel l types, muscle activity, maintained

muscle mass, 0 2 consum ption, skin hea lth and visua l abilities.

57. The method according t o claim 55 wherein after at least two weeks have elapsed

from initiation of pa rt d), parts a) through d) are repeated with an outcome that a desired

androgen concentration remains is circu lation.

58. The method according t o claim 54 further comprising: delivering t o said selected

anima l a promoter of mitochond ria l function that is also selected to improve at least one

physiologic function in the selected anima l, said at least one physiologic function being

identica l t o or differing from the at least one physiologic function targeted by the

hormone or prohormone.

59. The method according t o claim 58 wherein su bsequent to mitochondria l f unction in

said anima l being assessed, said method further com prises choosing a su bsta nce to

improve said mitochondrial function, and administering said substa nce t o said animal.

60. The method according t o claim 56 further comprising assessing mitochond ria l

function in said anima l, choosing a su bstance to improve said mitochond ria l function, and

administering said su bstance to said anima l.

61. The method according t o claim 54 wherein the at least one com position comprises

one selected from the grou p consisting of: beef, elk, chicken, sa lmon, protein binder and a

vita min.

62. The method according t o claim 54 wherein the at least one com position comprises

one in a form selected from the group consisting of: a capsule, a tablet, a caplet, a liquid

beverage, a powder, a liquid or powder beverage additive, a gel, a ready-to-eat food,

either moist or dry, a chun k, a ba r and a toy. 63. A method for improving wel l-being in a non-hu man anima l, said method com prising

increasing circu lating levels of SH BG protei n in the blood.

64. The method according t o claim 63 wherein SH BG is produced by enteric orga nisms

cultured into the anima l's microbiome.

65. The method according t o claim 63 wherein a SH BG porous ca psule is introduced

su bcutaneously, said ca psu le com prising in its interior an expression system producing

SH BG.

66. The method according t o claim 63 wherein the animal is genetica lly modified t o

increase SH BG expression.

67. The method according t o claim 63 comprising a lipoporous capsu le is introduced su bcutaneously, said capsu le comprising in its interior a system releasing androgenic su bstance capable of binding with SH BG.

68. The method of claim 54 further com prising delivering to said animal a com pound

having or supporting can na binolic activity.

69. A method for improving a non-hu man anima l's wel l-being com prising ad ministering

t o said animal at least one mitochondrial meta bol ic booster selected from the group

consisting of: Riboflavin (B2), L-Creatine, CoQio, L-a rginine, L-carnitine, vita min C,

cyclosporin A, manganese, magnesium, carnosine, vitamin E, resveratrol, a-lipoic acid,

folinic acid, dichloroacetate, succinate, prostagla ndi ns (PG) prostacyclins, t hrom boxanes,

prosta noic acid, and glutathione in association with administering to said animal at least

one com pound having or su pporting ca nnabinolic activity.

70. A method for improving a non-hu man anima l's wel l-being com prising: ad ministering

t o said animal at least one com position designed t o impact a system or output selected

from the grou p consisting of: oxidative phosphorylation, cou pling efficiency (energy

versus heat production), free radical generation, free radical scavenging, initiation of

apoptosis, mtDNA transcription, mtDNA maintena nce, generation of reactive oxygen

species, control ling DNA acetylation, control ling DNA methylation, histone modification,

mitochondria l protein translation, post tra nslational modification or mitochondria l proteins, mitochondria l protein import o r tra nslocation, ion im port, ion homeostasis,

nucleotide tra nslocation, ATP tra nslocation, mitochondrial fission, mitochondria l fusion,

Ca++ compartmentalization o r homeostasis, steroid biosynthesis, a com ponent of the urea

cycle, fatty acid oxidation, a com ponent of the trica rboxylic acid cycle, pyruvate

metabolism, cellu la r redox ba la nce, synthesis of precursor com pou nds for a mitochond rial

function o r activity, iron metabolism, oxygen metabolism and any com ponent o r activity

of the electron tra nsport chain in said anima l; and bala ncing said im pact t hrough

administering to said animal at least one com pou nd having o r su pporting can na binolic

activity.

71. A method for improving a non-hu man anima l's wel l-being com prising ad ministering

t o said animal at least one com pou nd havi ng o r supporting can na binolic activity for

rebala ncing at least one physiologic system in said animal and wherein said anima l has

been recognized as one as likely to benefit from such rebala ncing.

72. The method of claim 71 wherein said at least one compound com prises one o r more

compounds selected from the grou p consisting of: CBGA, CBGAM, CBG, CBG M; CBGVA

and CBGV.

73. The com position of claim 2 com prising a can na binoid selected from the grou p

consisting of: CBCA, CBC, CBCVA, CBCV, CBDA, CBD, CBDM, CBD-C4, CBDVA, CBDV, CBD-

CI, THCA-A, THCA-B, 6a,10a-trans-6a,7,8,10a-tetra hydro-6,6,9- trimethyl-3-pentyl-6H-

dibenzo[b,d] pyra n-l-ol, THC,) THCA-C4, THC-C4, THCVA, THCV, A7-cis-isotetra hydro-

ca nna biva rin, THCA-C1, THC-C1, A -TCA, A -THC, CBL, CBLA, CBLV, CBEA-A, CBEA-B, CBE,

CBNA, CBN, CBN M, CBN-C4, CBV, CBN-C2, CBN-C1), CBN D, CBDV,CBT, 10-EH DT, 8,9-DH DT,

CBTV, CBTVE, DCBF, CBF, CBCN, CBT, OTHC, cis-THC, 2H-iso-H HCV, CBR, triOH-THC,

abinene, -pinene, 4,8-di methyl-l,7-nonadien-4-ol, 2-hyd roxy-4-methyl-valeric, acid,

methyl, ester, octanal, O-cymene, euca lyptol, a-phella ndrene, cis-sa binene, hyd roxide,

myrcenol, terpinen-4-ol, a-terpineol, β -thujene, ς -terpinene, tra ns-a-ocimene, carveol, β -

citral, guanidine, gera niol, bornyl, acetate, β-pinene, thymol, geranic, acid, methyl, ester,

a-terpinyl, acetate, d-limonene, eugenol, geranyl, acetate, dihyd roca rvyl, acetate, -

yla ngene, cis-dodec-5-ena l, 3-phenyl-2-propenoic, acid, methyl, ester, β -elemene, c,

vanil lin, epoxy-a-terpenyl, acetate, buta noic, acid, 2-methyl-, 3,7-dimethyl-2,6-octadienyl, ester, l-methyl-4-( l-acetoxy-l-methylethyl)-cyclohex-2-enol, l,2,3,4,4a,5,6,8a-octahydro-

4a,8-dimethyl-2-(l-methylethenyl)-, [2r-(2a,4aa,8aa)]-naphthalene, p-mentha-l(7),8-dien-

2-o\, ς-muu rolene, hydroxy-a-terpenyl, acetate, nerolidol, gera nyl, bromide, (-)- - pa nasinsen, pyrocatechol, ς-elemene, 9,10-dehyd ro-isolongifolene, a-ca lacorene, cis- verbenol, acetic, acid, l-methyl-l-(4-methyl-5-oxo-cyclohex-3-enyl)ethyl, ester, alloaromadend rene, z,z-2,6-dimethyl-3,5,7-octatriene-2-ol, 4-epi-cubedol, 2- oxa bicyclo[2.2.2]octa n-6-ol, 1,3,3-trimethyl-acetate, patchou lane, farnesol, caryophyllene, oxide, cis-la nceol, ledene, oxide-(ii), farnesol, acetate, 6-epi-shyobunol, falca rinol, phytol, aromadend rene, oxide-(2), heptacosa ne, longipinene, epoxide, hentriacontane, deca methyl-cyclopentasiloxa ne, gera nyl, isobutyr, hexa methyl-cyclotrisiloxane, 1- docosene, tetratetracontane, dodecamethyl-cyclohexasiloxane, URB597, URB937,

AM374, ARN2508, BIA 10-2474, BMS-469908, CAY-10402, JNJ-245, JNJ-1661010, JNJ-

28833 155, JNJ-40413269, JNJ-42119779, JNJ-42165279, LY-2183240, Ca nnabidiol, M K-

3168, M K-4409, M M-433593, OL-92, OL-135, PF-622, PF-750, PF-3845, PF-04457845, PF-

04862853, RN-450, SA-47, SA-73, SSR-411298, ST-4068, TK-25, URB524, URB597 (KDS-

4103), URB694, URB937, VER-156084, V-158866, AM3506, AM6701, CAY10435,

CAY10499, IDFP, JJ KK-048, JNJ-40355003, JNJ-5003, JW618, JW651, JZL184, JZL195, JZP-

372A,KM L29, MAFP, M JN110,M L30, N-arachidonoyl aleimide, OL-135, OL92, PF-

04457845, SA-57, ST4070, URB880, URB937, indomethacin, M K-886, resveratrol, cis- resveratrol, aspirin, COX-1 inhibitor II, loga nin, tenida p, SC560, FR 122047 hydrochloride, valeryl salicylate, FR122047 hyd rate, ibu profen, TFAP, 6-methoxy-2-na phthylacetic acid, meloxicam, APHS, etodolac, meloxicam, meloxicam sodium sa lt, N-(4- aceta midophenyl)indomethacin amide, N-(2-phenylethyl)indomethacin amide, N-(3- pyridyl)indomethacin amide,indomethacin heptyl ester, SC236, sulinac, sulindac sulfide, pravadoline, naproxen, naproxen sodiu m sa lt, meclofenamate sodiu m, ibu propfen, S- ibu profen, piroxicam, ketoprofen, S-ketoprofen, R-i buprofen, Ebselen, ETYA, diclofenac, diclofenac diethyla mine, flurbiprofen, fexofenadine, Pterostil bene, Pterocarpus marsupiu m, 9,12-octadecadiynoic acid, Ketorolac (trometha mine sa lt), NO-indomethacin,

S-flu rbiprofen, seda nolide, green tea extract (e.g., epicatechin), licofelone, lornoxicam, rac ibu profen-d3, ampirxicam, zaltoprofen, 7-(trifluoromethyl)lH-indole-2,3-dione, aceclofenac, acetylsa licylic acid-d4, S-ibu profen lysinate, loxoprofen, CAY10589, ZLJ-6, isoicam, dipyrone, YS121 and M EG (merca ptoethylgua nidine). INTERNATIONAL SEARCH REPORT International application No.

PCT/US20 17/056685

A . CLASSIFICATION O F SUBJECT MATTER IPC(8) - A23K 20/1 16 ; A61 K 3 1/352; A61 K 31/568 (201 8.01 ) CPC - A23K 20/1 16 ; A23K 20/1 84; A61 K 3 1/352; A61 K 31/568 (201 8.02)

According to International Patent Classification (IPC) o r to both national classification and PC

B . FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols) See Search History document

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

USPC - 514/183; 514/10.2; 514/17.5 (keyword delimited)

Electronic data base consulted during the international search (name o f data base and, where practicable, search terms used) See Search History document

C . DOCUMENTS CONSIDERED T O B E RELEVANT

Category* Citation o f document, with indication, where appropriate, o f the relevant passages Relevant to claim No.

W O 2016/141069 A 1 (MEDLAB CLINICAL U.S., INC.) 0 9 September 2016 (09.09.2016) entire 1, 2 , 6 , 7 , 9 , 20, 2 1, 26, document 28, 35-37, 42, 44, 48, 50-52, 54, 6 1, 62, 68, 69, 73

3-5, 8 , 10-19, 22-25, 27, 29, 34, 38-41, 43, 45-47, 49, 53, 55-60

US 2014/0065099 A 1 (ALVAREZ et al) 0 6 March 2014 (06.03.2014) entire document 30, 3 1

32

US 2012/0077845 A 1 (DALTON e t al) 2 9 March 2012 (29.03.2012) entire document 63

64-67

W O 2007/008548 A 2 (MILBURN MICHAEL et al) 18 January 2007 (18.01 .2007) entire 70 document

US 2015/0313868 A 1 (KOTZKER CONSULTING LLC) 0 5 November 2015 (05.1 1.2015) entire 7 1, 72 document 3-5, 8 , 10-12, 14, 16, 27, 29

Further documents are listed in the continuation o f Box C . | | See patent family annex.

Special categories of cited documents: "T" later document published after the international filing date or priority document defining the general state o f the art which is not considered date and not in conflict with the application but cited to understand to b of particular relevance the principle or theory underlying the invention earlier application or patent but published on or after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art document published prior to the international filing date but later than "&" document member of the same patent family the priority date claimed

Date o f the actual completion o f the international search Date o f mailing o f the international search report 14 February 2018 MAR 2018

Name and mailing address o f the ISA/US Authorized officer Mail Stop PCT, Attn: ISA/US, Commissioner for Patents Blaine R . Copenheaver P.O. Box 1450, Alexandria, V A 22313-1450 Facsimile No. 571-273-8300

Form PCT/ISA/2 10 (second sheet) (January 201 5) INTERNATIONAL SEARCH REPORT International application No.

PCT/US201 7/056685

C (Continuation). DOCUMENTS CONSIDERED T O B E RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

Y US 2016/0250270 A 1 (EBBU LLC) 0 1 September 2016 (01 .09.2016) entire document 13, 15, 17, 18, 22-24

Y WO 201 /004676 A 1 (IRONWOOD PHARMACEUTICALS, INC.) 03 January 2014 19 (03.01.2014) entire document

Y US 2015/0152018 A 1 (RABER et al) 04 June 2015 (04.06.2015) entire document 23, 25

Y US 2015/0080353 A 1 (SINGH et al) 19 March 2015 (19.03.2015) entire document 24

Y US 2007/0060639 A 1 (WERMELING) 15 March 2007 (15.03.2007) entire document 32

Y NAGASAWA et al. "Dog's gaze at its owner increases owner's urinary oxytocin during social 33, 34 interaction," Hormones and Behavior, 3 1 March 2009 (31 .03.2009), Vol. 55, No. 3, Pgs. 434-441 . entire document

NINAN, I. "Oxytocin suppresses basal glutamatergic transmission but facilitates 33, 34 activity-dependent synaptic potentiation in the medial prefrontal cortex," Journal of Neurochemistry, 20 September 201 1 (20.09.201 1), Vol. 119, Iss. 2, Pgs. 324-331 . entire document

US 2015/0307728 A 1 (TUFTS UNIVERSITY) 29 October 2015 (29.10.2015) entire document 38, 53

US 2008/0302678 A 1 (HUNWISK et al) 1 December 2008 ( 1 .12.2008) entire document 39

US 201 1/0269828 A 1 (FRANTZ) 03 November 201 1 (03.1 1.201 1) entire document 40, 4 1, 43

US 2008/0131494 A 1 (REED et al) 05 June 2008 (05.06.2008) entire document 45

US 2008/0279837 A 1 (CLEMENT et al) 13 November 2008 (13.1 1.2008) entire document 46, 47, 58-60

US 2013/0123175 A 1 (HILL et al) 16 May 2013 (16.05.2013) entire document 49

US 2015/0290217 A 1 (ACERUS PHARMACEUTICALS SRL) 15 October 2015 (15.10.2015) 55-57, 60 entire document

US 2004/0198705 A 1 (WILLNOW et al) 07 October 2004 (07.10.2004) entire document 64, 65, 67

US 2012/0277290 A 1 (COLLARD et al) 0 1 November 2012 (01.1 1.2012) entire document 66

Form PCT/ISA/2 10 (continuation of second sheet) (January 20 1 )