Anti-Aging Medicine As It Relates to Dermatology 1 Rafaela M

Chapter 1 Anti-Aging Medicine As It Relates to Dermatology 1 Rafaela M. Quiroga

1.7 Growth Hormone in the Aging Process 6 Core Messages 1.8 Consequences í of Reduced Growth Hormone Secretion Anti-aging medicine physicians, scien- on the Skin ...... 6 tists, and researchers are dedicated to the belief that the process of physical 1.9 Can Human Growth Hormone Reverse the Effects of Aging? ...... 8 aging in humans can be slowed, stop- 1.9.1 Growth Hormone Secretagogues . . . 8 ped, or even reversed through existing medical and scientific interventions. 1.10 Side Effects of Growth Hormone Therapy . . . . . 9 í Possible theories of the aging process 1.11 A Brief Guide include the free radical theory of to Anti-Aging Supplements and Growth-Hormone-Releasing aging, oxidation, cell senescence, and Nutrients for the Skin ...... 10 cleavage of telomere during DNA synthesis. 1.12 Oral Antioxidant Nutrients ...... 10 1.12.1 Vitamin C ...... 10 1.12.1.1 Food Sources ...... 11 í A good diet slows the aging process 1.12.1.2 Risks with High Doses ...... 11 and adds healthier years to life. 1.12.2 Vitamin E ...... 11 1.12.2.1 Role in the Body and Consequences í A therapeutic guide for vitamin sup- of Deficiency ...... 11 plements and recommended anti- 1.12.2.2 Recommended Daily Allowance . . . . 11 1.12.2.3 Food Sources ...... 12 aging doses is provided. 1.12.2.4 Risks with High Doses ...... 12 1.12.2.5 Interactions with Other Nutrients and Drugs ...... 12 1.12.3 Carotenoids ...... 12 1.12.3.1 Role in the Body and Consequences Contents of Deficiency ...... 12 1.12.3.2 Recommended Daily Allowance . . . . 13 1.1 Introduction ...... 2 1.12.3.3 Food Sources ...... 13 1.12.3.4 Risks with High Doses ...... 13 1.2 The Clinical Science of Anti-Aging Medicine ...... 2 1.12.4 Selenium ...... 13 1.12.4.1 Role in the Body and Consequences 1.3 The Aging Process ...... 2 of Deficiency ...... 13 1.12.4.2 Recommended Daily Allowance . . . . 13 1.4 Free Radical Theory of Aging . . . . . 3 1.12.4.3 Food Sources ...... 13 1.4.1 Antioxidizing Processes ...... 3 1.12.4.4 Risks with High Doses ...... 14 1.5 Diet and Nutrition ...... 3 1.12.4.5 Interactions with Other Nutrients . . . 14 1.6 Hormonal Regulation of Aging . . . . 4 1.13 Glycemic Index ...... 14 1.6.1 Adrenopause ...... 5 1.14 Final Remarks ...... 14 1.6.2 Menopause ...... 5 References ...... 14 1.6.3 Andropause ...... 5 1.6.4 Somatopause ...... 6 2 Rafaela M. Quiroga

1 1.3 The Aging Process O ld age is the most unexpected of all things that happen to man. Aging can be viewed as the accumulation of Leon Trotsky changes in cells and tissues resulting from a greater disorderliness of regulatory mecha- ’’ nisms that result in reduced robustness of the organism to encountered stress and disease. The notion of greater disorderliness in aging is illustrated by the erosion of the orderly neuro- endocrine feedback regulation of the secretion 1.1 Introduction of luteinizing hormone (LH), follicle stimulating hormone (FSH), adrenocorticotropic hor- Changes in diet and increasing exercise, togeth- mone (ACTH) and growth hormone (GH). er with a regimen of antioxidants, nutritional These changes are manifested as menopause, supplements, and growth factors, can alter how andropause, adrenopause, and somatopause. the genes express themselves. Both factors can Skin aging is part of the slow decline in ap- greatly enhance the healing capability of the pearance and function that appears to be at- skin and can improve the results of cosmetic tributed in large part to the drastic decline of surgeries. hormones in the body after adulthood. At the Beyond the obvious advantages of a bal- cellular level, several processes are involved in anced diet and exercise there are the physiolog- the physiology of aging and the development of ical ones that help people feel more alive with some age-related diseases.The process of apop- renewed and vital well-being. tosis signifies the process of nontraumatic and noninflammatory cell death [1]. Dysregulation of apoptosis has been impli- 1.2 The Clinical Science cated in the increased incidence of cutaneous of Anti-Aging Medicine malignancies that are more prevalent in older individuals, such as basal cell carcinoma, squa- Anti-aging medicine is practiced by physicians, mous cell carcinoma, and malignant melano- scientists, and researchers dedicated to the be- ma. Cell senescence limits cell divisions in nor- lief that the process of physical aging in hu- mal somatic cells and may play a central role in mans can be slowed, stopped, or even reversed age-related diseases. Telomeres are thought to through existing medical and scientific inter- play a role in cellular aging and might contrib- ventions. This specialty of medicine is based on ute to the genetic background of human aging the very early detection and prevention of age- and longevity. It has been speculated that the related diseases. Physicians practicing anti-ag- limited proliferation potential of human cells is ing medicine seek to enhance the quality of life a result of the telomere shortening that occurs as well as its length, limiting the period of ill- during DNA synthesis at each cell division. ness and disability toward the end of one’s life. Photoaging may accelerate the shortening of Anti-aging medicine encompasses lifestyle telomeres and push cells into senescence soon- changes (diet and exercise); hormone replace- er.That could be the reason why various growth ment therapies, as needed, determined by a factors may affect the speed and quality of physician through blood testing (DHEA, melat- wound healing [2]. Biochemical insults also onin, thyroid, human growth hormone, estro- arise within aging cells, in part from the action gen, testosterone); antioxidants and vitamin of reactive oxygen species generated and scav- supplements; and testing protocols that can enged incompletely throughout the cell cycle. measure not only hormone levels and blood Aging-associated changes also occur between chemistry but every metabolic factor right and among cells via alterations in the intercel- down to the cellular level. lular matrix, the intercellular exchange of Anti-Aging Medicine As It Relates to Dermatology Chapter 1 3 trophic factors, the release of inflammatory cy- oxidant metabolites are glutathione (GSH) and tokine mediators, and the degree of infiltration vitamin C (ascorbic acid), which reside primar- by other associated cell types. In addition, the ily in the cytoplasm and mitochondria. Many quantity and distribution of various growth water-soluble enzymes also catalyze these reac- factors may affect wound healing [2]. Decline of tions. Glutathione peroxidase catalyzes the re- DNA repair in combination with loss of mela- action between GSH and hydrogen peroxide to nin increases the risk of photocarcinogenesis form water and oxidized GSH, which is stable and can also cause the decline of enzymatically [6].Vitamin E and the carotenoids are the prin- active melanocytes (10–20% each decade) that cipal lipid-soluble antioxidants. Vitamin E is contributes to increased sensitivity to ultravio- the major lipid-soluble antioxidant in cell let (UV) radiation. membranes that can break the chain of lipid However, it is not known why free radical peroxidation. Therefore, theoretically, it is the damage does not adversely affect all of the most important antioxidant in preventing oxi- body’s cells (e.g., gonadal germ cells) [3]. dation of these fatty acids.Vitamin E is recycled by a reaction with vitamin C [7]. Despite the actions of antioxidant nutrients, 1.4 Free Radical Theory of Aging some oxidative damage will occur, and accumulation of this damage throughout life is be- Antioxidizing nutrients are believed to play a lieved to be a major contributing factor to aging role in the prevention and treatment of a varie- and disease [6]. ty of chronic diseases. The proposed mecha- nism by which antioxidants protect cells from oxidative stress is by scavenging free radicals 1.5 Diet and Nutrition and halting lipid peroxidation chain reactions, which can cause DNA damage [4]. A good diet slows aging and can improve overall success of surgical procedures and wound healing. Among other benefits, a good diet: 1.4.1 Antioxidizing Processes

Two forms of chemical reactions, oxidation and í Provides the food,water,and oxygen that reduction, occur widely in nature. Oxidation is cells need to reproduce, transmit infor- the loss of electrons, and reduction is the gain mation, and repair damage of electrons. Oxidation and reduction reactions always occur in pairs. Highly reactive mole- í Assures the body of a continuous supply cules can oxidize molecules that were previous- of usable energy, which improves emo- ly stable and may cause them to become un- tional stability and energy levels stable species, such as free radicals. A free radi- í Helps eliminate free radical damage, cal is a chemical with an unpaired electron that damage that can increase risk of cancer can be neutral, positively charged, or negatively and other degenerative diseases charged. Thus, without termination by an agent such as an antioxidant, a single free radical can í Decreases the risk of cancer, arterioscle- damage numerous molecules. A certain amount rosis, hypertension, heart disease, osteo- of oxidative function is necessary for proper porosis, senility, and depression health. For example, oxidation processes are í Synchronizes the body, helping people used by the body’s immune systems to kill mi- function physically, mentally, and emo- croorganisms [5]. tionally at peak efficiency Cells contain a number of antioxidants that have various roles in protecting against free í Adds healthier years to life radical reactions. The major water-soluble anti- 4 Rafaela M. Quiroga

The diet that will most support healthy longev- 1.6 Hormonal Regulation of Aging 1 ity follows these principles: It’s nontoxic. That means it contains a minimum of preservatives, additives, pesticides, antibiotics, food coloring, Aging involves a decline of GH, which causes and chemical flavoring. The diet should contain the immune system response to decline and the enough nutrients to satisfy daily needs. Since amount of oxygen and free radicals to increase. most fresh fruits and vegetables lose much of The skin suffers from the consequences of the their nutritional value within hours after being decline in GH, which is reduced nourishment picked, it is necessary to supplement with vita- and repair of cells in the different tissues. The mins and minerals. overall functions of the skin decrease with ag- According to the American Journal of Public ing. The decline is noted in cell replacement, Health, studies show that less than one-third of sensory perception, thermal regulation, and Americans meet the U.S. government’s Healthy chemical clearance. Also, there is a higher People 2000 goal of eating five or more servings threshold for pain, predisposing to skin irrita- of fruits and vegetables per day; people eat only tions, ulcerations, and wounds [8]. 1.2 servings of fruits and 3.1 servings of vegeta- Additional changes of skin aging include bles daily. flattening of the dermal–epidermal junction, Another element of the healthy diet benefi- which decreases the contact surface between cial for women should be soy proteins due to the dermis and epidermis. This change may the phytoestrogens that regulate endogenous compromise communication and nutrient estrogen production, which is helpful in easing transfer between skin layers.There is a decrease hot flashes and hormonal acne associated with in epidermal filaggrin, a protein required to menopause. Topical estrogen induces an in- bind keratin filaments into macrofibrils, that crease in skin thickness through proliferation, contributes to skin dryness and flaking. In ad- resulting in decreased rhytids. Scientists at the dition, there is an increased dermal separation University of Pennsylvania School of Medicine that may cause increased blistering or tearing. found that soybeans contain a protease inhibi- The endocrine system regulates body com- tor called the Bowman-Birk inhibitor, which is position, fat deposition, skeletal mass, muscle so versatile against various cancers that it has strength, metabolism, body weight, and physi- been dubbed “the universal cancer preventive cal well-being. Multiple endocrine changes agent.” evolve with aging in all species and,not surpris- Natural fats provide a concentrated form of ingly, some of the physiologic manifestations of energy and create the environment in which fat aging are related to the effects of declining hor- soluble vitamins can be digested; they also pro- mone levels. The central nervous system (CNS) vide the essential fatty acids that the body uses regulates the pituitary gland, which secretes to maintain its cellular structure. Examples of hormones to target tissues that, in turn, pro- fat are “saturated,” from dairy, meat, and fish duce substances that feed back on the hypotha- products; “unsaturated,” from vegetable and lamic–pituitary axis. This feedback-control fish oils; “polyunsaturated,”, such as sunflower network can be assessed via novel entropy sta- seed oil and sesame seed oil; and “hydrogenat- tistics. ed,”such as margarine and highly heated or re- In humans, aging is associated with a de- heated fats. crease in the gonadal production of estrogen in The American Heart Association and the females (menopause) and testosterone in males National Cholesterol Education Project recom- (andropause), the adrenal production of dehy- mend that the “prudent” diet for everyone, re- droepiandrosterone (DHEA) and DHEA sulfate gardless of gender, race, or age, should not ex- (DHEA-S) (adrenopause), and a decrease in the ceed 300 mg of cholesterol daily and 65 mg to- activity of the GH/insulin-like growth factor tal fat for the person who eats an average of (IGF) axis (somatopause). Replacing hormones 2,000 daily, inclusive of 22 g of saturated fat. that decline with age had been shown to have a Anti-Aging Medicine As It Relates to Dermatology Chapter 1 5 broad anti-aging and anti-disease effect on the Physical complaints such as breast tender- skin and in the body. As a result, hormone re- ness, irregular menstrual bleeding, dyspareu- placement regimens are being developed as a nia, and hot flushes may precede the onset of strategy to delay or prevent some of the conse- anovulatory cycles in perimenopause in addi- quences of aging. tion to emotional concerns such as disrupted sleep,fatigue,tension,and irritability,which are equally represented among menopausal wom- 1.6.1 Adrenopause en in North America [11]. Skin changes that may occur include hyperpigmentation as well The enzymatic machinery of the adrenal zona as wrinkles, laxity, pallor, and pruritus. These reticularis fails in aging men and women. How- changes are associated with estrogen depriva- ever, the ability of the zona fasciculata to pro- tion, which leads to decreased skin elasticity duce cortisol is preserved (based on ACTH in- and blood supply [12]. Histologically, although fusion, insulin tolerance, and metyrapone test- the stratum corneum is unaltered in thickness, ing). Mineralocorticoid and glucocorticoid re- there is apparently a slow replacement of neu- ceptors in the hippocampus are variably down tral lipids adversely affecting the barrier func- regulated in aging humans. Excessive lifelong tion [13, 14]. adrenal cortisol feedback on the brain may ex- acerbate the aging-associated loss in neuronal synapses and plasticity. Potential implications 1.6.3 Andropause of aging skin includes a decrease in vascular re- sponsiveness due to involution of the dermal In the hypogonadal male, reduced libido is of- vascular bed, which decreases thermoregula- ten accompanied by diminished well-being tion and contributes to skin pallor; there is a and/or depression that may be relieved by an- decrease in subcutaneous fat and changes in drogen replacement [15]. Cognitive decline, vis- distribution that may limit conductive heat loss ceral obesity, osteopenia, and relative sarcope- that decreases the protective ability in bony ar- nia also accompany androgen deficiency in ag- eas such as the ischial tuberosities; and there is ing [16]. These conditions respond favorably to a delayed recovery of the stratum corneum’s androgen supplementation, especially in men function as a barrier, which may increase the with very low testosterone levels [17]. Enhanced penetration of certain types of topical medica- physical performance has not been established tions leading to systemic absorption [9]. in this context. Few studies have examined whether testosterone supplementation enhanc- es cognitive function in elderly men [18]. Al- 1.6.2 Menopause though it appears that neoplastic transforma- tion of prostate tissue is not elicited by physio- There is still no known biochemical signal that logic testosterone repletion, proliferation of ex- reliably indicates the onset of menopause.How- isting androgen-responsive carcinomas may be ever, serum FSH levels tend to rise in regularly stimulated. Thus, a normal prostate-specific menstruating as well as premenopausal women antigen (PSA) and prostatic digital examina- (42–50 years of age). The pulsatility and order- tion should precede any androgen treatment in liness of LH release also change before men- older individuals. strual cyclicity falters [10]. Estrogen secretion Skin decreases in elasticity, extensibility, and in perimenopause is variable and includes turgor. Appendages, including hair follicles, ap- intervals of increased production. A greater ocrine, and eccrine glands, are decreased in stimulation by FSH may increase follicular number. Pacinian and Meissner’s corpuscles, aromatase activity and induce estrogen excess responsible for pressure and light touch sensa- while inhibin concentrations fall perimenopau- tion, are similarly decreased. The epidermis sally and contribute to heightened FSH release. may exhibit variable thickness, cell size, and shape with occasional nuclear atypia. 6 Rafaela M. Quiroga

1 1.6.4 Somatopause 1.7 Growth Hormone in the Aging Process Gender markedly influences GH secretion in young adults. Premenopausal women exhibit a GH is the most abundant pituitary hormone. two-fold less rapid decline than men in daily Although GH and prolactin are closely related, GH production with increasing age. Young GH secretion depends upon hypothalamic women also manifest less vulnerability to the stimulation, without which GH secretion falls suppressive effects of increased total body fat to low levels and somatotrophs atrophy.Growth and reduced physical fitness on GH secretion hormone-releasing hormone (GHRH), in full [19].An important ongoing clinical issue relates sequence a 44-amino-acid peptide, is the prin- to the uncertain role of sex-hormone deficien- cipal identified hypothalamic stimulator of pi- cy in the aging-related impoverishment of GH tuitary GH synthesis and secretion, activating and IGF-I production in both women and men specific GHRH receptors on the surface of pi- [20]. Preliminary data from clinical studies tuitary somatotrophs. GHRH and GHRH-relat- raise the possibility that combined GH and an- ed peptides have a very restricted distribution drogen repletion in older men can have an ad- in the CNS but are also synthesized in gut, pan- ditive effect on increasing muscle mass [19]. creas, and gonads, where their physiological Levels of the nutritional signaling peptide roles are still uncertain. Somatostatin [soma- leptin,mostly produced in white adipose tissue, totropin-release-inhibiting factor, (SRIF)], a conveys signals to the hypothalamus about fat group of 14- and 28-amino-acid peptides, is a stores and, in response, hypothalamic efferents potent noncompetitive inhibitor of GH secre- regulate food intake and energy expenditure. tion.As with LH and other pituitary hormones, Leptin inhibits the hypothalamic release of the the pattern of GH secretion is episodic, with six orexigenic (appetite-inducing) peptide neuro- to eight pulses per day and very low levels peptide Y (NPY) and activates the sympathetic between pulses. Some of these pulses are asso- nervous system. The latter stimulates lipolysis ciated with meals, stress, exercise, or slow-wave in adipose tissue via the beta-3 adrenergic re- sleep. The traditional view has been that the ceptor, cAMP accumulation, and increased ac- pattern of episodic GH secretion arises from tivity of mitochondrial uncoupling protein the interaction of GHRH and SRIF secretion (UCP)-3, thus generating heat (which is dissi- modulated by peripheral feedback by circulat- pated) rather than ATP (which is stored). Lep- ing IGF-I and other factors. tin-receptor signaling may be attenuated in aging [21]. The aging process causes certain areas of the 1.8 Consequences of Reduced Growth face to undergo fat atrophy while others experi- Hormone Secretion on the Skin ence a persistence or hypertrophy of fat. Fat atrophy occurs in the periorbital, forehead, GH declines with age in every animal species buccal, temporal, and perioral areas. Fat hyper- that has been tested to date. In humans, the trophy, however, is seen submentally, in the amount of growth hormone after the age of 21 jowl, lateral nasolabial fold, lateral labiomental to 31 falls about 14% per decade, so that the to- crease, and lateral malar areas. The suborbital tal 24-hour growth hormone production rate is area may display atrophic changes with concav- reduced by half by the age of 60. In numerical ities and evidence of the underlying orbital rim values, humans produce on a daily basis about or hypertrophy with infraorbital fat accumula- 500 µg at 20 years of age,200 µg at 40,and 25 µg tion and festooning [22]. at 80 [23]. The skin of adults with growth hormone deficiency (GHD) is thin, dry, and cool, rendering venous access difficult. These changes probably arise because of the loss of a direct anabolic influence of GH on skin cells exacer- Anti-Aging Medicine As It Relates to Dermatology Chapter 1 7 bated by reduced cardiac output. In addition, “gold standard” for establishing a biochemical GH regulates eccrine sweat glands, and sweat- diagnosis is the peak GH response to insulin- ing is impaired in GHD, very likely contributing induced hypoglycemia in an insulin tolerance to poor exercise capacity. test (ITT). Other GH stimuli such as arginine, Many of the undesirable changes that ac- glucagon, L-dopa, and clonidine are used in company aging mimic those manifest in the provocative tests, but none is as powerful as the GHD syndrome,including central obesity,mus- ITT [25]. Despite vast clinical experience with cle atrophy, exercise intolerance, decreased the ITT, controversy remains over what peak metabolic rate, dyslipidemia, cardiovascular GH value constitutes a diagnostic cutoff. Most deterioration, osteopenia, thinning of skin, patients respond to insulin-induced hypoglyce- mild anemia, loss of vigor, sleep disturbances, mia with a peak GH greater than 5 ng/ml. “Se- and depression. Aging is thus a partial pheno- vere GHD” is currently defined by a peak GH copy of adult GHD. This has prompted specula- less than 3 ng/ml [26]. Because of the lack of tion that pituitary somatotroph activity may be standardization of GH assays, each laboratory a pacemaker of aging and has raised the pos- should ideally establish its own diagnostic sibility that GH supplementation might retard threshold values rather than blindly accepting geriatric deterioration because replacement these recommended cutoffs. The diagnosis of therapy reverses most features of GHD in GHD is increasingly likely when additional an- young adults. terior pituitary hormones are found to be defi- Most organic adult GHD arises from pitui- cient, as GH is one of the first of such hormones tary lesions. The loss of GH secretion associat- to be lost in adult hypopituitarism of most ed with aging alone results from hormonal causes. Hence, isolated adult GHD should be changes upstream of the pituitary. Pituitary re- confirmed with two biochemical tests. Al- sponsiveness to GHRH persists in aging, although an ITT is safe when carefully adminis- though the magnitude of GH release may de- tered, it is contraindicated in the setting of doc- cline somewhat. The practical implication of umented ischemic heart disease and seizure this difference is that GH secretagogues should disorders [26]. Some investigators do not per- be useful for stimulating GH secretion in nor- form the ITT in anyone over 65 years of age be- mal older people whereas they are ineffective in cause of potential occult cardiovascular disease most organic forms of adult GHD. At any age, (CVD) [25]. In such cases, arginine (or arginine including advanced ages; individuals with or- plus GHRH) is probably the best alternative. ganic GHD have significantly lower measures Unfortunately, distinguishing organic GHD of basal and stimulated GH secretion than do from the hyposomatomedinemia of aging is a age-matched normal subjects [24]. challenge. Although GH secretion is lower at A careful study of the aging face reveals it to any age in patients with organic GHD than in be more than just surface textural wrinkling or age-matched normal subjects, the spread loose skin. Changes in three-dimensional to- between these groups diminishes with advanc- pography are responsible for the distinctive ing age such that GH levels differ by only 13% phenotypic presentation of the face throughout between elderly adults with GHD and their nor- life. These geometric alterations are secondary mal peers [27]. Thus, confirming GHD in an to apportioning in the fat compartments and older person may not be possible, especially if result in the fat dysmorphism characteristic of only one or no additional pituitary hormones senescence. Redistributing this fat can rebal- are deficient [25]. The situation is similar for ance the facial fat compartments and mimic the morbidly obese patients in whom GH secretion facial structure present in youth [22]. may be suppressed to a similar degree as in or- There is no single sign or symptom that is ganic GHD. Even among people in whom the pathognomonic of GHD in adulthood or pro- diagnosis of normal, age-related, hyposomato- vides any biological end point for diagnosis. A medinemia is clear, the question remains low serum IGF-I in adults suggests GHD, but a whether such individuals might benefit from normal value does not exclude the disease. The restoration of GH to youthful levels. 8 Rafaela M. Quiroga

1 1.9 Can Human Growth Hormone 1.9.1 Growth Hormone Secretagogues Reverse the Effects of Aging? Because the aging-related decline in GH secre- GH had proven tissue healing effects, and cells tion results from changes upstream of the pi- regenerate and repair faster, accelerating the tuitary, hormonal replacement can theoretical- process of wound healing in patients injured, ly be achieved with GHRH or growth-hor- severely burned,recovering from surgery,or se- mone-releasing peptides (GHRPs). There are verely malnourished.All these effects take place several conceptual advantages of these thera- through new formation of collagen. The impact pies over exogenous GH itself [32]. First, even of GH treatment on body composition in adult when administered continuously, they preserve GHD is unequivocal: fat mass and volume are the physiological pulsatility of GH release, pre- decreased (by 7–15%), with the greatest reduc- sumably mediated via intermittent endogenous tions seen in abdominal visceral depots; lean somatostatin secretion. In addition, the normal body mass and skeletal muscle volume are in- negative feedback regulation by IGF-I upon GH creased (by 5–10%). Most studies showed [28, release confers relative protection against over- 29] little change in overall body weight but treatment with these agents. rather a shift from fat to lean mass [30, 31]. Al- The only GH secretagogue presently ap- though the increase in lean body mass can be proved for use as replacement therapy is GHRH

partially accounted for by GH-induced water (1–29) NH2 (Geref, Serono), which has been li- retention, observed elevations in total-body K+ censed to treat childhood GHD but is being demonstrate that GH also promotes genuine tested in adults as well. Various GHRPs and muscle growth. These favorable body composi- nonpeptide GHRP mimetics are also under in- tion changes are more pronounced in men than vestigation in elderly subjects [32]. Only short- women and more so in young patients with low term trials have been published to date, suffi- GH binding protein levels. cient to assess only hormonal effects. IGF-I has Studies of the effect of GH replacement on been raised to youthful levels in older individu- psychological and social end points in adults als with once- or twice-daily subcutaneous in- with GHD have universally reported a thera- jections of GHRH as well as with infusions or peutic benefit [32]. Improvements were found daily oral preparations of GHRPs. Data on body in subjective well-being, mood, energy, sleep, composition and functional end points are emotional reaction, behavior, pain perception, being compiled. Side effects resulting from in- and overall quality of life [33]. advertent overtreatment with secretagogues Although adult growth hormone replace should be less common than with exogenous therapy is controversial, the initial dose usually GH because of the moderating effects of feed- recommended is 150–300 ng SQ qhs (approxi- back regulation; studies to date have generally mately 2–4 mg/kg per day). Older patients are found this to be true. However, some patients started at the lower level of 150 ng, and dose ti- do report typical GH-related symptoms of fluid tration should be done monthly or at longer retention as well as allergic reactions at injec- intervals controlling IGF-1 level clinical re- tion sites. Current GH secretagogue formula- sponse, side effects, and individual assessment. tions delivered transnasally and orally are lim- The goal dose is based on finding levels of IGF- ited and quite short-acting and therefore are 1 at or slightly below the 50th percentile for age unpredictable. For these compounds to become and gender unless side effects are significant. clinically useful, development of more potent Cancer screening should be done periodically preparations, adjuvants to enhance potency, or and routinely [34, 35]. synergistic GHRH-GHRP combinations is nec- At this time, the best therapy against aging is essary. to limit the damage to the DNA with antioxidants, vitamins, and minerals, and try to increase the levels of GH naturally with diet, exercise, and growth hormone releasers. Anti-Aging Medicine As It Relates to Dermatology Chapter 1 9

Warnings have been voiced that GH could 1.10 Side Effects have mitogenic properties. These theoretical of Growth Hormone Therapy concerns derive from highly controversial in vi- tro data obtained with a variety of cell lineages The side effects of GH therapy arise from the from the observation that most human solid tu- hormonal impact of overreplacement because mors express IGF-I receptors [37] and from epi- rhGH is identical to the endogenous hormone demiological evidence that patients with and thus should not elicit hypersensitivity reac- acromegaly have increased incidences of colon tions, except in the very rare patients with con- and breast cancer [38, 39]. At present, the pru- genital GH gene deletions. Fluid retention due dent course of action for patients receiving GH to the antinatriuretic actions of GH is by far the would be to adhere strictly to guidelines re- most common untoward effect among adults garding prostate examinations and PSA levels with GHD receiving replacement therapy. In in men and breast examinations and mammo- experimental trials, ~40% of subjects reported grams in women. Doctors should also inform clinically apparent edema, ~20% developed high-risk patients of these reports. However, it joint swelling (especially in the hands) and/or is inappropriate to extrapolate conclusions noninflammatory arthralgias, and ~15% suf- drawn from patients with acromegaly who have fered from myalgias [36]. Arthralgias probably grossly elevated GH levels to adults with GHD result from fluid accumulation in joint spaces receiving only physiological restitution. as inflammatory changes and radiographic Reports of associations between circulating anomalies are not found. These side effects are IGF-I concentrations and the development of generally mild and resolve within a few weeks prostate and breast cancer have further raised of therapy. However, ~10% of subjects develop concerns about the long-term risks of GH ther- carpal tunnel syndrome. Increased hyperten- apy [40]. However, IGF-I levels in the groups sion is typically not reported even after up to 3 with increased cancer incidences were higher years of treatment. Gynecomastia and atrial than those that would be sought in carefully ti- fibrillation have occasionally been attributed to trated physiological replacement therapy. Thus, GH administration in elderly patients. All GH- the applicability of these observations to the related side effects are dose related, and older latter situation is questionable. Furthermore, people are particularly susceptible to them. there is no strong evidence for increased inci- As GH directly antagonizes insulin action, a dences of prostate or breast cancer in patients theoretical risk of its use is hyperglycemia. This with acromegaly, which argues against a causal is a particularly important concern for the eld- relationship between IGF-I and these malig- erly as ~40% of people 65–74 years old and nancies. ~50% of those older than 80 years have im- GH administration is currently contraindi- paired glucose tolerance or diabetes mellitus cated for patients with active malignancy, be- [36]. Careful studies specifically examining this nign intracranial hypertension, and prolifera- risk in GHD adults have shown that GH replace- tive or preproliferative diabetic retinopathy ment does, indeed, initially decrease insulin [34]. Early pregnancy is not a contraindication, sensitivity. However, the effect is reversed with- but GH therapy may be discontinued in the sec- in 3–6 months of therapy, and carbohydrate me- ond trimester as a GH variant is secreted by the tabolism returns to baseline. This is presumably placenta. due to the counteracting effect of losing central One setting in which GH therapy has proved body fat and thus increasing insulin sensitivity. detrimental is in the critically ill.These individ- Although GH-induced increases in basal insulin uals have impairments of both GH secretion or glucose have been seen in some studies, these and action. Hence, two randomized, multicen- values generally remained within normal rang- ter trials were undertaken to determine wheth- es and have never been associated with signifi- er GH treatment in several hundred intensive cant increases in hemoglobin A1c. care unit patients might speed recovery [41]. 10 Rafaela M. Quiroga

Unexpectedly, there was a near doubling of in foods that significantly decreases the adverse 1 mortality, from 20 to 38%, in both studies. effects of reactive species, such as reactive oxygen and nitrogen species, on the normal physiological function in humans” [43]. 1.11 A Brief Guide to Anti-Aging Supplements and Growth-Hormone-Releasing 1.12.1 Vitamin C Nutrients for the Skin Vitamin C is the predominant plasma antioxi- Updated recommendations, developed in a col- dant. This water-soluble vitamin scavenges laboration between the United States and Can- plasma free radicals and prevents their entry ada, incorporate three types of values: the esti- into low-density lipoprotein (LDL) particles mated average requirement (EAR), the recom- [44]. Vitamin C regenerates active vitamin E mended dietary allowance (RDA), and the tol- and increases cholesterol excretion and im- erable upper intake level (UL). Collectively, proves endothelium-dependent vasodilation these values are referred to as dietary reference and reduces monocyte adhesion. Supplementa- intakes (DRIs). EAR is the intake value that is tion with vitamin C (1,000 mg) and vitamin E estimated to meet the requirements of a de- (800 IU) before the ingestion of a high-fat meal fined indicator of adequacy in 50% of the pop- has been found to reverse endothelial dysfunc- ulation (note that this means that the needs of tion and vasoconstriction following the meal. 50% of the population are not being met). RDA On the skin, the function of vitamin C is the is the dietary intake level that is sufficient to production of collagen, which forms the basis meet the nutrient requirements of nearly all infor connective tissue in bones, teeth, and cartil- dividuals in the group. UL is not intended to be age. It also plays an important role in wound a recommended level of intake but represents healing,immunity,and the nervous system,and the highest level of intake that is unlikely to acts as a water-soluble antioxidant. Because vi- have any adverse health effects in most individ- tamin C is water soluble, its antioxidant func- uals. It is important to note that the UL is not tions take place in aqueous body compart- meant to apply to individuals receiving supplements. It also helps protect low-density lipo- ments under medical supervision and should protein cholesterol (LDL-C) against free radical not be used to limit doses investigated in clini- damage. As an antioxidant, it helps protect cal trials [42]. DRIs for antioxidant nutrients against cancer [43], CVD [45, 46], and certain were developed by considering the roles of effects of aging [47]. antioxidant nutrients in decreasing the risk of Severe deficiency of vitamin C leads to diseases, including chronic diseases and other scurvy, which includes symptoms of bleeding conditions,and by interpreting the current data gums, joint pain, easy bruising, dry skin, fluid on intakes in the United States and Canada. retention, and depression. Marginal deficien- cies may play a role in the development of cancer [48, 49], CVD [50], hypertension [51], de- 1.12 Oral Antioxidant Nutrients creased immunity, diabetes [52], and cataracts [53]. The RDA for vitamin C is 75 mg/day for In light of new research on the importance of women and 90 mg/day for men. Smokers re- these vitamins to overall health, the Institute of quire an additional 35 mg/day due to increased Medicine (IOM) in Washington, D.C., recently oxidative stress and other metabolic differenc- released new dietary guidelines for intake of es. The UL for vitamin C is 2,000 mg/day [43]. It the antioxidant nutrients vitamin C, vitamin E, remains possible that higher vitamin C intake carotenoids, and selenium. In addition, a varie- may be beneficial in the treatment or preven- ty of other nutrients are believed to be involved tion of certain diseases, particularly cancer and in antioxidant processes.According to the IOM, respiratory disorders. a dietary antioxidant is defined as “a substance Anti-Aging Medicine As It Relates to Dermatology Chapter 1 11

α 1.12.1.1 Food Sources eight stereoisomers of -tocopherol, four 2R- stereoisomers, and four 2S-stereoisomers). The most active and available form of vitamin E is Important sources of vitamin C include citrus α-tocopherol. Vitamin E is the predominant fruits, strawberries, kiwifruit, papaya, and veg- antioxidant in LDL. This vitamin also inhibits etables such as red peppers, broccoli, and brus- platelet activation and monocyte adhesion. sels sprouts. Vitamin C can easily be destroyed during cooking and storage; therefore, food handling and preparation can have a signifi- 1.12.2.1 Role in the Body cant effect on vitamin C content. and Consequences of Deficiency

1.12.1.2 Risks with High Doses The primary role of vitamin E is to act as an antioxidant. Vitamin E is incorporated into the Vitamin C is relatively safe at high doses,but in- lipid portion of cell membranes and other take of doses higher than 2 g/day may result in molecules, protecting these structures from ox- diarrhea, nausea, stomach cramping, excess idative damage and preventing the propagation urination, and skin rashes [54]. More recently, of lipid peroxidation [11]. Vitamin E appears to 4 g/day has been said to be well-tolerated and have protective effects against cancer [35],heart safe, except in some patients with renal dys- disease [4], and complications of diabetes [4]. It function [55]. In rare cases, daily 2-g doses have is necessary for maintaining a healthy immune been associated with kidney stones [56]. Intake system [57], and it protects the thymus and cir- of greater than 1 g/day increases oxalate excre- culating white blood cells from oxidative dam- tion without clinical consequence in normal age. Also, it may work synergistically with vita- healthy individuals but could lead to adverse min C in enhancing immune function [5]. In consequences in those with underlying renal the eyes, vitamin E is needed for the develop- disease. Dietary needs of vitamin C are in- ment of the retina and protects against cata- creased by smoking, pollutants, aspirin, alco- racts and macular degeneration [58]. hol, estrogen, antibiotics, and corticosteroids. It Vitamin E deficiency is rare and occurs may also interact with various laboratory tests, mostly in people with chronic liver disease and causing false readings [7]. fat malabsorption syndromes such as celiac disease and cystic fibrosis. It can lead to nerve damage, lethargy, apathy, inability to concen- 1.12.2 Vitamin E trate, staggering gait, low thyroid hormone levels, decreased immune response, and anemia. Vitamin E is the name given to a group of eight Marginal vitamin E deficiency may be much fat-soluble compounds. The most abundant more common and has been linked to an inform of vitamin E is α-tocopherol, and this is creased risk of CVD and cancer [42]. the only form that is active in humans [43]. However, research suggests that the mixed forms found in food may be more beneficial 1.12.2.2 Recommended Daily than the isolated α-tocopherol form that is Allowance used in some supplements [7]. Vitamin E supplements are available in natu- Of the fatty acids, polyunsaturated fatty acids ral forms from soybean or wheat germ oil, indi- are most likely to undergo oxidation in the cated by a “d”prefix (also referred to as the ster- presence of oxygen or oxygen-derived radicals. eoisomer RRR-a tocopherol), and synthetic The necessary amount of vitamin E depends on forms manufactured from purified petroleum the amount of polyunsaturated fatty acids in oil, indicated by a “dl” prefix (which includes the diet. The greater the amount of these fats in 12 Rafaela M. Quiroga

the diet, the greater the risk they will be dam- of vitamin E with anticoagulants (e.g., warfar- 1 aged by free radicals and exert harmful effects. in) may enhance their effects [44, 47]. However, Because it is impossible to obtain a high intake a randomized clinical trial that investigated the of vitamin E without consuming a high-fat diet, effects of vitamin E administration in patients use of vitamin E supplements is often recom- on long-term warfarin therapy found no signif- mended [4]. icant change, and the researchers concluded that vitamin E may safely be given to patients receiving warfarin [48, 49]. 1.12.2.3 Food Sources

The best sources of vitamin E are certain vege- 1.12.3 Carotenoids table oils (including wheat germ oil, hazelnut oil, sunflower oil, and almond oil), wheat germ, Carotenoids (also referred to as carotenes) are a whole grain cereals, and eggs. group of more than 600 highly colored plant compounds; however, only 14 have been identified in human blood and tissue [50]. The most 1.12.2.4 Risks with High Doses prevalent carotenoids in North American diets include α-carotene, β-carotene, lycopene, lu- According to the IOM, vitamin E is relatively tein, zeaxanthin, and β-cryptoxanthin. Only safe at doses as high as 1,000 mg/day [11], three (α-carotene, β-carotene, and β-cryptox- Short-term administration of doses as high as anthin) are converted to vitamin A and are con- 3,200 mg/day has not been found to be toxic, sidered pro-vitamin A carotenoids [11]. but adverse effects have been reported with ex- tended intake of 1,100–2,100 mg/day of α-tocopherol [11, 43]. Reported adverse effects in- 1.12.3.1 Role in the Body clude increased risk of bleeding, diarrhea, ab- and Consequences dominal pain, fatigue, reduced immunity, and of Deficiency transiently raised blood pressure. Some research suggests that very high doses may be The only specific effect of carotenoids in hu- pro-oxidant (i.e., acting as free radicals), espe- mans is to act as a source of vitamin A in the cially in smokers [45, 46]. diet, but they also have important antioxidant actions. The latter are based on the carotenoids’ ability to quench singlet oxygen and trap per- 1.12.2.5 Interactions oxyl radicals, thereby preventing lipid peroxi- with Other Nutrients dation [50]. As a result, carotenoids protect and Drugs against the development of cancer, CVD, and ocular disorders. Carotenoids also affect cell Vitamin E exerts antioxidant effects in combi- growth regulation and gene expression. Diets nation with other antioxidants, including β- low in carotenoids may lead to increased risk of carotene, vitamin C, and selenium. Vitamin C cancer and heart disease. Lycopene is the most can restore vitamin E to its natural reduced potent antioxidant for quenching single oxygen form. Vitamin E is necessary for the action of and scavenging free radicals [51]. vitamin A and may protect against some of the Isotretinoin currently is approved for the adverse effects of excessive vitamin A. Because treatment of nodulocystic acne, and there have inorganic iron destroys vitamin E, the two been reported benefits in using 10–20 mg three should not be taken simultaneously. Cholesty- times a week for 2 months for the treatment of ramine, mineral oil, and alcohol may reduce the cutaneous aging [59]. absorption of vitamin E [44]. Based on the results of a single case report, there has been concern that coadministration Anti-Aging Medicine As It Relates to Dermatology Chapter 1 13

ity and have been associated with an increased 1.12.3.2 Recommended Daily risk of lung cancer in smokers. Allowance Interactions with other nutrients: Caroten- oids require bile acids in order to be absorbed. Currently, there are no DRIs for carotene in- Conversion of carotenoids to vitamin A re- take, as it is believed that the current state of re- quires protein, thyroid hormone, zinc, and vita- search on these nutrients is not strong and con- min C. sistent enough to support any recommendations. An intake of -carotene 6 mg is needed to meet the vitamin A RDA of 1,000 mcg retinol 1.12.4 Selenium equivalents (RE) [44]; RE is a measurement of vitamin A intake that allows for comparison of different forms of the vitamin. One IU of vita- 1.12.4.1 Role in the Body min A is equivalent to -carotene 0.6 mcg [60]. and Consequences Due to insufficient data demonstrating a of Deficiency threshold above which adverse events will occur, no UL has been set for any carotenoid [6]. The most important antioxidant mineral is selenium.Selenium is essential for the function of the antioxidant enzyme glutathione peroxi- 1.12.3.3 Food Sources dase, and it is also important for healthy immune and cardiovascular systems. Selenium’s Primary sources of -carotene include carrots, anti-inflammatory properties have been dem- sweet potatoes, pumpkin, cantaloupe, pink onstrated by its ability to inhibit skin-damag- grapefruit, spinach, apricots, broccoli, and most ing, UV-induced inflammatory cytokines [61]. dark green leafy vegetables; -carotene is not de- Results from a Nutritional Prevention of Can- stroyed by cooking. Lycopene is abundant in to- cer trial conducted among individuals at high matoes, carrots, green peppers, and apricots. risk of nonmelanoma skin cancer demonstrat- Lycopene is concentrated by food processing ed that selenium supplementation is ineffective and therefore may be found in high concentra- at preventing skin cancer and basal cell carci- tions in foods such as processed tomato prod- noma and that it probably increases the risk of ucts (e.g., spaghetti sauce and tomato paste). squamous cell carcinoma and total nonmela- Lutein is found in green plants, corn, potatoes, noma skin cancer. spinach, carrots, and tomatoes, and zeaxanthin is found in spinach, paprika, corn, and fruits. 1.12.4.2 Recommended Daily Allowance 1.12.3.4 Risks with High Doses The RDA of selenium for men and women is Carotenoids are believed to be safe at fairly 55 mcg/day, and the UL is 400 mcg/day. high doses. Some areas of skin may become orange or yellow in color (carotenodermia) if high doses of -carotene (30 mg/day or greater) 1.12.4.3 Food Sources are taken for long periods but will return to normal when intake is reduced [6]. This effect Dietary intakes depend on the content of the can be used therapeutically in clinical practice soil where plants are grown or where animals to treat patients with erythropoietic photopor- are raised. Good sources of selenium include phyria (a photosensitivity disorder). Such pa- organ meats and seafood.Because plants do not tients have been treated with doses of approxi- require selenium, concentrations of this antiox- mately 180 mg/day without reports of toxic ef- idant in plants vary greatly, and food tables that fects [6].Carotenes have enhanced bioavailabil- list average selenium content are unreliable for 14 Rafaela M. Quiroga

plant foods. In the United States and Canada, drates with a lower GI index include pears, nat- 1 the food distribution system ensures that re- ural yogurt, lentils, grapefruit, peanuts, and gions with low selenium concentrations in the fructose. soil do not have low selenium dietary intakes [6]. 1.14 Final Remarks

1.12.4.4 Risks with High Doses When approaching the patient with aging skin, the aim is not to make the skin simply appear The UL for selenium is 400 mcg/day; toxicity is smoother or less wrinkled but to make the en- noted at mean doses greater than 800 mcg/day, tire body and mind appear or feel younger. with a 95% confidence limit of 600 mcg/day [62]. Doses above this range result in early symptoms of selenosis,including fatigue,irritability, and dry hair [6, 63, 64]. More advanced References symptoms include dental caries, hair loss, loss of skin pigmentation, abnormal nails, vomit- 1. Perez G, Tilly J (1997) Cumulus cells are required for ing, nervous system problems, and bad breath the increased apoptotic potential in oocytes of aged mice. Hum Reprod 12 : 2781–2783 [63]. 2. Ashcroft G,Horan MA,Ferguson MW (1997) The effect of aging on wound healing: Immunolocaliza- tion of growth factors and their receptors in a mu- 1.12.4.5 Interactions rine incisional model. J Anat 190 : 351–365 with Other Nutrients 3. Banks D, Fossel M (1997) Telomeres, cancer, and aging. Altering the human life span. JAMA 278 : 1345–1348 The combination of selenium and vitamin E 4. Sun Y (1990) Free radicals, antioxidant enzymes, seems to have synergistic effects for the treat- and carcinogenesis. Free Radic Biol Med 8 : 583–599 ment of heart disease, ischemia, and cancer.Vi- 5. Winkler BS, Boulton ME, Gottsch JD, Sternberg P tamin C may also produce synergistic effects, (1999) Oxidative damage and age-related macular degeneration. Mole Vis 5 : 32 but large doses of vitamin C may result in de- 6. Institute of Medicine (2000) Dietary reference increased absorption [65]. takes for vitamin C, vitamin E, selenium, and carotenoids. National Academy Press, Washington, DC 7. Christen S, Woodall A, Shigenaga MK et al (1997) 1.13 Glycemic Index Gamma-tocopherol traps mutagenic electrophiles such as NOx and complements alpha-tocopherol: physiologic implications. Proc Natl Acad Sci 94 : Overeating carbohydrate foods can prevent a 3217–3222 higher percentage of fats from being used for 8. Yaar M, Gilchrest BA. Aging skin (1999) In: Freed- energy and lead to a decrease in endurance and berg IM, Eisen AZ, Wo HK, et al (eds) Dermatology in general medicine, 5th edn. McGraw-Hill, New an increase in fat storage due to insulin. High York pp 1679–1706 insulin levels suppress two important hor- 9. Gilchrest BA, Chiu N (2000) Aging and the skin, In: mones: glucagon and GH. The best solution to Beers MH, Berkow R (eds) The Merck manual of utilize more fats is to moderate the insulin re- geriatrics. Merck, Whitehouse Station sponse by limiting the intake of refined sugar 10. Pincus S, Mulligan T, Iranmanesh A, Gheorghiu S, Godschalk M,Veldhuis J (1996) Older males secrete and keeping all other carbohydrate intake to luteinizing hormone and testosterone more irregu- about 40% of the diet. The glycemic index (GI) larly, and jointly more asynchronously, than young- is a measure of how much insulin increases af- er males. Proc Natl Acad Sci USA 93 : 14100–14105 ter eating carbohydrates. High GI foods include 11. Scheiber M, Rebar R (1999) Isoflavones and post- sugar and sugar-containing foods, bagels, menopausal bone health: a viable alternative to estrogen therapy? Menopause 6 : 233–241 breads and potatoes, cereals, and other foods 12. Cook MJ (1993) Perimenopause: an opportunity for containing sugar maltose, as well as oatmeal, health promotion, J Obstet Gynecol Neonatal Nurse bran muffins, pasta, and bananas. Carbohy- 22(3) : 223–228 Anti-Aging Medicine As It Relates to Dermatology Chapter 1 15

13. Lavker RM (1979) Structural alterations in exposed 28. Bengtsson BA, Johannsson G, Shalet SM, Simpson and unexposed aged skin. J Invest Dermatol 73(1) : H, Sonken PH (2000) Treatment of growth hor- 59–66 mone deficiency in adults. J Clin Endocrinol Metab 14. Yaar M, Gilchrest BA (1999) Aging skin. In: Freed- 85 : 933–942 berg IM, Eisen AZ, Wo HK, et al (eds) Dermatology 29. Drake WM, Howell SJ, Monson JP, Shalet SM (2001) in general medicine, 5th edn. McGraw-Hill, New Optimizing GH therapy in adults and children. York 1697–1705 Endoct Rev 22 : 425–450 15. Wang C, Iranmanesh A, Berman N et al (1998) Com- 30. Gibney J, Wallace JD, Spinks T et al (1999) The ef- parative pharmacokinetics of three doses of percut- fects of 1 years of recombinant human growth hor- aneous dihydrotestosterone gel in healthy elderly mone (GH) in adult GH-deficient patients. J Clin men – a clinical research center study. J Clin Endo- Endocrinol Metab 84 : 2596–2602 crinol Metab 83 : 2749–2757 31. Ezzat S, Fear S, Gaillard RC et al (2002) Gender-spe- 16. Morley J, Perry HM (1999) Androgen deficiency in cific responses of lean body composition and non- aging men. Med Clin North Am 83 : 1279–1289 gender-specific cardiac function improvement alter 17. Snyder P,Peachey H, Hannoush P et al (1999) Effect GH replacement in GH-deficient adults. J Clin En- of testosterone treatment on body composition and docrinol Metab 87.2725–2733 muscle strength in men over 65 years of age. J Clin 32. Cummings D, Merriam GR (1999) Growth hormone Endocrinol Metab 84 : 2647–2653 and growth hormone secretagogues in adults. In: 18. Bhasin S, Bagatell C, Bremner W et al (1998) Issues Meikie AW (ed) Contemporaty endocrinology: hor- in testosterone replacement in older men. J Clin En- mone replacement therapy. Humana, Totowa 61–88 docrinol Metab 83 : 3435–3448 33. Hernberg-Stahl E, Luger A, Abs R et al (2001) 19. 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Mericq V, Cassorla F, Garcia H et al (1995) Growth death in mice homozygous for a null allele of the in- hormone (GH) responses to GH-releasing peptide sulin receptor gene. Nat Genet 12 : 106–109 and to GH-releasing hormone in GH-deficient chil- 22. Donofrio LM (2000) Fat distribution: a morpholog- dren. J Clin Endocrinol Metab 80 : 1681–1684 ic study of the aging face. Dermatol Surg 26 : 36. Harris MI (1990) Epidemiology of diabetes mellitus 1107–1112 among the elderly in the United States.Clin Geriartr 23. Abribat T et al (1994) Alteration of growth hormone Med 6 : 703–719 secretion in aging: peripheral effects.” In: Bbercu 37. Lamberts SWJ, Van den Beld AW, Van der Lely AJ BB, Walker RF (eds) Growth hormone 2, basic and (1997) The endocrinology of aging. Science 278 : clinical aspects. Springer-Verlag, Berlin Heidelberg 419–424 New York 38. Ezzat S, Melmed S (1991) Clinical review 18: Are pa- 24. 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