Two Unusual Potential Sources of Funding for Longevity Research

Appendices: Two Unusual Potential Sources of Funding for Longevity Research

Editorial Note

The following appendices (A and B) provide information that may be useful to investigators seeking funding for experimental types of aging intervention that may be difﬁcult to fund through more traditional sources. The Editors make no represen- tations about the ability of the presenting organizations to fund research or about the veracity of the presenting organizations’ views about the biology of aging or of the prospects for intervening into aging in the ways envisioned by either of these organizations. Our intention here is simply to inform readers about additional possible sources of support for their research. – The Editors

G.M. Fahy et al. (eds.), The Future of Aging, DOI 10.1007/978-90-481-3999-6, 807 C Springer Science+Business Media B.V. 2010 Appendix A SENS Foundation: Accelerating Progress Toward Biomedical Rejuvenation

Michael Rae

A.1 Invitation to Submit Research Proposals

SENS Foundation (website: http://www.sens.org/) is positioned as the most effective philanthropic organization investing in biomedical gerontological research today: a California-based biomedical nonprofit1 committed to critical-path research within a comprehensive panel of therapeutics that is aimed at curing age-related disease, disability, suffering, and death. This mission most obviously distinguishes the Foundation from the large number of nonprofit organizations devoted to treatments for specific age-related diseases. However, the Foundation’s unique strategic approach to advancing progress toward the cure of biological aging is also unique even within the small field of organizations devoted to biogerontological research. The Foundation’s focus is on the development of biomedical interventions rather than on descriptive studies – and on interventions that will not simply retard the rate of aging, but restore the aged body’s original biomolecular- and cellular-level fidelity – and through it, replace the frailty of biological age with the robust homeostatic resilience of biological youth. To this end, SENS Foundation directly funds research projects aimed at the ultimate development of interventions to remove, repair, replace, or render harmless molecular and cellular damage prevalent in the body in situ late in life. We are now inviting all qualified researchers in the biological or medical sciences to submit proposals aimed at molecular- and cellular-level structural ‘rejuvenation’ of the aging body. Established fundable program areas and Requests for Proposals (RFPs) for specific projects are outlined below.

M. Rae (B) SENS Foundation, 1230 Bordeaux Drive, Sunnyvale, CA 94089, USA e-mail: [email protected] 1SENS Foundation is a California nonproﬁt organization, and is in the process of applying for recognition of exemption from taxation under section 501(c)(3) of the Internal Revenue Code. The organization expects to receive tax-exempt status effective as of the date of incorporation.

809 810 M. Rae

A.2 Funding Priorities and Principles

SENS Foundation’s research funding priorities emerge from critical-path analy- sis of areas of high biomedical importance within the “Strategies for Engineered Negligible Senescence” (SENS) platform proposed by Dr. Aubrey de Grey to develop a comprehensive panel of robust anti-aging interventions. As explained in detail elsewhere (de Grey 2003; de Grey et al. 2002; de Grey and Rae, 2007), SENS is based on an “engineering” heuristic for the development of therapeutics targeting biological aging, in contrast to the so-called “gerontological” approach that underlies most past and present attempts to do so. SENS Foundation is the only nonprofit organization whose research funding is devoted to biomedical gerontology, but whose remit allows it to avoid the diversion of funds into the inefficient “gerontological” approach. Instead, SENS Foundation’s research program targets funding to research that advances the development of the specific biotechnologies identified through the “engineering” approach to anti-aging biomedicine: in essence, the extension of regenerative medicine principles to aging. I will now outline these two approaches, and the reasons why the Foundation’s strategy of targeted investments in the former rather than the latter can be expected to yield anti-aging interventions of dramatically greater benefit.

A.2.1 The “Gerontological” Approach: Modulation of Metabolic Pathways Contributing to Biological Aging

There is broad-based consensus in biogerontology (e.g., Kirkwood, 2008; Hayflick, 2007; Holliday, 2004; de Grey et al. 2002) that aging is the result of accumulating stochastic damage to the body’s cellular and molecular structures, as a result of unintended biochemical side-effects of metabolism such as reactive oxygen species (ROS), nonenzymatic glycation, and errors in DNA replication and epigenetics. Most biogerontology research, therefore, is based on enhancing our understanding of those metabolic processes and their mechanistic links to aging damage, in hopes that those pathways can be modulated in ways that reduce the rate at which such damage forms and accumulates, leading in turn to a slower loss of physiological integrity and retarded organismal aging. Within this framework, putative interventions might downregulate pathways responsible for ROS generation, sequester reactive intermediates of glycolysis, upregulate repair mechanisms, interfere in the action of anabolic pathways responsible for cellular proliferation, or otherwise antagonize or cushion such pathways. Examples will come readily to mind, and pervade the choice of interventions selected for inclusion in the NIA’s Interventions Testing Program (ITP (Nadon et al. 2008; National Institute on Aging 2008). This way of pursuing anti-aging intervention is grounded in the logic of basic research science: analyze a phenomenon in progressively finer detail to discover its underlying basis, and then use the results of such studies to modify hypotheses, thereby generating new questions in a recursive process of scientific progress. Appendix A: SENS Foundation 811

The same strategy is also widely employed as part of conventional drug development. Researchers begin by analyzing and characterizing the various components of a metabolic pathway that is defective in the disease state, identifying the normal function of each. They then compare the function of those components in health and disease, thereby revealing the dysfunctional steps in the process that form the molecular basis of the illness. Such components then become therapeutic targets, subject to manipulation to normalize function, whether by small molecules or other means (such as gene therapy or prosthesis). Unfortunately, this strategy is ill-suited to the near-term development of interventions against the biological aging process, for the overarching reason that aging damage is not the result of the de novo dysfunction of metabolic pathways, but of the undesirable biochemical side-reactions of normal metabolic activity.This is precisely why aging is a universal disease, and why many physicians and even biogerontologists are reluctant to characterize it as a “disease” at all: biological aging is the pathological result of perfectly-functioning, “healthy” – but necessarily imperfect – metabolic processes. Hence Dr. de Grey’s quip that “aging is a side- effect of being alive.” In other words, any “gerontological” anti-aging intervention would of necessity be grounded upon interfering with the biochemical processes that sustain our very lives – and doing so day in and day out, from the day that a “patient” first begins therapy until his or her death. The pathways whose reactive products contribute to aging are there for a reason, even though they have long-term downsides, and we begin dialing them up or down at our peril. Even the reactive products that link metabolism to aging damage are often indispensable, evolution having learned to harness them for metabolic purposes, such as when ROS are used as signaling molecules (DAutréaux and Toledano, 2007). Indeed, the body’s metabolic processes are already embedded within hopelessly complex regulatory pathways and interlocking feedback loops, precisely in order to ensure that they continue to operate in strict coordination with one another, and within a range that natural selection has ‘learned’ to be optimal for sustaining fitness. This fact is illustrated in the very phenomena that advocates of “gerontological” intervention seek to mimic pharmacologically: animals that age slowly because of either genetic mutations or the imposition of calorie restriction. Slow-aging organisms are vanishingly rare in natural populations for a reason: not that evolution “wants us to age” as is often mistakenly said, but because the metabolic abnormal- ities that are responsible for such animals’ slow-aging phenotype also ensure that they can only survive in the sheltered conditions of the laboratory. In the wild, these organisms would be unfit relative to their normally-aging cohorts for most of their natural lifespans, and the more aggressively the interventions are applied to enhance the anti-aging effect, the more severe the phenotype would become. An additional, and equally crucial, limitation to “gerontological” intervention is that no matter how much the accumulation of further aging damage is slowed by such means, it cannot be entirely stopped without turning off the underlying metabolic processes entirely. Nor can such interventions do anything about the pre- existing burden of molecular and cellular lesions. Therefore, the ultimate benefits 812 M. Rae of “gerontological” interventions will by definition be inversely proportional to the degree of medical need of the recipient. This weakness of all interventions whose expected effect is to decelerate aging changes has been acknowledged as a significant impediment to a realistic program of human clinical testing in a recent review by current NIA Director Richard Hodes, past Biology of Aging program director Huber Warner, and their colleagues (Hadley et al. 2005). It also limits the potential benefits of such therapies even supposing they were developed, tested clinically, and widely disseminated. For example, while calorie restriction (CR) imposed from weaning extends total, largely healthy lifespan by approximately 30%, the total lifespan extension declines when CR is imposed for the first time in adulthood or in early seniority. Based on a direct extrapolation from the available rodent data, (Rae, 2004) a small-molecule mimetic of severe CR beginning at weaning, at age 35, or at age 54, would extend human life expectancy to 110.5, 100, or 94.3 years, respectively. A 54-year-old would gain only 9.3 years compared to the 85 year life expectancy that would otherwise result from “aging as usual.”

A.2.2 The SENS Heuristic: Regenerative Biomedical Gerontology

In contrast to pure science, pioneering engineering is a highly empirical endeavor, oriented not so much to detailed description of reality but to its practical manipulation. While informed by available scientific knowledge, it is very much a second-order discipline, utilizing proven rules of thumb in the absence of fully fleshed-out theoretical understanding of the phenomena within whose parameters it advances. The subject of concern is not whether a phenomenon is fully under- stood, but whether it can be reliably and advantageously manipulated to achieve some outcome. Thus, for example, Edison and others were able to harness the power of electric- ity to great practical effect decades before the discovery of the electron was made, and when indeed the mysterious electrical “fluid” was mistakenly believed to flow from the cathode to the anode, rather than vice-versa. In terms of public health, the earliest (and most dramatic) advances were made on the same basis: contrast the weakness of the understanding of microbiology possessed by the likes of John Snow, Jenner, or Pasteur with the effectiveness of the solutions they pioneered. Even today, the very names of such high-tech fields as tissue “engineering” and biomedical “engineering” accurately reflect their highly empirical basis in replicating the key structural-functional characteristics of native tissues, even when the materials and processes used are highly remote from their biological originals. But while the engineering heuristic is well-established in other fields of biomedicine, its use in biomedical gerontology is a recent, dramatic, and even dis- ruptive departure from the “gerontological” approach that has dominated thinking on the subject to date – a genuine paradigm shift. Dr. de Grey is responsible for first explaining the distinction between the two strategies as they apply to intervention in aging (de Grey 2003; de Grey et al. 2002) and then using its heuristic principles (in collaboration with experts in widely diverse relevant fields) to develop Appendix A: SENS Foundation 813 a specific suite of emerging or foreseeable biotechnologies that comprise a platform of comprehensive rejuvenation biotechnology: the SENS program.

A.2.2.1 Principles of “Engineered” Rejuvenation The engineering paradigm begins with the same understanding of the ultimate cause of biological aging as the “gerontological” paradigm: that the progressive increase in frailty that characterizes aging is the result of the accumulation of cellular and molecular damage that ensues from the normal operation of metabolic processes. Also shared with (but rarely emphasized in) “gerontological” thinking is the fact that, while the formation and accumulation of aging damage is an ongoing process that begins with life itself and continues throughout the lifespan as a result of normal metabolism, neither the metabolic processes that cause the accumulation, nor the accumulation process per se, have a significant impact on functionality for the first three to four decades of life. This is because of the great redundancy of the body’s systems. Thus, there is little difference in the physical performance or risk of death between reasonably health-conscious people aged twenty, thirty, or forty, despite the fact that the burden of aging damage progressively accumulates over each additional decade. It is only once the total burden of such damage reaches a critical “threshold of pathology” that aging begins to impact our health and increase our risk of imminent death. Granted these shared premises, the key strategic departure separating the engineering heuristic from that of “gerontology” is the identification of the cellular and molecular damage of aging itself as the preferred therapeutic target, rather than the metabolic pathways that contribute to the formation of that damage. By removing, repairing, replacing, or rendering irrelevant damaged cells and biomolecules, the body’s structural fidelity can, logically, be maintained at – or, indeed, restored to – that of a young adult. And just as the degradation of such structural fidelity causes the progressive loss of function that characterizes biological aging, so the restoration of such fidelity necessarily must lead to the restoration of youthful functionality – to rejuvenation, in a word. This shift in therapeutic targets yields several practical advantages to engineering interventions. First, it escapes the core dilemma of “gerontological” interventions: the risk to normal functionality entailed in perturbing normal metabolic processes in hopes of reducing the production of their unintended molecular and cellular side- effects. Instead, those metabolic processes can be allowed to proceed unimpeded, targeting only their deleterious consequences. Second: because aging damage is initially inert, its removal should be intrin- sically benign (again, something that is not the case for the manipulation of metabolism). Third: because such damage takes so long (several decades) to accumulate to pathological levels, aging damage can be allowed to accumulate to levels within the range encountered over the two decades or so between maturity and early middle age before reaching the ‘threshold of pathology’ and requiring a cycle of biomedical removal to restore youthful molecular fidelity. Such a periodic schedule of intervention affords an extended period between cycles, during which the body can 814 M. Rae rest and recuperate from the rigors of treatment and engage its own intrinsic capacity for repair and regeneration; it also reduces the risk that a subtle side-effect of therapy can gradually lead to long-term, cumulative negative consequences. This is again in contrast to “gerontological” intervention, which requires chronic dosing because the metabolic pathways that it targets are continually active and the ensuing accumulation of damage proceeds on an unremitting basis. Fourth: a focus on aging damage as the therapeutic target greatly reduces the number of such targets required to impact aging globally. While the metabolic processes that generate aging damage are hopelessly complex, multifarious, and interlocking, their direct consequences – aging damage itselfÐ consists of a relatively small number of classes of lesion which can be directly targeted for removal (see next section). Fifth, interventions designed to reverse aging changes can be tested on much more rapid timescales than can those designed to retard them: the clinical testing of any intervention whose effect is to “decelerate aging changes ...must be initiated relatively early in life and sustained for decades before clinical effects occur, [making] the logistical challenges of conducting a trial ...extremely formidable ...[By contrast,] If the intervention is expected to reverse in older persons adverse aging changes that increase their risk of clinical outcomes, it may be possible to design a study to measure the effect of the intervention on these outcomes directly” (Hadley et al. 2005) (my emphasis). Finally, the magnitude of the benefits of such therapies to recipients – in delayed or escaped age-related disease, disability, dementia, dependence, and ultimately, premature death – can similarly be expected to be correspondingly greater when they can undo, rather than merely hold back, the molecular and cellular ravages of decades of normal metabolism. This implication is elaborated and modeled in (ii) Prospects, below.

A.2.2.2 Speciﬁc Engineering Targets Decades of exhaustive characterization of the aging of mammals indicate there are no more than seven major classes of cellular and molecular aging lesions (see Table A.1). We can be conﬁdent this listing is exhaustive, not least because of

Table A.1 Classes of aging damage, dates of identiﬁcation, and foreseeable solutions

Aging damage Identiﬁed SENS biotechnology

Intracellular aggregates 1959 Novel lysosomal hydrolases (“LysoSENS”) Mitochondrial mutations 1972 Allotopic expression (“MitoSENS”) Extracellular aggregates 1907 Immunotherapeutic clearance (“AmyloSENS”) Nuclear [epi]mutations 1959, 1982 Interdiction of telomere-lengthening (“OncoSENS”) Death-resistant cells 1965 Targeted ablation (“ApoptoSENS”) Loss of elasticity 1958, 1981 De-stiffening (“GlycoSENS”); tissue engineering Cell loss, tissue atrophy 1955 Stem cells and tissue engineering (“RepleniSENS”) Appendix A: SENS Foundation 815 the lack of any progress in identifying new ones in nearly a generation of ongoing research, despite the ever-increasing number of detailed descriptive studies, the increasingly-sophisticated molecular-level probes and tools deployed, and the discovery of ever more layers of complexity in metabolic processes. As Table A.1 also indicates, the path ahead to repairing these forms of damage is also discernable: for each major aging lesion, biotechnology for its removal or repair either already exists in prototype form, or is clearly foreseeable from existing scientiﬁc developments. Each of the biotechnologies in the SENS panel (Table A.1) is intended to remove (or, in two cases, obviate) aging damage central to the eti- ology and pathogenesis of major age-related diseases, and so should individually constitute actual cures for distinct therapeutic indications, in addition to collectively contributing to the global rejuvenation of the body. This fact will greatly ease the regulatory hurdles facing each individual intervention and provide incentives for private industry ﬁnancing to advance their development.

A.3 Comparative Effectiveness Modeling

SENS provides a detailed roadmap of the way ahead for biogerontological engineering, based on our existing knowledge of aging damage and on the existing or foreseeable biotechnologies whose maturation will be needed for us to repair it. The first iterations of these technologies will repair the forms of aging damage that contribute most to age-related frailty, disease, and death within a currently-normal lifetime; thereafter, normal biomedical progress will iteratively refine and expand the SENS platform, repairing increasingly subtle or slowly-accumulating forms of aging damage. This will allow us to live progressively longer – and healthier – lives, until these technologies can clear all aging damage and our rejuvenation is complete. This prospect is qualitatively illustrated in Fig. A.1. In principle, damage- removal protocols could become sufficiently comprehensive to place their benefi- ciaries permanently in a condition similar to those of healthy twenty- to thirty-year olds, having negligible age-related mortality risk and possessing a healthy life expectancy that is literally indefinite. A model of the impact on successive gen- erations of progressively improved engineering interventions for various cohorts (Phoenix and de Grey 2007) is also illustrated in Fig. A.2 below. Even a mature “gerontological,” damage-prevention strategy cannot address patients’ pre-existing burden of aging damage and can only slow down the ongoing progression of aging. By contrast, engineering interventions can potentially remove already existing aging damage, thereby reducing biological age in the face of increasing chronological age and leading to a progressive reduction in age-related mortality risk, suffering, and resulting medical costs. Therefore, continuing on the traditional road has a large opportunity cost, entailing the consignment of 100,000 people each and every day, indefinitely, to death from aging, and of many hundreds of times this number of person-days to progressively-increasing frailty, disability, 816 M. Rae

Fig. A.1 Comparison of the effects of various interventions on a middle-age person’s arrival at a “frailty threshold” (loss of homeostatic reserve). “Normal” aging (solid line); “gerontological” intervention that halves the rate of further damage accumulation (dashed dot) and its iterative improvement every 7 years (the typical human mortality-rate doubling time) (dotted line); an “engineering” therapy that removes half the damage (thick double line) and its iterative improvement every 20 years (thin double line). (Adapted from Phoenix and de Grey 2007)

Fig. A.2 Survival curves for “normal aging” (leftmost solid line) and for cohorts that are aged 10, 20, ... 80 when the ﬁrst therapy arrives, assuming a 42-year cycle of doubling of the efﬁcacy of damage removal. (Adapted from Phoenix and de Grey 2007)

disease, and dementia – not forgetting the enormous cost to friends, loved ones, government entitlement budgets, and economic productivity. SENS Foundation believes we know enough today – both about aging damage, and about the path toward its repair – to start advancing toward a cure for aging using engineering principles, with expected success on a foreseeable timescale, subject only to the magnitude of investment in this research. Appendix A: SENS Foundation 817

A.4 SENS Foundation-Funded Research

The clear advantages of the engineering paradigm make hastening progress in the development of the SENS platform the focus of the Foundation’s core venture: direct investment in the development of SENS’s constituent biotechnologies (Table A.1). SENS Foundation has continued and expanded the SENS research projects formerly under the aegis of the Methuselah Foundation, and ongoing fundraising continues to expand our research budget, and the number and size of our investments. SENS Foundation is based in California, but has global reach through its staff, funded researchers, and wider network of contacts. The day-to-day operations of the Foundation are overseen by its senior management team, who themselves report to the SENS Foundation Board. Research priorities are identified by the Chief Science Officer and Research Advisory Board (RAB), based on their ability to advance the progress of the SENS platform. Funding priorities are identified on a critical- path basis. While a complete panel of anti-aging biotechnologies will be required in order to implement a comprehensive rejuvenation program, progress toward clinical implementation of those interventions stands at widely disparate stages of development; the Foundation allocates funding to the foreseeable bottlenecks in progress of the platform as a whole. Thus, some SENS-platform interventions are not subject to Foundation funding because they have progressed to the very rim of the therapeutics pipeline indepen- dently, rendering additional Foundation funding superfluous. A notable example of this is immunotherapy for the removal of the accumulating beta-amyloid protein (Solomon 2008); the recent FDA approval of the first human clinical trial of embryonic stem cell-based therapy in patients with acute spinal cord injury (Geron 2009) is another. In other cases, research is still at a relatively preliminary stage, but the level of scientific interest and private and government funding is sufficient to give confi- dence in the developmental trajectory, leaving the Foundation in a similar position as with interventions already in late testing. However, many of the key components of a comprehensive panel of rejuvenating biotechnologies have been the subject of little or no development to date, despite their biomedical importance. In these “bottleneck” areas, seed funding from the Foundation can have a very large effect on the rate of progress of that plank of the platform, and thus toward the ultimate goal of a comprehensive panel of rejuvenation biotechnologies. The SENS Foundation Research Center (SENSF-RC) is the Foundation’s intramural facility, and undertakes mid-level translational research between early cellular models and work in mammalian systems within the SENS platform. Originally based in Tempe, AZ, the SENSF-RC has relocated to Sunnyvale, CA, to facilitate collaboration with the strong life science/biotech industry in the Bay Area. Extramural research grants are directed to academic centers with specialized expertise for the relevant projects, and with consideration for the availability of matching grants and/or existing infrastructure to leverage Foundation dollars to produce research deliverables. The small size and highly focused remit of the Foundation allows for a relatively rapid review of proposals and dispersions of research investments. Foundation 818 M. Rae grants are typically for approximately US $100,000 per year per researcher (typically a graduate student or postdoc) per annum, tailored to the needs and available resources of the principal investigator. A brief discussion of active and projected Foundation research activities – including areas where the Foundation is actively inviting proposals from extramural researchers – follows.

A.4.1 LysoSENS: Medical Bioremediation

The initial goal of the “LysoSENS” project is to identify microbial enzymes capable of breaking down the metabolic waste products that accumulate in aging cells, impair or destroy their function, and thereby contribute to a range of age-related diseases, including atherosclerosis, Alzheimer’s disease, age-related macular degeneration (primarily the “dry” form) (de Grey et al. 2005), and other age-related disorders. Once identified, suitably-modified versions of such enzymes would be used to fortify our cells’ own enzymatic armamentarium, thereby allowing the removal of such wastes and restoring normal cell function. Currently, three Foundation-funded labs (the SENSF-RC, and labs at Rice and Arizona State Universities) are employing complementary approaches to pursue this benchmark. Significant progress has been made in identifying and characterizing enzymes for the degradation of 7-ketocholesterol, an oxidation product of serum cholesterol widely thought to be central in the progression of atherosclerotic plaque (Rittmann and Schloendorn 2007; Mathieu et al. 2008; Mathieu et al. 2009). Additionally, the ASU team has (with outside collaboration) identified other enzymes that efficiently degrade A2E, a recalcitrant metabolic byproduct whose accumulation is central to most age-related macular degeneration. The team is now collaborating with Dr. Janet Sparrow of Columbia University, who has repeated and confirmed the ASU group’s results in A2E-loaded retinal pigment epithelial cells (RPE), the population vulnerable in macular degeneration (Rittman et al. 2008), and is now being funded to lend her expertise to the further characterization and development of the candidate enzymes. After identifying the products of A2E degradation by the enzymes, her lab will perform preliminary safety and efficacy screens in RPE. If the cell culture results are promising, the Foundation will fund the testing of potentially viable enzymes in a mouse model of macular degeneration similar to Stargardt’s disease, a human congenital form of macular degeneration. As the Foundation’s research budget continues to expand, we will expand these intramural and extramural research efforts in the identification, characterization, and testing of important microbial enzymes.

A.4.2 MitoSENS: Obviation of Mitochondrial Mutations

The “MitoSENS” project aims to address another form of aging damage: mutations in mitochondrial DNA. Although most of the genes that encode the proteins used in the mitochondrial energy-harvesting process are safely housed in the cell Appendix A: SENS Foundation 819 nucleus, 13 such proteins are instead encoded by genes situated within the mitochondria themselves. These genes are extremely vulnerable to mutations resulting from the ongoing production of reactive waste products during energy production. While the mechanisms linking mitochondrial mutations to aging and age-related pathology continue to be debated (de Grey 2002, 2004; Khrapko et al. 2004, 2006; Smigrodzki and Khan 2005), such mutations (and especially large mitochondrial DNA deletions) accumulate in individual postmitotic cells with aging and are widely held to play an important role in human aging and age-related disease. The technical hurdles of repairing such mutations are not generally thought to be surmountable with foreseeable biotechnologies. There are, however, a small number of potentially viable solutions to the problem of mitochondrial mutations. The most promising is allotopic expression (AE), the placement of “backup copies” of the 13 vulnerable genes into the nuclear genome, suitably modiﬁed to ensure the delivery of their encoded proteins from their remote site of synthesis in the cell body to their appropriate location within the mitochondria. Even if the native mitochondrial DNA is irreparably damaged, the existence of this alternative source of functional energy-harvesting proteins would prevent any dysfunctional metabolic consequences, effectively rendering any such mutations harmless. Foundation-funded work on AE is centered in the Quinze-Vingts National Center of Ophthalmology in Paris, to support ongoing work based on the extremely promising early fruits of a novel AE strategy developed by Dr. Marisol Corral- Debrinski (Kaltimbacher et al. 2006), extending most recently to the initiation and reversal of an animal model of the mitochondriopathy Leber hereditary optic neuropathy (LHON) (Ellouze et al. 2008). With further Foundation support, Dr. Corral-Debrinski’s team is working to further validate and systematize the tech- nique, and if successful, to extend it to obviation of other mitochondrial mutations in cellular and laboratory animal models of mitochondrial disease.

A.4.3 AmyloSENS: Removal of Pathological Extracellular Aggregates

A range of bodily proteins suffer damage that causes them to aggregate into small, soluble oligomers and larger ﬁbrillar formations; these accumulate with age and are evidently pathological. The most prominent of these is beta-amyloid, widely thought to be a key pathogenic species in Alzheimer’s disease; others of concern are aggregated islet amyloid polypeptide (IAPP), apparently responsible for beta- cell death in diabetes; alpha-synuclein in Parkinson’s disease and other so-called synucleinopathies; and wild-type transthyretin (TTR), deposition of which underlies senile cardiac amyloidosis (SCA) which increasingly impairs cardiac function with age and appears to be a signiﬁcant contributor to death in centenarians (Tanskanen et al. 2008; Bernstein et al. 2004; Hashizume et al. 1999; Steve Coles, Los Angeles Gerontology Research Group (LA-GRG), personal communication). Multiple pharmaceutical companies and academic labs are actively pursuing immunological removal of beta-amyloid, and there is early work with similar 820 M. Rae strategies for human IAPP (Lin et al. 2007) and alpha-synuclein (Masliah et al. 2005) aggregates in transgenic mice. To our knowledge, however, no group is yet pursuing immunotherapeutic removal of wild-type human TTR. The Foundation is now inviting proposals for projects aimed at the development and subsequent testing in transgenic mice of such an intervention.

A.4.4 OncoSENS: Containment of All Cancers

SENS Foundation believes that a comprehensive program for the indefinite extension of healthy human life requires a comprehensive cure for all cancers. This is a very challenging requirement, because of cancer’s uniquely evolutionary nature: due to its rapidly proliferating, genetically unstable, highly heterogeneous subpop- ulations, a malignancy is an engine of rapid evolution, generating mutations that ultimately elude the mechanism of any given intervention that targets a particular feature of the original cancer. This perspective and the WILT (“Whole-body Interdiction of Lengthening of Telomeres”) plan for dealing with it have been described elsewhere (de Grey 2005; de Grey et al. 2004) and in Chapter 22 of the present volume (de Grey 2010), and the reader is referred to this chapter for additional discussion. WILT is the most complex and technically challenging part of the SENS platform – but, as a roundtable report including recognized experts in all aspects of this intervention has concluded (de Grey et al. 2004), no aspect is theoretically insurmountable; in fact, all of the required biotechnology is foreseeable from current developments, positioning WILT firmly within the timescales of the rest of the SENS platform. One concern surrounding WILT is that some reports suggest that the telomere maintenance machinery may have indispensable physiological functions beyond the actual lengthening of telomeres (Fauce et al. 2008; Ju et al. 2007; Passos et al. 2007; Flores et al. 2005; Sarin et al. 2005; Liu et al. 2004). The evidence in all cases is ambiguous, but SENS Foundation is now funding research by Dr. Zhenyu Ju (formerly of Dr. K. Lenhard Rudolph’s laboratory and now at the Chinese Academy of Medical Sciences) to help resolve the issue by monitoring the effects of trans- planting telomerase-deficient but ex vivo telomere-extended bone marrow into mice. Additionally, a few genes have recently been identified that appear to be involved in noncanonical, non-cancer telomere maintenance, and SENS Foundation is now funding work at SENS-RC and extramurally to test their involvement in ALT cancers. Finally, there is the question of the intuitive, widely-accepted, but theoretically and empirically debatable (de Grey, 2007), notion that age-related, somatic nuclear (epi)mutations other than those leading to cancer accumulate to a degree that mean- ingfully limits a currently-normal lifespan. For some time now, this important question has been the chief research interest and occupation of Dr. Jan Vijg, an innovative and productive researcher in this area, who is enthusiastic to further test this hypothesis. The Foundation has now funded a project developed with Dr. Vijg for a more rigorous test of this idea in the brains of aging mice. Appendix A: SENS Foundation 821

A.4.5 ApoptoSENS: Ablation of Maladaptive Cells

During aging, a variety of cells undergo maladaptive changes causing them to enter into abnormal metabolic states that appear to be highly detrimental to the organism as a whole, and which simultaneously render them resistant to cell death programs that are designed to ensure the removal of such cells. Identiﬁed cases exhibiting this problem include visceral adipose tissue macrophages (thought responsible for the metabolic syndrome associated with abdominal obesity), “senescent” cells (which secrete factors that create a permissive environment for cancer), and “anergic” CD8+ and possibly CD4+ T-cells (which appear to be major contributors to immunological senescence) (de Grey 2006). ApoptoSENS is dedicated to the selective removal of such cells, employing techniques similar to those used in modern targeted cancer therapies. SENS Foundation is currently funding an experimental protocol for restoration of youthful immune function in aged mice involving clearance of anergic T-cells – combined with efforts aimed at restoring the declining function and cellularity of the thymus gland – in the lab of prominent immunosenescence researcher Dr. Janko Nikolich-Zugich. Separately, the SENSF-RC recently completed a proof- of-concept study, in which putative anergic T-cells were “scrubbed” from the blood of aged mice ex vivo using magnetic nanoparticles coated with antibodies to target cell surface markers, reducing cell count 7.3-fold (Rebo et al. 2010). We would also be open to proposals and preliminary discussions for similar projects for the depletion of age-related accumulations of other dysfunctional cell types.

A.4.6 GlycoSENS: Cleavage of Extracellular Protein Crosslinks

Long-lived structural proteins undergo occasional nonenzymatic crosslinking by advanced glycation endproducts (AGE). Because such crosslinks tend to accumulate with age, such tissues progressively lose their elasticity and other functionality. In the cardiovascular system, this leads to age-related diastolic dysfunction in the heart and the systemic rise in systolic blood pressure and decline in resilience in the vasculature, resulting in stroke, kidney damage, and other pathologies of major organs. Because nonenzymatic AGE crosslinks are structurally distinct from physiologic proteins (including the products of enzymatic glycosylation reactions) they can in principle be selectively targeted for cleavage by appropriately-designed pharmaceuticals. Indeed, the lead member of one class of such drugs (Alagebrium/ALT-711) has been documented to restore elasticity and improve cardiovascular functions and outcomes in a range of animal models, and advanced into limited human clinical trials (Zieman et al. 2007; Thohan et al. 2006; Little et al. 2005; Bakris et al. 2004; Kass et al. 2001). However, the results of those trials have been disappointing, likely because the class of crosslinks that Alagebrium severs (alpha-diketone bridges) is relatively rare in humans; indeed, current evidence suggests that the unrelated glucosepane is by far the most important AGE crosslink in human collagen. 822 M. Rae

The development of a pharmaceutically-acceptable glucosepane-cleaving agent is therefore the clear priority within this arm of SENS, and the Foundation invites preliminary discussion and/or proposals from investigators with relevant medicinal chemistry or other expertise to engage in a research project to identify, modify, or design such an agent. Another likely contributor to age-related cardiovascular stiffening is mechanical fatigue of the large arteries, mediated by the fraying of the anchored lamellar structures responsible for the cushioning of pulse pressure in the arterial wall (O’Rourke, 2007). If such mechanical fatigue proves to be the dominant contributor to arterial stiffening during the course of a currently-normal lifetime, then a solution based on advanced tissue engineering to restore lamellar connectivity may abrogate or greatly forestall the need for a pharmaceutical AGE-cleaver. Work on such a solution is in progress, albeit only in very early stages at this time (e.g. Zavan et al. 2008; Gao et al. 2008; Mendelson et al. 2007).

A.4.7 RepleniSENS: Restoration of Lost Cellularity

As humans age, cells are continuously lost to mechanical damage, internal and external toxins, accumulation of metabolic damage, and active removal by cell death and senescence programs. In long-lived tissues in which cell replacement is limited, this leads to gradual loss of tissue function, contributing to global aging and a range of age-related diseases. These facts are already widely appreciated, and thus nearly all of the relevant clinical indications are already under vigorous pursuit by biotech companies and academic institutions. Since the marginal gains that might be reaped by additional investment from the Foundation at this stage are therefore likely negligible, we have no plans for RFPs in this area. The principal exception to this generalization is thymic regeneration, which (perhaps because it is not linked to a narrowly-deﬁned “disease” indication) has been the subject of remarkably little work; moreover, much of the work that has been done has focused on enhancing residual organ function using ‘gerontological’ strategies, rather than restoring cellularity (Chidgey et al. 2007). As noted above (Section A.4.5), SENS Foundation is currently testing a combination immunorejuvenation protocol that includes thymic cell therapy in aging mice; if results are positive, we anticipate the advancement of this protocol for testing in a nonhuman primate model.

A.5 The Past, the Present, and the New Future of Aging Research

As most biogerontologists will readily admit, a great deal of current research investment aimed at alleviating the suffering and loss of life expectancy caused by the “diseases of aging” is ultimately misplaced. Conventional medical charities, and even the National Institutes of Health, continue to pursue the piecemeal treatment of age-related diseases in isolation from the underlying biological aging process. This Appendix A: SENS Foundation 823 approach has been successful in alleviating much of the early mortality resulting from poor social conditions and lifestyle choices, but is increasingly ill-suited to a population in which increasingly large numbers of people reach the limits of a ‘normal’ lifespan and the synergistic, exponential increase in frailty which comes with aging becomes the dominant reason for disability, death, and disease. A few organizations – primarily the Buck Institute, the Ellison Medical Foundation, and the NIA’s Division of Aging Biology – recognize this fact, and have focused some of their energies and resources on research whose ultimate goal is intervention in the basic processes of aging. However, all of these organizations continue to pursue their new goal within a framework inappropriately modeled on conventional disease research science and pharmacology: the “gerontological” paradigm. SENS Foundation’s strategy is therefore unique, having pioneered and embraced the new “engineering” approach in biomedical gerontology and initiated targeted, critical-path research to advance its core rejuvenation biotechnologies. Such research investments can be predicted to yield more rapid and more robust medical advances in the prevention of age-related disease, disability, dementia, and ultimately risk of death, delivering larger expansions of youthful, healthy lifespan than those focused on conventional disease-oriented medicine or even traditional biogerontological research. As funding continues to expand, SENS Foundation will accelerate the move- ment of core SENS science through the therapeutic pipeline and on into the clinic, reversing aging damage and restoring youthful health and vigor. We invite investigators to submit preliminary sketches of research project proposals for funding, or via email to Dr. de Grey

References

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(2008) Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. J Immunol 181(10):7400–7406 Flores I, Cayuela ML, Blasco MA (2005) Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309(5738):1253–1256 Gao J, Crapo P, Nerem R, Wang Y (2008) Co-expression of elastin and collagen leads to highly compliant engineered blood vessels. J Biomed Mater Res A 85(4):1120–1128 Geron (Press Release) (2009) Geron Receives FDA Clearance to Begin World’s First Human Clinical Trial of Embryonic Stem Cell-Based Therapy. Available online at http://www.geron.com/media/pressview.aspx?id=1148. Accessed 2009-07-01 Hadley EC, Lakatta EG, Morrison-Bogorad M et al. (2005) The future of aging therapies. Cell 120(4):557–567 Hashizume Y, Wang Y, Yoshida M (1999) Neuropathological study in the central nervous system of centenarians. In: Tauchi H, Sato T, Watanabe T (eds) Japanese Centenarians: Medical Research for the Final Stages of Human Aging. Institute for Medical Science of Aging, Aichi, Japan, 137–154 Hayflick L (2007) Biological aging is no longer an unsolved problem. Ann NY Acad Sci 1100:1–13 Holliday R (2004) The close relationship between biological aging and age-associated pathologies in humans. J Gerontol A Biol Sci Med Sci 59(6):B543–B546 Ju Z, Jiang H, Jaworski M et al. (2007) Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med 13(6):742–747 Kaltimbacher V, Bonnet C, Lecoeuvre G et al. (2006) mRNA localization to the mitochondrial surface allows the efficient translocation inside the organelle of a nuclear recoded ATP6 protein. RNA 12(7):1408–1417 Kass DA, Shapiro EP, Kawaguchi M et al. (2001) Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation 104(13):1464–1470 Khrapko K, Ebralidse K, Kraytsberg Y (2004) Where and when do somatic mtDNA mutations occur? Ann NY Acad Sci 1019:240–244 Khrapko K, Kraytsberg Y, de Grey AD et al. (2006) Does premature aging of the mtDNA mutator mouse prove that mtDNA mutations are involved in natural aging? Aging Cell 5(3):279–282 Kirkwood TB (2008) A systematic look at an old problem. Nature 451(7179):644–647 Lin CY, Gurlo T, Kayed R et al. (2007) Toxic human islet amyloid polypeptide (h-IAPP) oligomers are intracellular, and vaccination to induce anti-toxic oligomer antibodies does not prevent h- IAPP-induced beta-cell apoptosis in h-IAPP transgenic mice. Diabetes 56(5):1324–1332 Appendix A: SENS Foundation 825

Little WC, Zile MR, Kitzman DW et al. (2005) The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail 2005;11(3):191–195 Liu L, DiGirolamo CM, Navarro PA et al. (2004) Telomerase deficiency impairs differentiation of mesenchymal stem cells. Exp Cell Res 294(1):1–8 Masliah E, Rockenstein E, Adame A et al. (2005) Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease. Neuron 46(6):857–868 Mathieu J, Schloendorn J, Rittmann BE, Alvarez PJ (2008) Microbial degradation of 7-ketocholesterol. Biodegradation. 19(6):807–813 Mathieu JM, Schloendorn J, Rittmann BE, Alvarez PJ (2009) Medical bioremediation of age-related diseases. Microb Cell Fact 8:21 Mendelson K, Aikawa E, Mettler BA et al. (2007) Healing and remodeling of bioengineered pulmonary artery patches implanted in sheep. Cardiovasc Pathol 16(5):277–282 Nadon NL, Strong R, Miller RA et al. (2008) Design of aging intervention studies: the NIA interventions testing program. AGE 30(4):187–99 National Institute on Aging. Interventions Testing Program (ITP) (2008) Online at http://www.nia. nih.gov/ResearchInformation/ScientificResources/InterventionsTestingProgram.htm. Accessed 2008-05-21 O’Rourke MF (2007) Arterial aging: pathophysiological principles. Vasc Med 12(4):329–341 Passos JF, Saretzki G, von Zglinicki T (2007) DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res 35(22):7505–7513 Phoenix CR, de Grey AD (2007) A model of aging as accumulated damage matches observed mortality patterns and predicts the life-extending effects of prospective interventions. AGE 29(4):133–189 Rae M (2004). It’s never too late: calorie restriction is effective in older mammals. Rejuvenation Res 7(1):3–8 Rebo J, Causey K, Zealley B, Webb T, Hamalainen M, Cook B, Schloendorn J (2010) Whole- animal senescent cytotoxic T cell removal using antibodies linked to magnetic nanoparticles. Rejuvenation Res 13(2–3):298–300 Rittman BE, Kemmish K, Schloendorn J, Jiang L (2008) Cleaning out the junk with medical bioremediation. Understanding Aging: Biomedical and Bioengineering Approaches. Conference Program and Abstract Book:12 Rittmann BE, Schloendorn J (2007) Engineering away lysosomal junk: medical bioremediation. Rejuvenation Res 10(3):359–365.33 Sarin KY, Cheung P, Gilison D et al. (2005) Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 436(7053):1048–1052 SENS Foundation (2010) Scientific Publications. Online at http://www.sens.org/publications. Accessed online 10-06-14 SENS Foundation Website: http://www.sens.org Smigrodzki RM, Khan SM (2005) Mitochondrial microheteroplasmy and a theory of aging and age-related disease. Rejuvenation Res 8(3):172–198 Solomon B (2008) Immunological approaches for amyloid-beta clearance toward treatment for Alzheimer’s disease. Rejuvenation Res 11(2):349–357 Tanskanen M, Peuralinna T, Polvikoski T et al. (2008) Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med 40(3):232–239 Thohan V, Koerner MM, Pratt CM, Torre G (2006) Structural, hemodynamic and clinical improvements among patients with advanced heart failure treated with Alagebrium (a novel oral advanced glycation end-product crosslink breaker). J Heart Lung Transplant 25(2 Suppl 1):151 Zavan B, Vindigni V, Lepidi S et al. (2008) Neoarteries grown in vivo using a tissue-engineered hyaluronan-based scaffold. FASEB J 22(8):2853–2861 Zieman SJ, Melenovsky V, Clattenburg L et al. (2007) Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension. J Hypertens 25(3):577–583 Appendix B The Manhattan Beach Project

David Kekich

B.1 Introduction: The Problem(s) and the Need

Traditional venture capital funding for companies focused on life extension technologies has generally been difficult to acquire. Such technologies are perceived as being too risky, having exit horizons that are too far into the future, and even lacking credibility. The Maximum Life Foundation (MaxLife), a 501(c)3 corporation, was formed in 1999 to address this problem. It currently raises funds as a not-for-profit corporation to support both basic and applied research. The Foundation may support some of the MaxLife Capital projects described in this chapter as well as new projects that it will review over time. The Foundation has only raised a few hundred thou- sand dollars to date, and has invested most of it in promising stem cell technologies. Smaller amounts have gone to support kindred organizations as well as three scientific conferences. Aggressive fund raising campaigns will start in the last quarter of 2010, and the author welcomes suggestions as to how to make them more fruitful. You can find more information at www.MaxLife.org. MaxLife strongly believes in the promise of anti-aging therapeutics and has cre- ated a unique funding mechanism tailored to the development of such treatments on the one hand and to the exceptional reward of investors on the other. Because of this it is believed that the MaxLife approach may be a particularly attractive way for ideas such as those described in this book to be converted into anti-aging treatments. Historically, significant financing for biomedical technologies in the U.S. has come from government-related and other private non-profit sources. Over time, the changing political economy has led to a shortfall of these traditional funding sources.2 This is especially true for life extension technologies targeted at maximizing longevity while maintaining a high quality of living.

D. Kekich (B) Maximum Life Foundation, Huntington Beach, CA 92648, USA e-mail: [email protected] 2This is not a world-wide trend. The governments of Australia, China, Singapore and Taiwan, for example, have launched expansive programs of aggressive government-based financial and infrastructure support to capitalize on the financing difficulties occurring in the U.S.

827 828 D. Kekich

For a while, private equity venture capital fund managers perceived this trend as an opportunity for venture capital placements. Some prominent successes have been achieved. However, this biomedical sector generally could not keep pace with the high returns obtained in ever decreasing time periods in other non-regulated (or less regulated) technology sectors. Most venture funds have become increasingly impatient to harvest returns from their investments, many expecting an “exit” within only 2–4 years. This trend has been adverse for many biomedical technologies, since they generally have a much longer gestation cycle than communications, electronics or information technologies. In addition, technologies requiring regulatory approvals further increase development costs and lengthen the investment cycle. Since most biotech investments will require FDA approval, compliance is a hurdle that must be overcome before most of the developments will reach the US and most other markets. Other forms of non-currency financial underpinnings have also begun to dry up for the biomedical sector. The 1990s were marked by a rapid expansion of technology incubators (both public and private) that provided infrastructure and mentoring to technologists. Many of these incubators evolved into real estate projects, whereby a building or business park is developed to be inhabited by promising technology companies. Too frequently, the incubator primarily became simply a vehicle for cheap subsidized rent for entrepreneurial ventures without sufficient process or controls to direct successful outcomes. And, many incubators found it was very difficult to fill their projects with clients, or to evict those clients that weren’t making progress. The incubator managers have been under continuous economic pressure to fill space in their project buildings, and consequently many end up lowering selection criteria to increase occupancy. As a result, incubator outcomes generally have failed to produce many successful enterprises. Because of the preceding events, a clear picture of needs has begun to develop:

• Provision of long-term “patient” capital to commercialize promising biomedical technologies over time frames of up to ten years or longer • Supplemental backing in terms of a developmental infrastructure provided by premium services providers and managerial oversight • Reasonable assurance of good ﬁnancial returns to investors

I outline here strategies developed by MaxLife that can in principle overcome these and most other barriers to raising the necessary capital. One particular strategy has the advantages of combining the beneﬁts of capital preservation, liquidity, annual dividends and attractive venture capital returns. In fact, this strategy, known as LIVESTM, may actually be able to give investors a higher than average return on investment with lower than average risk compared to traditional investment mechanisms. LIVESTM, as well as a more traditional funding approach, could provide the capital required to fund much of the research described in this book. These funding strategies are designed to maximize health and longevity in minimum time ... and maximize investment returns while minimizing risk. It Appendix B: The Manhattan Beach Project 829 is MaxLife’s intent to generate signiﬁcant funds from current associates and to be in the position to fund some of the more important emerging life extension technologies.

B.1.1 Visualizing the Need for Investment in Life Extension

An exercise that is useful in bringing home the need for investing now in life extension technologies begins with constructing a diagram that represents the length of the investor’s life. In Fig. B.1, each square represents one month, and each row represents two years for a total of 80 years. Ten years ago, the author drew this chart for himself on his 55th birthday. You’ll notice some of the squares are ﬁlled in, and some are empty. The gray squares represented the months I already lived. Actuarial tables tell us men 55 years of age can expect to live to about 80 years of age (statistically, half die before the age of 80 and half after). The empty squares therefore represented the number of months I could have expected to have left. Based on this diagram, I noticed a serious problem: I had already used up most of my years...and the most healthy, vibrant and productive ones at that! So after some thought, I came up with the solution shown in Fig. B.2: I needed to add more squares!

And that’s how Maximum Life Foundation was born. This idea is at the heart of the strategy: “Live long enough to live as long as you want.”

Fig. B.1 Diagram of a typical human life today. Each row equals 24 months, each ﬁlled box is a year already lived, and each white box is a year of remaining life 830 D. Kekich

Fig. B.2 Diagram of a modiﬁed human life Appendix B: The Manhattan Beach Project 831

MaxLife intends on fast tracking key research and making the beneﬁts available to most people alive today.

B.1.2 The New Timescale for Progress in Biology

MaxLife intends to achieve extreme life extension in the intermediate future. What could justify such an aim, especially in light of the fact that we haven’t even been able to cure cancer after spending hundreds of billions over several decades? In the modern era, our knowledge has been advancing by quantum leaps compared to most of human history. For instance, scientiﬁc knowledge doubled from the year 1 to 1500 A.D. But by 1967, it doubled ﬁve more times ...and each time, faster than before. Now it doubles in less than 5 years. Supercomputers, like the kind now being used in bioinformatics, are part of the reason. These computers can do some experiments in 15 seconds that used to take years. Also, for example, newly developed research tools, gene chips, can do some tissue studies in hours –orevenminutes – that used to take years of animal studies (or that couldn’t be done at all). Ray Kurzweil made perhaps the most profound observation (Kurzweil 2005). He observed that the rate of change itself is accelerating. This means the past is no longer a reliable guide to the future. The 20th century was not 100 years of progress at today’s rate but, rather, was equivalent to about 20 years at the rate of change in the year 2000 because we’ve been speeding up to current rates of change. And we’ll make another 20 years of progress at that rate, equivalent to that of the entire 20th century, by 2014. Then we’ll do it again in just 7 years, and so on. Because of this exponential growth, the 21st century should equal 20,000 years of progress at year 2000s rate of progress (Kurzweil 2005) – 1,000 times greater than what we witnessed in the 20th century, an amazingly progressive century in itself. These are some of the reasons why we foresee dramatic interventions in the aging process in the next ten to twenty years. We’re making progress faster, better and cheaper, and at a continually accelerating rate (Kurzweil and Grossman 2010). But why not make progress faster still? To further accelerate progress, MaxLife has positioned itself directly in the path of this major trend.

B.1.3 Aging Intervention as a Major Emerging Growth Industry

The human life-extension segment of the life sciences industry, commonly known as “Anti-Aging Medicine”, is still in its infancy, but some think it will grow to become a trillion-dollar industry (Pilzer 2002), and it offers proﬁt opportunities today. As stated above, the current venture capital community is not designed to take advantage of many of the most promising opportunities in this area. 832 D. Kekich

The largest segment of the US population, the Baby Boomer generation, is enter- ing the anti-aging marketplace right now. Baby Boomers are already interested in longer quality of life, looking and feeling younger, enjoying a longer period of sexual health, tissue regeneration, memory enhancement, curing the very diseases they will face shortly, extending the healthy human life span, and so on. Tomorrow’s pursuits are more ambitious. Sights are set on maximum intervention of the aging process – reversing the biological effects of aging. Throughout the last half of the 20th century, the international medical community invested heavily in interventions that treat aging-related diseases and conditions. As a result, signiﬁcant advancements designed to delay the onset of aging-dependent health challenges are emerging, and research is proceeding that may gradually lead to the prevention or cure of most age-dependent chronic diseases.

B.2 A Brief History of MaxLife Activities

Over the past ten years, MaxLife has sponsored four life extension scientific conferences. About a dozen world-class research scientists attended each working weekend. The first two were brainstorm sessions to better understand how to intervene in the aging process. The objective was to develop a cross disciplinary approach which by the year 2030 would dramatically intervene in human aging, and allow us to repair much of the damage done by the aging process – and to identify specific market opportunities for such technologies in the interim. The results of these dialogs were spectacular, and somewhat surprising. The meetings brought to light several interesting things, including:

• How to get around two of the biggest obstacles of turning good science into marketable products. • Most of the best independent and university researchers in this ﬁeld spend valu- able time teaching, writing grant proposals and performing administrative duties rather than thinking creatively and doing research. Funding will enable them to maximize their talents and productivity.

We also concluded, in June of 2000, that the upcoming convergence among biotechnology, information technology and nanotechnology will change the world as we know it. This conclusion later received validation by the National Science Foundation’s 450-page report titled, Converging Technologies for Improving Human Performance (Roco and Bainbridge 2002). The likely imminence of such a convergence has further impelled us to fast-track the MaxLife mission.

B.2.1 The Manhattan Beach Project

Two years after the author’s “squares exercise,” MaxLife launched the “Manhattan Beach Project”. This focused and targeted all-out assault on the human aging Appendix B: The Manhattan Beach Project 833 process was spawned during MaxLife’s first international scientific conference on June 24th and 25th, 2000 in Manhattan Beach, California. The plan is to assemble some of the world’s leading anti-aging researchers in a focused effort, with definite deadlines and ambitious goals, much like the “Manhattan Project” that ended World War II. Unlike its namesake, the Manhattan “Beach” Project’s goal is life building rather than life threatening. Another difference is that the Manhattan Beach Project will be a commercial enterprise driven by the private sector. It marries a scientific roadmap developed by our non-profit foundation to intervene in the human aging process with a for-profit enterprise, called MaxLife Capital. MaxLife Capital has developed a traditional funding strategy as well as LIVESTM, an optional, reduced-risk, financial model to fund the research and development. It will carry out these goals by funding and developing technologies having growth or value creation potential in the fields of anti-aging, medical nanotechnology, and artificial intelligence. The Project’s core team includes many of the world’s leading doctors and scientists in the fields of genetics, genomics, stem cell biology, gerontology, nanotechnology and artificial intelligence. In addition to these leading scientists, MaxLife’s Advisory Boards also include top business, marketing and finance minds. Starting with the inaugural scientific conference, MaxLife’s scientific advisors and others formulated a scientific roadmap to control and reverse the aging process. Now that the science is being tackled by some of the world’s leading scientists, the author decided to concentrate not on the scientific mysteries related to aging, but on the problem of overcoming the financial roadblocks standing in the way of funding the research. Since investors typically want safety and a healthy return, the primary focus was to establish a funding strategy that elimi- nates the reasons investors don’t invest in an area that is perceived as risky and uncertain. FDA approval is one such issue. MaxLife plans on helping take companies through Phase I or even possibly Phase II where necessary. Some technologies may be developed and tested under FDA guidelines, but preferably in countries where they may be commercialized with fewer regulatory hurdles. And finally, some technologies may be developed into nutraceuticals that need little or no regulatory approval in the United States. The author also wanted to make it possible for investors to be among the first to enjoy the health benefits the funding might provide. Our plans for accomplishing these goals are outlined below and will be found also in more detail and in continually updated form at www.manhattanbeachproject.com and www.maxlife.org/mbp.pdf.

B.3 Speciﬁcs of the Manhattan Beach Project

Most of the Project’s resources will be dedicated to developing speciﬁc technologies in the ﬁelds of Molecular Biology; Stem Cell Therapy; Organ and Tissue 834 D. Kekich

Regeneration; Whole Genome Reengineering3; Gene Therapy; Nutraceuticals; Pharmaceuticals; and Therapeutic and Diagnostic Devices. Some of the focus will be in the field of nanotechnology, broken down into various types of devices and therapies, including nanorobots (cell-sized robots with molecular sized components) acting as artificial blood cells, repairing DNA, providing energy to cells, and interfacing with extracellular devices. In addition, MaxLife intends to support companies that are striving to create human-level artificial general intelligence (AGI), which it believes can be harnessed to accelerate anti-aging research at all levels. Table B.1 outlines potential general technologies MaxLife plans to help develop and when they might become available to benefit investors, principals, and members of the general public. Although the major technologies are projected to mature beyond typical venture capital time horizons, the reader will see that some profitable interventions may be possible in the near future. Projections are hypothetical and are best-case estimates of when the author believes they could be developed once they are fully funded.

Table B.1 Gant chart for the development of exemplary milestones

Years from initiation of funding

Longevity technology 1 2 3 4 5 6 7 8 9 10 12 15 20 25

Reprogram IP Biochemistry1 Nutraceuticals2 IP Genetics3 IP Genome IP Reengineering4 Escape Velocity5 IP Nanomedicine6 IP

1 Supplementation Activity Lifestyle Anti-aging medicine Diet Stress reduction. See report at http://maxlife.org/salads.pdf for key present strategies for human lifespan extension. 2 New effective products are available now and others will be introduced in 2010–2011 3Oral supplements and diagnostic tools based on current genetic research will be available to the general public and clinics by 2011. 4Early versions of technology may be clinically proven by 2015 and available by 2020. 5“Escape Velocity” means to add 1 year for every additional year lived – best case scenario. 6Nanomedicine refers to aging reversal – best case scenario. I: When technologies may be available to investors, researchers, management, large donors. P: When technologies may be available to the general public.

3“Whole Genome Reengineering” refers to the process of gradually reconstructing genomes so they can be reengineered and become easier to reengineer over time. Viruses, e.g. CMV, HSV, HIV, do this over time, in that in various ways they corrupt the human genome. Scientists now argue that we can now take control of the process. Appendix B: The Manhattan Beach Project 835

Table B.2 Hypothetical project areas for investment by MaxLife and projected investment requirements for each project area

Industry Business Annual investment

Geneticsa Pharmaceutical/Nutraceutical $7,000,000 Molecular Biology Genome Reengineeringb $5,000,000 Nanotechnology Nanomedicinec $2,000,000 IT Artificial General Intelligenced $4,000,000 Regenerative Medicine Stem Cell Technologies $3,500,000 Genomicse Pharmaceutical/Nutraceutical $1,000,000 Various SENSf $8,000,000 Misc. $6,000,000 Annual Budget Years 1–3 $36,500,000 Total 1st Year $36,500,000 a “Genetics” includes modulation of gene expression. b “Genome Reengineering” includes key gene therapies related to aging mitigation. c “Nanomedicine” includes short-term projects that build toward the kind of capabilities indicated in Chapter 23 (by Freitas) but produce useful and profitable results in the short run. d The investment in “artificial general intelligence” is based on unique ongoing research known to MaxLife. e “Genomics” refers to gene chip studies targeted to the testing and production of useful new age-mitigating agents. f “SENS” refers to strategically targeted areas of de Grey’s “strategies for engineered negligible senescence.”

Funding will be allocated among at least five synergistic industries and seven business categories. In addition, opportunities within Dr. de Gray’s SENS project (de Grey and Rae 2007) and other industries and businesses falling in or outside these groups may be identified during the life of the Manhattan Beach Project. Table B.2 breaks down the presently-targeted average annual budget for the first three years. It covers key life extension technologies. MaxLife is investigating other promising technologies as well. The budget indicated is our targeted budget and is presented for purposes of illustration. It can be ramped up to accelerate progress beyond projections or scaled back in at least some disciplines with minimal delay in projections. Beyond year 3, a substantial increase in the genome reengineering and nanomedicine budgets is anticipated. Milestones have been worked out for many viable technologies, and more technologies will be investigated as they are incorporated into the Maxlife strategic planning process. One hypothetical overall scenario illustrating our objectives is shown in Fig. B.3.

B.3.1 Initial Vision

One key to our ambitious undertaking is to achieve at least one breakthrough that will make the world take notice. One goal is to rejuvenate lab animals (turning old mice into biologically “young” mice) while growing proﬁtable companies in the process. This goal is illustrated by Dr. Aubrey de Grey’s development of SENS, a 836 D. Kekich

Fig. B.3 According to statistics, a 75 year old has a 50% chance of dying within 10 years (about half the 75 year olds will die before age 85 and half after; 65 year olds can expect to die by age 81 without intervention). However, if the Manhattan Beach Project is successful, humans might potentially enjoy a series of life-extension breakthroughs leading ultimately to an open-ended and youthful future. MaxLife believes technologies developed prior to 2029 could add approximately 17 years to the subject’s life seven-pronged plan to accomplish rejuvenation based on already accepted scientific disciplines (de Grey and Rae 2007). Dr. de Grey has proposed that seven fundamental kinds of damage account for aging (generating such side effects as heart disease, arthritis, diabetes, cancer, etc.). MaxLife believes some of the SENS allied technologies could eventually lead to practical solutions for many of them. MaxLife may develop one or more equivalent proofs of concept. Once rejuvenation is proven in animals, the investing public should catch the vision and grasp the investment opportunities. Then all the necessary money could become available to fine tune intervention in human aging. MaxLife plans on being one of the catalysts to that next step. MaxLife will consider funding private companies, as well as limited basic research, in some of these seven disciplines. It plans on developing other technologies as well, including select nanotechnology and artificial intelligence projects, in addition to shorter term projects such as promising nutraceuticals, cosmeceuticals and diagnostics, some of which are aptly described in this book. MaxLife believes average human age can be extended by a few healthy decades in the intermediate future. In fact, MaxLife also has good reason to believe the Manhattan Beach Project might be able to see more than one year added to nearly everyone’s expected lifespan every calendar year in about fifteen years. This may greatly improve the reader’s odds of surviving long enough to take advantage of Appendix B: The Manhattan Beach Project 837 more extreme technologies. Further advances will then be made that could ratchet up the human lifespan dramatically. MaxLife’s Manhattan Beach Project spells out how a concerted effort over the next 19 years might result in full age-reversal capability for as little as $1.9 billion in addition to the $1 billion SENS project.

B.3.2 The LIVESTM Funding Mechanism

The strategy called “LIVESTM” was designed to give investors a higher than average return on investment with lower than average risk. The strategy will ﬁnance the research needed to proﬁtably develop life extending technologies. The LIVESTM acronym stands for:

1. Liquidity. Invested funds or “deposits” are redeemable, much like a bank CD. 2. Income. Depositors earn projected annual dividends. 3. Venture capital returns. Depositors earn an above average projected annual internal rate of return (IRR) over the 10 year life of the fund plus residuals from the 11th to 17th years or beyond. 4. Equity. Depositors get positions in potentially some of the world’s bigger and more proﬁtable companies. The projected returns do not reﬂect this potentiality. 5. Safety. Efforts will be made to insure deposits are never exposed to more than a 10% drawdown.

In the LIVESTM plan, a low-risk Renewal Account is set up to generate both immediate returns for investors and funding for the sponsored research entities through a separate Accelerator Fund without relying on investments to mature. Over the past 40 years, institutional venture capital has developed an effective model for due diligence, oversight, governance and investment liquidation that can be applied to successfully manage an Accelerator Fund. Through this mechanism, investors in MaxLife Capital can expect to achieve ﬁnancial returns approximately equal to venture capital rates of return. The management goals are to give depositors liquidity, safety, annual dividends equal to certiﬁcates of deposit plus potential venture capital returns. LIVESTM improves upon the traditional venture fund application in seven fundamental ways:

1. Instead of investing or donating, Partners make refundable deposits. 2. While reducing market risk, MaxLife’s institutional portfolio management team generates cash ﬂow from the deposited funds to pay Partners annual dividends and to fund portfolio companies. 3. This model helps build in insurance against losing money in today’s rapidly changing markets and technologies and is designed to put a ﬂoor under potential losses. 838 D. Kekich

4. The targeted return plus residuals is based on refundable deposits, not on invested cash and includes dividends as well as carried interest. 5. After the ﬁrst two years, deposits may be withdrawn with a 90 day notice. 6. The project has a ten-year term, with regular distributions, and with provisions for extensions. 7. If Partners are health care, biotech or technology companies, the Fund may joint venture with them by matching the portfolio companies with their strategic initiatives to add an immediate impact to their earnings and/or business plans.

These relationships should also accelerate the acceptance of the portfolio companies in the marketplace.

B.3.3 Supporting both Investor Needs and the MaxLife Companies

We have structured the MaxLife Capital Fund such that investments into various technologies could become profitable enough after the ninth year or sooner to self- fund two major technologies which we feel are needed to reverse aging, Genome Reengineering and Nanomedicine. The Fund will provide intensive hands-on participation with portfolio technologies and companies. This involves a structured role in portfolio selection, development of intellectual properties, organizational and personnel development, financial oversight and product and service commercialization. It also involves continuous participation of specialty professional service providers that work with the portfolio companies throughout their life cycle. In essence, it frees the innovators up to focus on the science while business and investment professionals manage the companies. MaxLife will manage its funds through a Fund Management team comprised of Managing Directors with approximately 100 person-years of venture capital experience in “finding and minding” successful opportunities that achieve prominence in their marketplaces, as well as healthy financial returns to investors. It will also associate with Consortium Innovation Centers (CIC) in Southern California, which has been derived from two of the pre-eminent technology accel- erators in the U.S. CIC has contracted with premium service providers such as Price-Waterhouse Coopers, Marsh & McLennan, Blaine Group, and Staubach Realty Advisors, etc. to mitigate problems before capital is invested. MaxLife has established an investment strategy with supporting tactics that emphasizes the following criteria:

• Industry emphasis will incorporate a focus on proprietary technologies that have potential for meeting optimum life extension objectives. • A tech-transfer emphasis, leveraging the Manager’s global network to identify the best qualifying opportunities, and then, if it is advantageous, to relocate their central operations to appropriate sites Appendix B: The Manhattan Beach Project 839

• A preference for companies that can rationally demonstrate the existence of a model of or a working proof-of-concept product(s) or process(es) that guide their R&D and/or commercialization • Preliminary screening and on-going grooming of investment opportunities by referral to CIC’s Success FormulasR process. This augments each opportunity with a virtual team of prominent management expertise by its pro bono spon- sors in the areas of Big-4 accounting, legal services and governance, executive recruitment, risk management, etc. • Initial individual investments ranging from $1.5 to $10 million with co- investment objectives to provide up to an additional $10 million in capital availability (some of which will be derived from members of CIC’s Capitalist Club) • Provision for follow-on investing for up to 8 years, provided predetermined progress benchmarks are achieved • A requirement that all investees have, or will establish, an administrative head- quarters located in the U.S. within 2 hours commuting time of a Fund (or afﬁliate) ofﬁce.

B.3.4 Summary: Advantages of the MaxLife Approach

Although a number of venture capital funds invest in companies that have products to treat diseases of aging, it is believed MaxLife Capital plans the only Fund that exclusively focuses on life extension. Also, LIVESTM may be the only funding mechanism capable of long-term exit strategy horizons of 7, 10 or more years, while still delivering an annual return to the investors. Although this funding strategy is in an early stage, MaxLife is currently in discussions with several funding sources and hopes to secure a partnership or partnerships in a reasonable amount of time. The advantageous features of the MaxLife approach are summarized in Table B.3.

Table B.3 The MaxLife value proposition √ √ Unique Niche √ Optional Refundable Deposits Instead of Investments or Donations TM √ Annual Dividend on Deposits with LIVES √ Numerous Funding Opportunities √ Socially and Personally Desirable Outcomes √ Societal Need √ Huge Markets √ Committed Management √ Strong Potential for Large Return with Managed Risk Synergistic advantages of fund focus and cross-pollination of portfolio companies as a √ result of shared technical, market and scientiﬁc data With LIVESTM, the only private venture funding structure capable of long term, 7+ year exit horizons 840 D. Kekich

B.4 Parting Thoughts

The Manhattan Beach Project, as envisioned by MaxLife Capital, offers an alternative to many popular investments that may be ruining our health and shortening our lives. Examples are popular investments in such areas as fast foods, processed foods, alcoholic and soft drinks and tobacco. MaxLife Capital encourages investors to com- mit a portion of their portfolios to investments that cure diseases, promote wellness and extend healthy life, anywhere in the world and with any viable investment group or with any emerging company. Over time, we expect to see more and more opportunities for both institutional and private investors. Not only would adding more healthy years to people’s lives be a positive and humanitarian thing to do, it could also represent one of the more important business and investment opportunities of all time. Consider. If you extended your healthy lifespan by just 15 years, your net worth would quadruple if it compounded at 10% per year. Consider. The human death toll in the Year 2001 from all 227 nations on Earth was nearly 55 million people. 52 million of these were “natural” deaths, and 37 million were aging related. As identified by Robert Freitas, each one of us carries within us a unique and complex universe of knowledge, life experience, and human relationships. Almost all this rich treasury of information is forever lost when we die. If the vast content of each person’s life can be summarized in just one book, then every year, natural death robs us of 52 million books, worldwide. So each year, we allow a destruction of knowledge equivalent to three Libraries of Congress. Consider. Natural death also destroys wealth on a grand scale, an average value of about $2 million for each human life lost in developed countries, or an economic loss of about $104 trillion if that value were assigned to every life – every year. That equals the tangible net worth of the entire world. Consider. If we can speed up developing dramatic life extending technologies by just a few years, we could ultimately save more lives than were lost in every war since the beginning of recorded history. Consider. We can do this. And better yet, we can do it with moderate financial risk and with potentially massive financial rewards. Can you think of a nobler legacy? Our life spans depend mostly on how soon real anti-aging medicine is developed and commercialized. Supporting this research could be our surest path to extreme health and longevity. Every life form fights for survival. That’s how each evolved. Therefore .... The Purpose of Life is, and always has been.... To Delay and Avoid Death.

References de Grey A, Rae M (2007) Ending Aging: The Rejuvenation Breakthroughs that Could Reverse Human Aging in Our Lifetime. St. Martin’s Press, New York Kurzweil R (2005) The Singularity is Near. Penguin Group, New York Appendix B: The Manhattan Beach Project 841

Kurzweil R, Grossman T (2010) Bridges to Life. In: Fahy GM, West MD, Coles LS, Harris SB (eds) The Future of Aging: Pathways to Human Life Extension. Springer, Berlin, Heidelberg, New York, pp. 3–22, Dordrecht Pilzer PZ (2002) The New Wellness Revolution: How to Make a Fortune in the New Wellness Industry. John Wiley & Sons, New York Roco MC, Bainbridge WS (2002) Converging Technologies for Improving Human Performance. National Science Foundation, Arlington Index

A Age-associated diseases, 150, 589, 600 ABCA1, 279, 287 Age and CR responsiveness, 374–375 Accident, 7, 738, 780–782 Age-related fat gain, 170 Accumulated damage, 89–92, 130 AGEs (advanced glycation endproducts), 588, Accumulated mutation theory, 94–95 591–594, 596, 598–603, 605–606, Acetylcarnitine, 158, 180, 184–186, 190 821 Active neutralization, 719 aggregation, 348, 380, 393, 458, 548, 600, 660, Active regulator of SIRT1 (AROS), 766 334–335 Aging Active safety devices, 780 as a basic “ground rule” of life history Acute phase response, 298 “design”, 169 Adaptation, 96–97, 101, 103–106, 108–114, biological control of, 127–202 268, 357–358, 361, 364, 376 Adaptive immunity/adaptive immune inescapable, 97–98, 137, 172 (response, system), 95–96, 99, Aging program, 88–89, 93, 152, 812 103–105, 108–109, 145, 314, 322, Aging-related diseases, 574–575, 577–580, 338–339, 376–377, 395, 524–526, 832 675 Airbags, 781 Adaptive pleiotropy, 103–104 AKT-1, 627–628, 631, 634 Adaptive theories of aging, 104–114 Alagebrium (ALT-711), 3-(2-phenyl-2- Additive genetic variance, 97, 105 oxoethyl)-4, 5-dimethylthiazolium, Adducts, glycation, 597–599, 603, 606 607, 767–768, 821 Adenylate cyclase, 629, 763 Albumin, 320 Adipocytes, 6, 336, 504, 590, 677, 769 Alcor Foundation, 783 Adipose and the health effects of CR, 405–406 Aldehyde, 593 Administration of DHEA, 240 ALEs (advanced lipoxidation endproducts), beneﬁcial effects, 170–172, 240 588, 592, 599, 602–603, 605 Administration of melatonin, 247 Allogeneic use, 323 prolonged life span in rodents and, 247 Allotopic expression, 531, 670, 814, 819 Adrenal hyperplasia, 144 ALT-711 (alagebrium), 607, 767, 821 “Adrenal involution”, 170, 172, 174 Advanced glycation endproducts, 588, ALT (Alternative Lengthening of Telomeres), 591–594, 596, 598–603, 605–606, 459, 675, 677–678, 680, 820 821 Alteon Pharmaceuticals, 607 Advanced lipoxidation endproducts, 588, 592, Alternative Lengthening of Telomeres(ALT), 599, 602–603, 605 459, 675, 677–678, 680, 820 Aerobic, 7–8, 107, 172, 186, 262–264, 268, ALT pathway, 459, 470 270, 284–285, 350, 628 Altruistic death, 145 AGE-1, 100, 152, 624–628, 632–634 Alzheimer’s dementia, 589

843 844 Index

Alzheimer’s disease (AD), 12–13, 17, 32, enzymes, 149, 160–161, 169, 173, 177, 96, 117, 348, 396, 525–526, 529, 190, 299, 301 592, 601, 610, 759, 762, 766–767, Antisense oligonucleotides (ASOs), 335, 818–819 647–648 Amadoriase, 606–607 against Duchenne muscular dystrophy, 647 Amadori ene-dione, 594 against hepatitis, 647 Amadori product, 593, 606–607 against human immunodeficiency virus, Ambystoma mexicanum, 612 647 American Academy of Anti-Aging Medicine Antler fly, 94 (A4M), 25, 27–30 Aortic disease, 283 Ames dwarf mouse, 153–154 Aβ peptide, 349 Aminoguanidine, 603–604 Apheresis, 323, 325, 734, 738 Amish families, 168 apoC III, 150 AMP-activated protein kinase (AMPK), Apo E (Apolipoprotein E), 13, 301 158–159, 186, 349, 398, 400–403, Apolipoprotein B (apoB), 286, 648 411, 631–633 Apolipoprotein A-I (apoA-I), 300–301 Amphibians, 612 Apolipoprotein A-I mimetic peptide (D-4F), AMPK, 158–159, 186, 349, 398, 400–403, 293–300 411, 631–633 action of, 294–295 Amyloid, 600–601, 610 and atherosclerosis, 295–296 Amyloid-beta protein, 525–526 and brain arteriole inflammation, 297 Amyloidosis, extracellular, 600–601 and cardiovascular complications, 297–298 Amyotrophic lateral sclerosis (ALS), 348–349, and endothelial health, 296–297 385, 396, 476, 762 and influenza A infection, 298 Anabolic, 93, 169, 172, 174, 230, 243, 267, Phase 1 clinical trial, 300 390–391, 810 and vasodilation, 296–297 Anabolic enzymes, 93 and vessel wall thickness, 296–297 Anabolism, 91–92, 170, 174 Apolipoprotein J (apoJ), 292, 299 Anaerobic, 321 Apoptosis, 96, 105, 115–117, 158, 183, 313, Anatomical maintenance, 776 319, 332, 335–337, 339, 343–345, Anemia, pernicious, 509, 604–605 376, 380, 387–390, 392, 394, 397, Aneurysm, 283, 559 400, 404, 411, 443, 522, 524, 526, Angiogenic agents, 564 528, 579, 600, 718, 756, 763, 769, Annual plants, 106, 145 777 Ansell’s mole rats (Cryptomys anselli), 175 and anticancer effects of CR, 388–389 Antagonistic pleiotropy, 99, 103–104, 136, of cancer cells, 344 138, 463 Arginine, 80, 171, 319, 590, 594, 597–598 Anti-aging interventions, 26, 30, 810 Argument for infinity, 782 See also Pharmacological and nutritional Arithmetic, 573–581 interventions, in mammals AROS (active regulator of SIRT1), 334–335 Anti-angiogenic agents, 564–565 Arteries, 13, 258, 283, 297, 300, 564, 589, 597, Antibiotics, 18, 29, 320, 361, 575, 686, 607, 732–733, 735, 742, 751, 822 728–729 Arthritis, 117, 286, 411, 509, 588, 609, 836 Anticancer activity, potential, 343 Artificial DNA repair technologies, 199, Anticancer effects of CR in rodents, 378, 641–661 387–391, 411 Artificial heart, 746 Antigenic response, 613 Artificial Intelligence, 4, 16–18, 833, 836 Antigen-specific therapies, 322 Ascites, 310–312 Antimicrobial effectors, 319 Asparagine, 595 Antimisfolding agent, 759, 767 Aspartate, 396, 591, 595, 598 Antioxidants, 27, 161, 177, 236, 247–248, 253, Asphyxia, 738 339, 526, 604 Aspirin, 171, 285, 603–604, 740 defenses, 154, 169, 172–174, 525 Associative learning, 349 Index 845

Atherosclerosis, 16, 117, 155, 238, 240, 252, Biocomputer, 701, 722 282, 285, 287, 293–296, 298–301, Bioethics, 27, 32, 41, 66, 78–79, 82, 368 373, 453, 462, 476, 578, 598, 732, Bioﬁlm, 729 759, 771, 818 Biogenesis, mitochondrial, 158, 186, 336, and P-selectin, 285 348–351, 399–401, 525–526 and serum amyloid A (SAA), 285 Biological constraints, 574–575 and tumor necrosis factor alpha, 285 Biological evolution, 15, 103 and vascular cell adhesion molecule Biologically controlled aging (VCAM-1), 280, 285 in iteroparous organisms, 146–159 Atherosclerotic plaque, 732, 818 Biological robots, 688 Athymic mice, 314 Biological warranty period, 575 Atomic force microscope (AFM), 705, 753 Biology, 4, 14–16, 18–19, 22, 167, 307, 576, ATP, 152, 186, 285, 287, 289, 320–321, 336, 578–579, 599, 812, 823, 831, 399–400, 524–528, 531, 606–607, 833–835 626, 760, 768, 772 Biomarker, 149, 233, 249, 290, 733 Atrophy of organs Biomaterials, 546–548, 552, 559, 725, 766, reversed by growth hormone, 195–197 770, 783 Augmentation, 757, 775, 782 acellular matrices, 546 Autoimmunity, 240, 395, 509 alginate, 546–547, 561–562, 564 Autologous cells collagen, 544, 546–547, 552–556 cavernosal, 555 naturally derived, 546–547 chondrocyte, 547, 560–562 synthetic polymers, 546–548 endothelial, 555, 559, 564–565 Biorobotic, 722–723 muscle, 548, 553–556, 558–559, 563–564 Biotechnology (biotechnological) revolution, urothelial, 545, 554 4, 18–19 Automated aircraft, 781–782 Bladder Autophagy, 152, 161, 165, 178, 183, 186–187, engineered tissue, 546, 553, 564 190, 380–381, 391–393, 627, 753 gastrointestinal segments in repair of, 554 Autopsy, 65, 76, 266, 382, 600 replacement in dogs, 554 Autoxidation, 603–604 replacement in humans, 561 Avon Products, Inc, 609 subtotal cystectomy, 554 Axolotl, 612 urinary, 597 B Blastocyst, 64, 67–71, 76–77, 452, 466, 469, Bacteria, live, anticancer effect of, 320–321 472, 548, 551, 556 Bakers yeast, 370, 623 Blastomere, 70 Balance and motor coordination Blindness, 14, 474, 534, 735, 771 improved, 350 Blood-brain barrier (BBB), 767, 771, 778 BALB/c mice, 311, 343, 504 Blood vessel, 70, 144, 239, 282–283, 296, Banking, 68, 325, 475 558–559, 589, 611, 688, 732, Base excision repair (BER), 181–183, 186, 740–743, 747, 749, 751, 755, 768 337, 653, 752 replacement with autologous graft, 553 Basophil, 322–323 replacement with synthetics, 556 Bats, 93, 236 B lymphocytes, 309, 579 Bax, 335, 348 Body mass index (BMI), 269–270, 293, Benfotiamine, 603, 605 372–374, 387, 406–408 Benzoic acid, 603–604 and all-cause mortality, 263, 269, 406–407 Beta-amyloid accumulation and smokers, 269 and deprenyl, 160 Boiling food, 602 Beta amyloid plaques, 592, 601, 610, 766 Bone Beta galactosidase, 464, 652 marrow, 68, 296, 323, 337, 395, 404, 469, Bifunctional oligonucleotides, 659–660 476, 494, 506, 510–511, 545, 559, Bim, 338 561, 579–580, 679, 766, 771 Biocompatibility, 546, 689, 717–718, 782 stem cells, 510, 559, 611, 766 846 Index

Bowhead whale, 137, 173, 199 lung, 335, 343 Brain state map, 778 prostate, 343 Brain-state monitoring, 779 resistance/resistant, 188, 311–312, Bridge one (life extension), 4–14 314–317 Bridge two (biotechnology/biotechnological -specific antigens, 322 revolution), 15–16 surveillance, 163, 173, 309–310, 314, 316, Bridge three [nanotechnology-AI (Artificial 318, 322, 324 Intelligence) revolution], 16–18 WILT and, 667–683 Broiling food, 602 Cancer-killing activity (CKA), 316 Brown adipose tissue, 334, 338–339 Carbon placement, 708–709, 715 Bush rat (Rattus fuscipes), 144 Carbonyl, 375, 594, 604 Butterflies, 153 Carboxyethyllysine, 594 Carboxymethyllysine, 591 C Cardiac computed tomography (CT), 195, 247, Caenorhabditis elegans, 4, 95, 100, 105, 285 107, 129–132, 138, 147–152, 154, Cardiomyocytes, 337, 348, 394, 559–560 165–167, 170, 175, 369, 380, Cardiomyopathies, 265, 337, 378, 394, 527, 383–385, 393, 398, 401, 403, 535, 589, 762 623–628, 630–633 Cardiovascular aging, 279–302 Caloric density, 6, 375 of heart, 282–285, 298 Caloric energy, 102 of vasculature, 284 Caloric restriction (CR), 4, 7, 16, 26, 88, 99, Cardiovascular disease (CVD), 7–8, 12–13, 102, 107, 115, 117–118, 261–262, 31–32, 117, 150, 166–167, 240, 334, 369, 374–375 252, 254, 264–265, 269, 281, 284, age of onset and, 138–139 349, 369, 371, 373, 394, 399, cardiovascular effects, 373, 394–395 406–408, 577, 668–669, 676 duration and lifespan, 411 Cardiovascular disease (CVD) risk, 283–284 effect, evolutionary origin of, 383 factors, novel, 285 exercise and, 404–405 genic effects of, 397 factors, traditional, 283–284 in animals, 7 diabetes, 282 in humans, 5–7, 371–374 modification, 284–285 hypothermia and, 403–404 saturated fat diet, 283–284 immunological effects of, 395 smoking, 284 intensity and lifespan, 375 Cardiovascular effects of CR, 373, 394–395 mimetics, 7, 115, 117–118, 159 Carnitines, total neurological effects of, 396–397 decline with age in brain and muscle, 186, physiological “memory” of, 377 190 reproductive effects of Carnosine, 603, 605 humans, 387 Carotenoids, 253, 603–604 rodents, 385 Carotid artery stenosis, 283 Calorie blockers, 6–7 Carrel, Alexis, 454 Calories Cartilage, 199, 244, 548, 560–562, 589, 591, dietary intake of, 262 598–600, 611, 769 food, definition of, 251 articular cartilage, 560–561, 591, 599, 611 and pounds of extra body fat, 269 chondrocytes, 561–562 and weight loss, 6 fetal tissue engineering, 545 Camouflage, 718–719 regeneration of, in humans, 199 Cancer trachea, 560–561 breast, 337, 343 Cartotaxis, 743 cells, 335, 343–344 Cassette transporter A1 (ABCA1), 279, 287 immunological killing of, 160 Castration killing by neutrophils (granulocytes), 313, and lifespan in humans, 144, 166–167, 176 317, 320–321 and lifespan in outbred male cats, 166 Index 847

and lifespan in salmon, 144 Charges, 319–321, 594 and likelihood of death by infection, 166 Charlesworth, B., 358, 508 Catalase, 92, 247 Chelating, 603 Cataracts, 137, 350, 462, 588–589, 735 Chemical inhibition, 719 β-Catenin, 336, 631 Chemical vapor deposition (CVD), 705–706, Cation peptides, and recognition of cancer 718 cells and bacteria, 319–320 Chemo-attractant/attractive, 312 CD28, 503, 579–580 Chemotactic sensor pad, 721, 743 CD28 antigen, 579 Chemotaxis, 292, 312, 319 CD4+ cells, 579 Childhood, 133, 172, 575, 578 CD4:CD8 ratio, 503 Chimeraplasty, 642, 643, 650–655, 657 CD8+ cells, 512, 579 Chimeric RNA/DNA oligonucleotides, 650, CDK1-cyclin B, 337 654, 656 Cell(s) Chloride, 252–253 cycle, 70, 335, 338, 402, 454–456, 461, Cholesterol 471, 576, 621, 629, 634, 645, 654, HDL, 255, 257–258, 279, 287, 381 674, 757 LDL, 240, 255, 257–258, 270, 279, checkpoint activation, 576 283–284, 373, 381 disassembly, 733 Cholesterol ester transfer protein (CETP), 150, herding, 733, 770 279, 287, 292 mill, 734, 742, 744, 746, 760, 770, Choline 772–773, 778 and brain structure, 199 morphology, 734 and centrophenoxine, 161, 199 nanosurgery, 753–755 and DMAE, 161 repair, 642, 687, 700, 731, 736, 751–753, Chondrocytes, 453, 547, 560–562, 590–591, 755, 757–761, 763, 772 598, 611, 677, 759 replication, 577, 773 Chromallocyte, 727, 755–757, 759–760, 763, survival, 297, 332, 335, 400, 680 771, 773 turnover, 381, 528, 752 Chromium picolinate, 159, 243 viability, 357, 754 Chromosomal linkage, 314 Cellular injection therapy Chromosome deletions bulking agents, 561–563 and increased human lifespan, 167–168 with chondrocytes, 561 Chromosome replacement therapy (CRT), 731, with hepatocytes, 560 755, 766, 774 for incontinence, 561–563 Chronic inflammatory response, 284 with muscle cells, 563 Chronological aging, 231, 628 for vesicoureteral reflux, 561–562 Cicada, 133 Cellular rejuvenation, 775–776 Cigarette smoking, 284, 298, 315, 348, 577 Cellular reprogramming Circulation, 9, 70, 294, 301, 316, 321–323, human fibroblasts, 550–551 325, 444–445, 559, 579, 589, 597, induced pluripotent state, 80–82, 548, 551 602, 679, 724, 730, 737 mouse embryonic fibroblasts, 548, 551 “Classical HDACs”, 332 retroviral integration, 552 Clinical trials, 28, 117, 300, 302, 321, 475, Cellular senescence, 96, 105, 154, 442, 474 562, 565, 580, 604, 607–608, 610, See also Replicative senescence 648, 677, 702, 768, 821 CEL (N-epsilon-carboxyethyllysine), 594–595, CLK-1, 95 602 Clonal deletion, 509, 719 Centenarians, 5, 150, 228, 300, 315, 369, 372, Cloning 464, 766, 819 nuclear, 549 See also Supercentenarians reproductive, 549 Centrophenoxine, 161, 177–180, 189–190 therapeutic, 544–545, 549–550, 556–558 CETP, 150, 279, 287, 292 See also Somatic cell nuclear transfer Charge-neutral, 320 Clottocyte, 735, 740–741, 743, 782 848 Index

CML (N-epsilon-carboxymethyllysine), 591, inhibitor, 442–443, 445 594–595, 599, 602 Cysteine, 165, 319, 594, 603, 605, 768 Cochlear hair cells Cystic fibrosis, engineered correction of, 645 regenerated by activating Atoh-1, 199 Cytocarriage, 758, 775–776 Coenzyme Q, 161–163, 186, 525 Cytochrome c, 185, 334, 339, 526, 760 See also Ubiquinone Cytocidal, 774 Cognition, 50–51, 76–78, 361 Cytokines, 285, 287, 319, 400, 443, 501, 591, Coley’s toxins, 321 599, 749 Coley, William, 320–321 Cytological maintenance, 775 Collagen, 5, 232, 267, 384, 394, 544, 546–547, Cytolysis, 313, 319, 718 552–556, 589–592, 594–598, Cytomegalovirus (HHV-5), 497–498, 502 601–602, 605–608, 610–612, 740, Cytopenetration, 721, 755–756 743, 745–746, 752, 758, 767–768, Cytoskeletal disease, 762 776, 821 Cytoskeleton, 753–754, 759, 761–762 Collagenase, 242, 461, 776 Cytostructural testing, 761–763 Colony size distribution, 464 Cytotoxic granules, 322–323 Common sense diet, 261 Complex trait, 576 D Compressed morbidity, 575 D-4FD-4F, see Apolipoprotein A-I mimetic Comte de St Germain, 490–491, 493 peptide (D-4F) Conatus, 47–55, 57–58 DAF, 100–101 Conditional semelparity, 144 Daf-2, 101, 146–148, 150, 152, 154, 393, Congestive heart failure (CHF), 265, 279, 281, 624–625, 632–633 589 Daf-12, 147, 625 Conserved genes for aging, 96 Daf-16, 147, 149–151, 393, 624, 627, 629, Contact zone, 313, 320 631–632 Cooking, 602 Daphnia pulex, 100, 140 Copper, 526, 594, 603 Data storage capacity of the human brain, 779 Coral, golden, 1800 year lifespan of individuals Dauer, 129–132, 148, 624, 779 of, 137 DCB6Ge, 704–705, 708–709 Coronary artery disease, 11, 144, 156, 269, 288 Deamidation, asparagine, 595 Coronary calcium, 285 Death rates for children, 781 Coronary heart disease (CHD), 13, 150, 279, Death-resistant cells, 765, 769, 814 281, 288–290, 348, 373 Decoys, 719 Corpora allata Deficiencies surgical ablation of, 153 of nutrients, 251–252 Cortisol, 144, 172, 230, 239, 317 of vitamins, 10, 270 CRC2, 349 Deglycation/deglycating, 606, 736, 768 C-reactive protein, 285, 371, 373, 397 Degranulation, 318–320 Crisis, 97, 459–460, 672 de Grey, Aubrey, 26–27, 29–30, 32–34, 89, Crosslinks 135, 174, 201, 360, 371–372, alpha-diketone, 768, 821 533, 667–683, 758, 764–767, dilysine, 590 769, 771–774, 810–812, 815–816, glucosepane, 594, 605, 609–610, 613, 768, 818–821, 835–836 821–822 Dehydroepiandrosterone (DHEA), 117, glycation, 591, 598, 605–607 170–172, 239–240, 372–373 tetralysine, 591 administration, beneficial effects of, “CR state” 170–172, 240, 244 rapidity and reversibility, 376–377 deficiency relative to GH/IGF-1, 170–171 Cryonic suspension, 68 and exercise capacity, 158, 171–172 Crystal deposition disease, 759 and GH-induced hyperinsulinemia, 170 Cultural construction of aging, 31 and LDL levels, 240, 257 Cyclin dependent kinase (CDK) side effects of, 172, 240 Index 849

Delayed maturation, 131 291, 295–298, 300, 302, 320, effect on lifespan, 129–134 322, 332, 336, 340, 345, 349, Dell’Orco, Robert, 454 360, 364, 369–370, 372, 384, Deme (deﬁnition), 109 394, 396, 407, 411, 462, 474–475, Dementia, 11, 14, 117, 464, 577, 589, 814, 493, 503, 509, 513–514, 522, 816, 823 525, 544, 550, 574–575, 577–581, Demographic homeostasis, 101, 110–111 588–589, 599–600, 614, 647, 649, Demographic theory of aging, 110 660, 668–669, 671, 674, 681, 688, Dentine, 752 722, 726, 736, 758–760, 762–763, Denuded endothelium, 578 766–767, 809, 815, 818, 822, 832, Deparasitization, 776–777 839–840 Deprenyl, 160–161, 177, 190, 194, 409 “Disorganized development”, 134 Dermal zipper, 742, 776 Disposable soma, 91–92, 97–104 “Developmental program” Dissipative structure, 58 ELT-5, ELT-6 and, 152 DMAE, lifespan extension by, 161 Developmental theories of aging, 201 DMS, 703–709, 711–713 dFOXO, 100 DNA, 623–635, 641–661 DHA (docosahexaenoic acid), 7, 11 DNA damage, 10, 93, 181–184, 199–201, DHEA, 117, 170–172, 239, 240, 372 315, 335, 374–375, 394, 446, DHEA sulfate (DHEA-S), 170–171, 239, 373 455, 458–459, 462, 465, 501, 576, DHF, 597, 609 641–661, 773 Diabetes, 5–7, 12, 16–17, 150, 170–171, 240, response, 335, 576 252, 258, 265, 269, 279, 282, 301, DNA polymerase, 181–183, 455–456, 523, 332, 339, 349, 351, 371, 381, 402, 527, 533 405–406, 408, 462, 464, 477, 514, DNA polymerase alpha 522, 535, 589, 601, 605, 669, 735, A1andA2forms,182 766, 769, 819, 836 DNA polymerase beta, 181 Diabetes mellitus (DM), 279, 282, 291, 296, DNA polymerase gamma, 182–183, 523 339, 349, 735 DNA repair, 5, 91, 149, 154, 169, 172–174, Diabetic complications, 588 181–182, 199–200, 332, 335, 337, Diamond/diamondoid, 142, 144, 171, 490, 562, 398, 523, 641–661, 752, 756, 768, 687, 690, 694, 701–715, 717–718, 777 720, 722, 724–726, 737, 747, 755, technologies, artiﬁcial, 199, 641–661 782–783 DNA ribonucleases, 646–650 Diamond particle, 720 DNA segments Diapause, 134, 153 block replacement of, in vivo, 199 Diastolic dysfunction, 589, 821 DNA stability, 346 Diastolic heart failure, 597, 609 DNA strand exchange, 644–645 Dideoxyosone, 594 Dogs, 160, 192, 411, 554, 609, 611, 655–656, Diet, 250–262, 408, 601–602, 834 680 Dietary composition and lifespan, 377–383 Double-strand breaks (DSBs), 645, 677, 752 Dietary restriction, 237, 369, 388, 625, Drexler, K. Eric, 690–693, 698 629–630, 634–635 Drosophila, 4, 99, 134, 148, 153, 161, 175, Diets 235, 338, 360, 370, 378, 382–386, common sense, 261 398, 401, 403, 623, 625, 630, 635 comparison of, 261 Drosophila melanogaster, 99, 161, 370 Differential gear, 710–711 Drowning, 736–738, 782 Diffusible molecules, 313 Drug resistance, 551–552, 675, 729 Dimer placement tool, 708–709 DS (disposable soma), 91–92, 97–104 Dimethylaminoethanol (DMAE), 161, 190 Duchenne muscular dystrophy (DMD), Diseases, 5, 7–8, 10–12, 14, 19, 32, 64, 115, 647–648, 657 117, 150, 200, 230–231, 233, ASO mediated exon skipping clinical trial, 245, 251, 257, 262, 265, 281–285, 648 850 Index

Dysdifferentiation, 235–236 eNOS, 279, 283, 296, 297, 599, 631 Dyskeratosis congenital, 469, 580, 774 Entelechy, 65 Dysnutrition, 252 Entropy, 52–55, 90–91, 371, 452 Environmental factors, 12, 231, 349, 573, 576, E 579 e1368 mutation, 146 Enzyme replacement therapies, 771 Ecdysone, 153 Enzymes, bioengineered, 601 ECM (extracellular matrix), 81–82, 461, Enzymes, fungal, 606 544–547, 588–596, 598, 601–602, Eosinophil, 322 606, 610–614, 752, 756, 761, 768, EPA (Eicosapentanenoic acid), 7, 11 770, 776–777 Epidemiology, 578 Ectoderm, 70, 466 Epigenetic, 149, 234, 551, 579, 773–775 Effector mechanism, 318–320 Epigenetic regulation of gene expression, Effect, Warburg, 321 331 Elastin, 589–591, 595–598, 600, 608, 743, Epigenetic state, 551, 773–774 767, 776 Epimutation, 670–671, 765–766, 773–775 Elastin-laminin receptor, 597 Epithelial progenitor cells, 578 Electromagnetic energy, 610 Epstein Barr virus (HHV-4), 458, 502–503 Electrophiles, 594 Erectile dysfunction, 554, 589, 597, 600, 609 Elongation factor 1a (EF1a), 179 Error-free chromosome, 775 ELT-5, ELT-6, 152 Escape velocity, 29, 834 programming of aging by, 152 E-selectin, 285 inhibition of elt-3 by, 152 Essential fatty acids, 256–257 Embryo, 64–65, 69–78, 80, 466, 471–474, 494, EST mutants, 456 545, 548–549, 678 Estrogen replacement therapy, 237 Embryonic progenitor cells, 467 Estrogen, transdermal, 245 Embryonic stem cells, 63–83, 340, 444–445, Ethanol, 628, 740 451–477, 544–545, 548, 551, 559 Eusocial mammals, 175 Emergence, 48, 56–58, 93, 459, 513, 579, 748 Every other day calorie restriction Emotional stress, 316–317 and IGF-1, 173 Endocrine disorder, 736 Every-other-day feeding and lifespan, 381 Endocrine replacement Evolution, 14, 88–89 cell encapsulation, 564 Evolution of aging, 89–90 Leydig cells for, 564 Evolutionary origin testosterone, 563–564 of lifespan and health beneﬁts of CR, 383 Endoderm, 70, 467, 548 Execution, 700, 722, 780 Endoparasites, 777 Exercise Endoscopic nanosurgery, 702, 723, 730, bone density loss in older adults offsetting, 734–735, 747, 775, 778–779 267 Endothelial and CR, 404–405 dysfunction, 283–285, 296–297 decreased intra-abdominal fat and, 265 progenitor cells, 296 favorable responses to, 262–263 sloughing, 297 how much?, 263 vasodilation, 297 lower arterial stiffness and, 264 Endothelial cells, 284, 294, 296–297, 300, 348, lower blood pressure and, 265 476, 548, 555, 564, 590, 597, 599, lower death rate and, 263 720, 734, 740 lowered all-cause mortality and, 263 Endurance, 8, 157–158, 186, 263–265, 350, lower plasma insulin levels and, 265 373 two to threefold increases in muscle Engineered gene repair, 645 strength and, 267 Engineered Negligible Senescence (ENS), 32, VO2max and, 264–265 686, 765, 835 weight loss interventions and, 267 English Sweat (sudor anglicus), 493 Exponential growth, 15, 831 Index 851

Extended lifespans Fibronectin, 506, 589, 592, 596–598, 600 in age-1 mutants, 100, 152, 624–626, 628, Fibrosis, 297, 373, 394, 395, 397, 580, 611, 632–634 645, 649 due to pharmacological and nutritional Finch, 117, 129, 136, 142, 151, 246, 599 interventions, in mammals, 159–165 FIRKO (Fat-specific Insulin Receptor Knock in genetically altered mice, 153–159 Out) mice, 6, 155, 405–406 in humans, 166–168 Fish oil, 7, 10–11 in mice with delayed maturation, 129 Flaxseed oil, 11 prior to sexual maturation, 129–134, FLCs (fibroblast-lineage cells), 590, 592, 596, 138–139 610–612 Extracellular matrix (ECM), 81–82, 461, Flexibility 544–547, 588–596, 598, 601–602, decline with age, 234 606, 610–614, 752, 756, 761, 768, Flies, 95, 97, 100, 107, 118, 140, 153, 161, 770, 776–777 165, 179, 332, 359–360, 364, 370, Extracellular senescence control by a single 377, 385, 574, 632–633 gene, 154 Foam cell, 285–286, 599, 733, 759 Extrachromosomal circles, 460, 462 Force of natural selection, 93, 136, 139, 358 Extra-uterine life, 577 FOXO, 100, 120, 150–151, 155, 172–173, 334, 338, 393, 398, 624, 627, 629, F 631–632 Fasting, 118, 133, 242–243, 254, 265, 292, FOXO1 (human analog of daf-16), 150 373, 381, 385, 387, 392, 397, 401, FOXO3, 335, 338, 631 601–603 Free energy, 53–54, 90–91 Fat accumulation Free radical damage, 14, 247 decreased, 336 Free radicals, 5, 234, 246, 253, 357, 523, 594, Fat blockers, 6–7 599, 725 Fat insulin receptor, 6, 15–16, 155 Freitas, Robert A., Jr, 17, 174, 200–201, Fat mobilization, 336, 349 685–783, 835, 840 Fatty acids French Paradox, 348 essential, 256–257 Fruit flies, 95, 99–100, 359, 363–364, 383 MUFAs, 256–258 Fruit and vegetable intake omega-3 and omega-6, 257 and risk of cancer, 253 PUFAs, 256–258 Frying food, 602 saturated (SFAs), 256–258 Full genome sequencing, 314–315 trans (TFAs), 257–258 Funding, 25–26, 30, 79, 82, 363, 668, 709, FDA, 82, 255, 323, 508, 547, 608, 715, 724, 810–815, 817, 820–821, 823, 817, 828, 833 827–828, 832–839 Fecundity, 100–101, 108, 132, 137, 158, 174, Fusitriton oregonensis, 131 201, 363, 369, 385, 624 Fuzzy logic, 71–72 Femtolaser surgery, 754 Fuzzy set, 64, 71–73 Fertility, 90, 92–93, 96–102, 107, 109–111, 115, 153–156, 160, 173, 363, 369, G 383, 385, 527 G0, 629, 634, 757 Fetus, 65, 69, 71, 74–76, 79, 182, 184, 548–549 Gastrulation, 70 Feynman, Richard P., 688 G-CSF or Neupogen, 323 Fiber, 6, 173, 251, 254–255, 260, 270, 293, Gene expression, 7, 128, 149–152, 159, 163, 399, 610–611, 740, 762, 768, 775, 174, 180–181, 200–201, 331, 778–779 349–350, 359, 362, 364, 374–376, hyperinsulinemia and, 170, 255, 261 390, 394, 397–398, 403, 410, Fibrinogen, 255, 285 441–443, 447, 458, 461, 467, 469, Fibroblast, 160, 182, 184, 460, 508, 558, 471, 473, 551, 590, 598, 628, 590–591, 596, 611, 653, 719, 722, 642–644, 646–647, 670, 673, 732, 725, 752, 775–776 736, 753, 756 852 Index

Gene repair Ghrelin, 245, 504–505 cystic ﬁbrosis, 645 GH secretagogues (GHS) engineered, 641–661 improvements in muscle strength and Huntington’s disease, 660 function and, 244–245 in vivo, 645, 649, 655–657, 659 Gilgamesh, 489, 490 Genes associated with extraordinary ages in GIS1, 629 humans, 95, 150, 394, 399 Gleevec Genescient, Inc., 359–364 and hair repigmentation, 197 Gene targeting, 477, 644–645, 659–660, Gliomas, 335 677–678, 680, 682, 774 Glomerular basement membrane, 589, 591, Gene therapy, 19, 446, 465, 531–535, 611, 599, 768 613, 642, 645, 647, 649–650, 670, Glucocorticoids, 391, 393–394, 411 672, 675, 677, 769, 771–772, 774, Glucose, 6, 158–159, 175, 186, 239, 241–244, 811, 834 254, 265, 292, 320–321, 339, SeealsoInvivogene repair 349–350, 373, 380–381, 385, Genetic, 12–14, 27, 54, 79–81, 93, 95, 97–98, 389–392, 398–403, 557, 593–594, 100–101, 103–108, 110, 114–116, 601, 603–605, 628–630, 695–696, 128, 138, 140, 143, 145, 148, 699, 721, 727, 736–737, 749, 150–154, 166–169, 176, 197, 200, 760–761, 763, 767 231–236, 282, 311–318, 324, 359, Glucosepane, 594, 605, 609–610, 613, 768, 440 821–822 Genetic disease, 10, 477, 726, 735–736 Glutathione, 165, 247, 380, 603, 605–606 Genetic engineering, 27, 81, 648–649, 658, Glycation 660–661 inhibitors, 602–603, 607, 613–614 Genetic exchange, 104 pathways, 592, 595, 606 Genetic pathways that shorten lifespan, 146 Glycolysis, 320–321, 397, 524, 529, 630, Genetic program, 90, 95, 97, 106, 143, 154, 810 235, 399 Glycoproteins, 589, 592 Genetic rejuvenation, 774 Glycosylation, nonenzymatic, 588 Genetic renatalization, 775 Glycoxidation, 592, 594, 601, 608 Genetic tradeoff, 98–101, 103 Gonadectomy, 141–143, 168 Genic effects of CR, 397 Granulocyte donation, 323 Genome, 11–12, 14, 70, 95–96, 104, 116, Granulocyte mobilization, 323, 325 128, 150–151, 186, 198–200, 235, Grasshoppers, 153 314–315, 322, 331, 359–360, 384, Grossman, Terry, M.D., 3–19, 28, 831 398, 410, 446, 470, 472, 477, Growth factors, 150, 153, 155, 160, 169, 188, 507, 521–525, 529–535, 558, 612, 199, 243, 246, 298, 343, 370, 373, 644–645, 649, 670, 674, 678, 686, 384, 389–390, 468, 504, 508, 514, 688, 700, 746, 766, 769, 771, 775, 546, 560, 564, 602, 611–612, 670, 782, 819, 834–835, 838 770, 778 Genomics, 11–14, 19, 314–315, 357–364, 686, Growth hormone (GH) 688, 833, 835 and acromegalics, 246 stability, maintenance of, 337 administration of, 244–245 testing, 11–14 and body composition, 244, 249 Germ line, 68, 103–104, 146–148, 154, 167, diabetogenic effects of, 170 170, 314, 358, 452–470, 472–473, and estrogen, 237–240, 245, 253 528, 551, 660 and prostate cancer, 245–246, 253 cells, negative effect of on lifespan, 147 and reversal of age-related atrophy, 196 transmission, 466 and “somatic involution”, 169, 171–174 GH/IGF/insulin system Growth hormone receptor knockout mice, 155, dual role as anabolic system and 157, 358 downregulator of antioxidant Growth hormone secretagogue, 244–245, enzymes and DNA repair, 172 504–505 Index 853

Guanido group, 594, 597 composition, 286–288, 292–293 Guppies, 94–95, 370 dysfunctional, 290–293 GWAS: Genome-Wide Association Studies, function, 282–288, 290–293, 296–298, 360 301–302 inflammatory index, 288–290, 293, 295, H 301 H2O2, 96 life cycle, 286 Hair repigmentation, 197 mature, 287, 294–296, 319, 324, 398 Hamiltonian gerontology, 358–359 particle size, 281, 299–300, 302 Hamilton’s Rule, 109 pre-beta, 287, 294–295, 298–301 Hamilton, W.D., 91, 358, 505 pro-inflammatory, 285, 288–295, 297–301 Hayflick, Leonard, 82, 188, 454 Hayflick limit, 188, 454, 457, 460, 576, 671 serum level (HDL-C), 288–290, 293, 295, Hazard function, 780–782 299 Health maintenance processes, 234–235 High throughput screening (HTS), 347, 617 Healthspan, 139, 159, 200, 228, 236, 361–365, Histidine, 255, 594, 603, 605 514, 574, 681, 686, 688, 715, Histone deacetylases, 331–332, 335 780–782 Histone H3K9, 337 Healthspan extension, 139, 159, 361–363, 365, Histones, 332–335, 375, 670 514, 681, 688, 715 History, 28–31, 47–50, 72–74, 229–230, Heart 390–391, 832–833 decellularized cadaveric heart, 559 HNP (human neutrophil peptides), 319 disease, 7, 11, 13–14, 16, 19, 116–117, Hobbes, 48–50, 52–53, 58, 83 150, 233, 252, 265, 283, 288, 348, Homicide, 64, 715, 736, 780, 782 372–373, 559, 688, 726, 732, 736, Hominization, 65 836 Homocysteine, 10, 285 failure Homologous genes, 95, 642 congestive, 265, 279, 281, 589 Homologous recombination, 458–459, 642, diastolic, 597 645, 651–653, 677 injectable cells for repair, 547 Hormesis, 96, 107–108, 380 patch repair, 559 hsp 16.2, 149 Heat-killed bacteria, 321 hTERT, 512 Heavy metal, 361, 759, 776 Human, 5–7, 63–83, 107, 135, 166–168, HeLa cells, 180, 184, 309, 316 195–197, 227–271, 315–318, HeLa cells fused with enucleated old 320–325, 336–339, 367–412, fibroblasts 451–477, 502, 508, 532, 548, reduced mitochondrial protein synthesis 573–581, 610, 685–783 eliminated by, 184 Human BMI, morbidity, and mortality, Hemangioblasts, 474, 476 406–408 Hematopoietic stem cells, 464, 467–468, 476, Human embryonic stem cells (hESCs), 63–83, 577 545, 548 Hematopoietic system, 476, 576 Human immunodeficiency virus (HIV), 340, Hemeoxygenase-1 (HO-1)ATP-binding, 296 345, 465, 504, 647, 677, 834 Hemostasis, 737, 740–741, 743 Heritable, 130, 149, 579, 643 Human neutrophil peptides (HNP), 319 Heritable differences in gene expression, 149 Huntington’s disease (HD), 336, 348–349, 393, Herpes virus, 502 396, 399, 402 Heterochronic, 443–444, 473–476 Hutchinson-Gilford syndrome, 461–462, 477 Heterochronic parabiosis, 187–188, 444 Hydrogen abstraction, 706–707, 709 Heteroplasmy, 522–523, 529 Hydrogen donation, 707, 709 High-calorie diets, 350 8-Hydroxy-2’-deoxyguanosine, 181 High-density lipoprotein (HDL) Hyperadrenocorticism, 142–143 anti-inflammatory, 287–289, 291–296, Hypercortisolemia, 144 298–301 Hyperinsulinemia, 170, 255, 261 854 Index

Hypertension (HTN), 16, 150, 254, 265, 269, INDY, 100 279, 281–282, 300, 399, 464, 476, Infant mortality, 781 529, 564, 589, 609 Infections, 72, 107–108, 115–117, 166–167, Hypertrophy, left ventricular, 589 230, 232, 239, 286, 292, 298, 300, Hypophysectomy, 141–142, 237 314, 318, 320–321, 323, 325, 340, Hypothermia and CR, 403–404 345, 395, 458, 469, 474, 491–493, 497–498, 502–504, 511–514, 558, I 560, 588, 599, 646, 656, 726–729, Ibuprofen, 603–604 752, 762, 777 IFN signaling pathway, 314 Infectious diseases, 513 IGF-1, 155, 160, 169–173, 196, 243–247, 602, Infiltration, 312, 323, 504, 547, 553 611, 624, 630, 632–634 Inflammation, 10–11, 115, 117, 170, 253, levels, inverse correlation with disability 285–293, 295, 297–301, 332, 348, and institutionalization, 172 351, 373, 394, 397, 399, 411, 461, signaling, 155, 630, 633–634 471, 508, 546, 580, 588, 592, 595, IGFI and insulin receptor signaling, 389–390 598–600, 602–603, 633, 717–720, IGF pathway, 95 723, 742, 767 IL-6, 230, 285, 298, 602 Influenza, 285, 292, 395, 497–498, 502, 507, IL-7, 170, 495, 504–508 514 and T cell production, 506–507 Information processes, 14–16, 18–19 and thymic involution, 170 Innate immunity, 633 Imatinib (Gleevec) Inositol, 186, 190, 603–604, 626–629 and hair repigmentation, 197 Institute for Molecular Manufacturing, 694 Immortal, 92, 137, 452–453, 455–460, 466, Insulin/IGF1-like signaling, 627–628 468, 477, 489, 491, 551 Insulin-like growth factor-1 (IGF-1), 155, 243, Immortality, 19, 29, 34, 59, 135, 452–455, 247, 602, 611 467–470, 477, 489–491, 513 and acromegalics, 246 Immortalization, 454–460 and binding protein balance, 173, 246 Immune risk phenotype, 503 and breast cancer, 238, 245, 253 Immune suppressor, 310, 316–317 and IGFBP3, 173 Immune system, 118, 160, 174, 191, 198, and prostate cancer, 173, 245–246, 253 240–241, 309–310, 312, 318, 322, receptor knockout mouse, 155 324–325, 384, 395, 489–514, 528, Insulin-like signaling pathways, 153 579, 674–675, 718–719, 724, 730, Insulin and/or IGFI signaling, 370, 383–386, 735–736, 766, 778 411 rejuvenation of, 241 Insulin resistance, 7, 16, 242–243, 255, 336, Immunity, 247, 311, 314, 318, 322, 324–325, 349–350, 373, 399, 401, 578, 736, 378, 498, 501, 510, 513–514, 633 769 Immunological effects of CR, 395 and chromium deficiency, 243 Immunosenescence, 170, 190, 769, 821 and risk of death in humans, 170 Insulin secretion, 242, 254, 336, 339, 349, 631 Immunotherapies, against cancer, 309–310, Insulin sensitivity, 118, 155–156, 158, 240, 322, 324 243, 262, 265, 349–350, 371, Implantation, 69, 71, 74, 77–78, 143, 191, 194, 379–380, 389, 401, 405, 410 281, 476, 544, 547, 550, 555, 557, Integrin receptor, 589–590, 598 559, 564 Intercellular adhesion molecule-1 (ICAM-1), Incontinence 285, 292–293 urinary, 589 Interferon (INF), 314 See also Cellular injection therapy Interleukin-7, 495, 504–508, 514 Increased intelligence, 782 receptor, 506 Individual fitness, 93–98, 108–110, 112 Interleukin-6 (IL-6), 230, 285, 298, 300, 602 Induced pluripotent stem cells, 80–81, Intermittent fasting and lifespan, 381 472–473, 551–552 Interventions Testing Program, 165, 810 Index 855

Intracellular aggregates, 670, 765, 770–771, Kidney disease, 291–292, 476, 556, 589, 763 775, 814 Kidney epithelial cells, 599 See also Lipofuscin Kilocalories, 251 Intracellular parasite, 759–760 Klotho, 155–156, 384, 389 Intracellular storage disease, 758, 771 polymorphisms in humans, 156 In vitro, 16, 177, 182, 187–188, 243, 295, Krebs cycle, 92, 339, 391 300–301, 313, 323, 337–338, kri-1, 147 340–341, 344–347, 349, 362, Ku70, 334–335, 348 401–402, 444, 452, 454, 458, Kurzweil Foundation, 783 460, 462, 466–469, 475–477, 495, Kurzweil, Ray, 3–19, 28–29, 831 502–503, 510–513, 533, 545, 548, 551, 554, 556, 558, 559–561, 577, 579, 594, 598, 600, 605–607, 610, L 613, 627, 645, 647, 653, 657, 659, Laboratory selection, 115 676, 678 Lactate (lactic acid), 157, 320–321 In vitro assay, 316, 342 Lagging strand DNA synthesis, 456–457 In vivo, 17, 187, 189, 194, 199–200, 295, Lamins, 756 301, 316, 321, 323, 335, 340–341, Laminin, 589, 597–598 344, 346, 348, 350, 388, 391, 401, Lampreys, 140–142 443–444, 452, 455, 459, 463–466, Laron dwarf mouse, 157 502, 510, 512, 523, 532–533, Laser, 100, 146–147, 610, 731, 747, 754 545–548, 551, 556, 558, 560–561, gonad ablation, 146 563–564, 577–580, 599–600, Lasker Foundation, 715–716 605–606, 608, 610, 627, 649, LAT1, 630 655–657, 659, 677, 682, 688, 696, Law of accelerating returns, 12, 18–19 699–700, 718, 724–725, 730, 745, Lead compound (drug development), 613 748, 750, 778, 782 Lecithin cholesterol acyltransferase (LCAT), In vivo gene repair, 199, 645 287, 292, 298–299 iPS Cells, see Induced pluripotent stem cells Leishmaniosis, 340, 345 IRS-1, 631, 633 Lens, 26, 58, 137, 199, 591, 752, 767 IRS-2, 384, 633 LESPs (long-lasting extracellular structural Isoaspartate, 595 proteins), 585, 588–590, 592, 597, Isochronic, 444 607, 610–611 Isomerization, 588, 590, 595 Leukocyte activation, 314 amino acid, 595 Levels of selection, 103 Isonicotinamide, 340 Life expectancy, 4–6, 15, 18–19, 134, 228, J 233, 240, 315, 368, 377, 574–575, JNK1, 631, 633 671, 681, 812, 815, 822 Juvenile hormone, 153, 175 Life-extending mutants, 153, 625 Life extension, 4–5, 16, 29, 39–59, 89, 99–102, K 107–108, 116, 118, 128, 133, Kekich, David, 32, 827–840 139–176, 188, 201, 228–231, 237, Keratinocyte growth factor, 504, 508, 514 240, 243, 270, 308, 325, 544–565, Kidney, 165, 181, 195, 197, 244, 291–292, 625, 630, 632–635, 678, 827, 829, 334–335, 338, 387, 392, 406, 476, 831–832, 835–836, 838–839 534, 556–558, 560, 564, 589–591, ethics, 42 598–600, 605, 608–609, 656, 735, by reproduction, 175 752, 763 Life Extension Foundation, 783 bovine model, 556 Life history (Life-history), 72, 98, 169, 229, extracorporeal renal unit, 556 372, 390, 575 rejection, 557–558 and anticancer effects of CR, 390–391 therapeutic cloning of, 556–558 “design”, and aging, 169 tissue engineering of, 556 evolution, 98 856 Index

Lifespan Longevity mutations, 159, 176, 361, 383–385, cost for eating excess calories, 261–262 408 extension, 133, 141, 146, 151, 155, 165, and molecular mechanisms of CR, 383–385 167–168, 229, 370, 374–376, 378, Longevity therapeutics, 408–411 380–381, 393, 398, 407 Lotka, A.J., 93–94, 110–113 fly, shortening by smelling food, 100 Low-density lipoprotein (LDL) increase, 131, 164–165, 173, 398, 624 minimally-modified (MM-LDL), 286, 293 maximum, 4–5, 131–132, 142–143, 146, native, 296 148, 152–156, 159–161, 163–166, oxidized (OX-LDL), 285–286, 296 168, 175–176, 182, 228, 263, 337, particle size, 299–300 368–369, 370, 372, 374, 377–379, serum level (LDL-C), 283–285, 293, 373, 383, 388, 402, 404–405, 625, 630 381 mean, 132, 146, 153, 155, 156, 161, Low socio-economic status, 577 164–165, 175–176, 182, 191, 194, Lung cancer, 315, 335, 343, 731 381, 404, 409, 574 Lungs, 16, 70, 162, 252, 315, 334–335, and methionine restriction, 164–165, 343–344, 388, 392, 404, 411, 589, 379–380 597, 600, 612, 672, 680, 731, and protein restriction, 378–379 737–738, 751–752 and protein synthesis, 151–152 Lymphocytes, 241, 309, 313, 389, 393, 395, and specific nutrients, 381–383 463–465, 469, 492–493, 497, 500, and tryptophan restriction, 163–165, 507, 510, 512, 558, 579, 689, 771 379 Lymphocytic, 313–314 LIFT (leukocyte infusion therapy), 324–325 Lymphoid, 503, 578 Lysine, 197, 255, 319, 331–332, 335, 340, Ligaments, 8–9, 267, 589, 767 593–595, 597, 605, 607, 647 Limbo, 70, 88 Lysosomes, 590, 758, 771 Lin-4 microRNA, 149 Lipid hydroperoxides (LOOH), 286, 291, 293–295, 298–301 M Lipids, 19, 118, 149, 161, 190, 234, 240, 254, Macrophages, 241, 285–286, 291, 293, 297, 262, 265, 281, 283, 285–287, 292, 300–301, 312–316, 395, 494, 588, 294–302, 319, 350, 371, 380–381, 590–591, 595, 598–599, 633, 720, 391–392, 397–399, 401, 411, 522, 724, 727, 752, 759, 766–767, 769, 588–589, 592, 594–597, 601–605, 771, 821 633, 686, 732, 758, 766, 770 Macular degeneration, 475, 529, 771, 818 Lipofuscin, 180, 186, 189–190, 283, 758 Macular degeneration, age-related, 14, 453, Lipofuscinolysis, 189–190 474–475, 758, 818 Malnutrition Lipoprotein (a), 285 deaths attributable to, 252 Lipotoxicity, 158, 170 Malthusian Parameter, 115 Lipoxidation, 588, 592, 594–595, 602–606 Mammalian analog of daf-16, see FOXO; Liquid nitrogen, 68 FOXO1; FOXO3 “Little mouse/mice”, the, 155, 384 Manganese superoxide dismutase, 155, 247 Liver MAPK, 187–188, 631–633 bioartificial device, 560 Margarines containing plant stanols and hepatocyte injection, 560 sterols, 258 Lizards, 118 Marginotomy, 454 Logic, fuzzy, 71–72 Marsupial mice, 144–145 Longevity, 18–19, 149, 377, 383–385, Martin, G.M., 176, 466 408–411, 573–581, 623–635, 834 Masterpiece of nature, 104 Longevity assurance, 624, 629 Matrix metalloproteinase (MMP), 547, genes, 624 591–592, 597 Longevity determinant genes (LDGs), 234–236 Maximal lifespan, 575 Longevity mutants, 146, 149, 169, 361–362 Maximum healthspan, 781 Index 857

Maximum lifespan, 4–5, 131–132, 142–143, Metformin, 7, 159, 401–402, 410, 604–605, 146, 148, 152–156, 159–160, 161, 607 163–166, 168, 175–176, 182, 228, Methionine, 10, 164–165, 255, 379–380, 263, 337, 368–370, 372, 374, 410 377–379, 383, 388, 402, 404–405, Methionine restriction and lifespan, 164–165, 625, 630 379–380 Maximum tolerated dose (MTD), 160, 312 Methuselah Flies, 359, 361, 364 MCF7 cells, 316 Methuselah Mice, 359 MCLK1, 95 Methuselah Mouse Prize, 26 Meal frequency and lifespan, 377–383 Methylation, 10, 149, 345, 380, 473, 551, 651, Mean lifespan, 132, 146, 153, 155–156, 161, 756, 773 164–165, 175–176, 182, 191, 194, Mice/mouse, 7, 26, 107, 144–145, 153–159, 381–382, 404, 409, 574 182, 186, 310–316, 323–324, 336, Mechanical senescence, 198–199 350, 359, 384, 398, 551, 632–633 Mechanisms of lifespan extension Microarray, 314, 384, 397, 402, 657 by protein, methionine and tryptophan Microbivore, 726–730, 733–736, 742, restriction, 380–381 757–760, 763, 766–767, 769, 771 Mechanosynthesis, 687, 703–705, 709, Microdebridement, 731 713–714 Microdeletions, 777 Meclofenoxate, 161 Microglobulin, 320 Median lifespan, 155–157, 159–160, 164–166, Microheteroplasmy, 522, 529 188, 404, 463, 781 Microneedle, 749, 770 Medical nanorobotics, 685–783 MicroRNA (miRNA), 149–150, 649–650 Mediterranean Agaves, 145 Microrobot/microrobotics, 17, 702, 713, 747, Melatonin, 164, 247, 371, 409 749–751, 753 Microsurgery/microsurgical, 689, 750 biological activities of, 247 Microtubules, 337–338, 343, 754 prolonged life span in rodents and, 247 Migration, 32, 106, 288, 314, 390, 443, 461, Membrane pores, 320 494, 508, 546, 589, 598, 612, 756, Memory cells, 395, 493, 497, 500–501, 503, 778 506, 579 Milk, pasteurized, 602 Memory T cell, 497, 499, 501 Mineral, 9–11, 244, 248–249, 251–253, 267, MEMS, 747–748 374, 377, 382 Men, 8, 50, 70–72, 144, 166–168, 172, Miniaturization, 16–18, 747 195–197, 238–240, 242–245, 247, Mitochondria/mitochondrial, 182–187, 334, 255, 258, 264–268, 288, 373–374, 338–339, 521–535, 670, 772–773, 406–408, 505, 510, 564, 577–579, 814, 818–819 609, 829 aging, reversal of, 182–187 Mendellian mutation, 314 and autophagy, 186–187 Merkle, Ralph C., 690, 692, 694, 704–706, protein synthesis decline with age, human, 708–709, 713, 715, 746 180, 184, 399–400 Mesenchymal, 199, 508, 552, 559, 561, 590, rejuvenation of, 180, 184–187, 530–535 611–612, 677, 680 Mitochondrial biogenesis, 158, 186, 336, Mesenchymal stem cells, 199, 559, 590 348–351, 399–401, 411, 525–526 Mesoderm, 70, 467, 548 Mitochondrial DNA Metabolic disease, 265, 349–351, 736 cloning, 530, 532 Metabolic effects of aging and CR, 391–392 damage, and down-regulation of BER, 183 Metabolic hibernation, 361 mutated, removal in cultured cells mtDNA, Metabolic pattern, 320, 324 645 Metabolic syndrome, 286, 291, 293, 300, 336, point mutations in, 182, 527 349–350, 399, 402, 410, 529, 821 purifying selection process in female germ Metabolic tradeoff, 98, 100, 102, 107 line cells, 660 Metaethics, 50–52 transfection, 186, 533 858 Index

Mitochonrial DNA mutations, see MtDNA mtDNA mutations, 182–183, 186, 522–530, mutations 532–535, 660, 670, 722, 773, 814, Mitochondrial gene therapy, 532–535 818–819 Mitochondrial number (number of Multiple vitamin/mineral formulation, 10 mitochondria), 186, 349, 399–401, Multipotent, 67–68, 494–495, 549, 552 525 Muscle aerobic capacity Mitochondrial oxidative damage increased, 157–158, 350 and aging, 182, 523, 525–526 Muscle regeneration Mitochondrial protection, 165 and fibroblast growth factor 2, 188 Mitochondrial protein synthesis and soluble frizzled-related protein 3 increased by acetylcarnitine, 180 (sFRP3), 187 restored by fusion with HeLa cells, 180, and TGF-beta, 187 184 and Wnt3A, 187 Mutant mitochondria, 765, 772 Mitochondrial size and/or number Mutational load, 93, 95 increases in, 186, 349, 400 Myelocyte-specific promoter, 315 Mitochondrial theory of aging, 521–530 Myelocytic, 313–314 Mitochondrial transcription Myeloid, 197, 337, 503, 578 restored by acetylcarnitine, 184–185 Myoblast, 440–441, 444, 563–564 Mitosis, 104, 337, 579, 611, 676, 753, 757 Myofiber, 440–441, 443, 563, 762 MMP (matrix metalloproteinase), 547, Myofibroblasts, 599 591–592, 597 Model organism, 359, 574, 624 N Moieties, glycoxidation, 601 N-acetylcysteine (NAC), 605 + Molecular bearing, 690 NAD -binding domain, 339 Molecular manufacturing, 687, 690, 692, 694, Naïve T cell, 395, 497, 499, 501, 503, 513 702–703, 712–713, 782 Naked mole rats, 93, 137–138, 236 Molecular motor, 689, 694–695, 718, 762 Nanapheresis, 734, 738 Monoamine oxidase, 160–161, 194 Nanobearing, 690–693 Monocarpic plants, 145, 148 Nanobot, 613 Monocyte chemoattractant protein-1 (MCP-1), Nanocar (Tour “nanocar”), 695 286, 293, 297–299 Nanocatheter, 749, 779 Monocyte chemotactic activity (MCA), 288, Nanocomputer, 688–690, 700–702, 722, 734, 293–295 737–738, 751 Nanocrit, 741 Monozygotic, 148–149, 469 Nanodissection, 754 Monozygotic twins, 149 Nanofactory/nanofactories, 702–704, 712–715, Morbidity, 27, 117, 196, 230, 302, 336, 372, 765 402, 406–408, 512, 514, 553, 561, Nanofactory Collaboration, 701, 703, 705, 575, 668, 685–783 708–709, 712–713, 715 Mortality rate, 97, 109, 134–137, 150, 166, Nanogear, 690–693 318, 363, 372, 498, 765, 816 Nanogerolytic treatments, 777 constant with age, 135–137, 765 Nanoinjector, 755, 761 declining with age, 134 Nanomachine, 686–689, 694, 702, 709–710, reduced, 150, 166 724, 726, 759, 783 Mosaic, 74, 100–101, 106, 754, 757 Nanomanipulator, 688, 690, 697–699 MSN2, 629 Nanomechanical, 689, 699, 700–702, 711, MSN4, 629 724–725, 730, 742 mtDNA, 155, 157, 182–184, 186, 374, 399, Nanomedical, 715, 717, 726, 735–737, 470, 522–533, 535, 557–558, 765–775 645, 660, 670, 757, 772–773, Nanomedically engineered negligible 818–819 senescence (NENS), 765–775 mtDNA deletion(s), 186, 522–523, 527, Nanomedicine, 686–690, 717–718, 732, 745, 819 766, 780, 782, 834–835, 838 Index 859

Nanomotor, 689–690, 694–697 Nitric oxide (NO), 280, 283, 284, 286, 296, Nanopump, 688, 694–697 300, 597, 599, 600, 603 Nanorobot/nanorobotics, 17, 685–783, Nitric oxide synthase, 599, 603–604 834 Nonimmunogenic, 718 Nanorobotic brain scans, 778 Nonmedical hazards, 781 Nanorobotic red blood cell, 17 NOS (nitric oxide synthase), 603–604 Nanosensor, 688, 690, 699–700, 749 Notch, 187–188, 439–447, 556 Nanosurgery, 723, 730, 734–735, 742–751, Nous, 65 753–755, 770, 776, 778 NSAID, 117 Nanosurgically, 746 Nuclear DNA mutations, 5, 172, 182, 199, 232, Nanosyringe, 749 308, 314, 387, 390, 399, 477, 525, Nanosyringoscopy/nanosyringoscope, 730, 641–643, 646, 650, 660, 670–671, 749–751, 770 766, 773–775, 777, 820 Nanosyringotomy, 750 Nuclear mutation, 671, 765, 773–775 Nanotechnology, 4, 11, 16–18, 687–689, 702, Nuclear transfer, 79, 471–472, 545, 548–552, 712, 722, 724, 764, 766, 780–781, 556, 558 832–836 Nucleophiles, 605 Nanotruck, 695 Nucleophilic, 604, 607 National Institute on Aging (NIA), 29, 231, Nude mice, 556, 563–564 812 Nutrient Nature of value, 41–43, 45–46, 58 absorption, 10, 254 Negatively charged, 319–320, 595 deprivation, 337, 387, 392, 403 “Negative reproductive costs”, 174–176 sensing, 629–630, 632 Negligible senescence, negligible aging, 129, Nutrigenomics, 357–365 137, 765 Nutritional supplementation/supplements, 6–7, Nematode, 129, 345, 359, 369, 574, 623–625, 9–11, 13, 362–364, 605–606 627, 629, 633–635, 649 NENS, 765–775 O Neonatal reserve length, 774–775 Obesity, 12, 16, 156–157, 239–240, 244, 251, Nervous signaling, 105–106 255, 257, 259, 265, 268–269, 332, Neural interfaces, 780 349–351, 397, 406–408, 577, 580, Neural prosthetic implants, 780 633, 736, 821 Neural restoration, 199, 777 Octopus, 106, 140–141 Neurodegeneration, 336, 349, 669, 771 Octopus hummelincki, 140–141 Neurogenesis, 396, 778 Odds of living to 100, 150 Neurological disease, 396, 767 Offspring, 39, 58, 91, 93–94, 109, 111, Neurological effects of CR, 396–397 114–115, 130, 137, 144–145, 150, Neuronal CRT, 777–778 175, 299–300, 311, 379, 383, 462, Neuropathy, 525, 589, 599, 605, 609 552, 579, 635 Neurotoxicity, 601 Okinawa, 5–6, 372 Neutrophils, 313–315, 317, 319–324, 395, 494, Olovnikov, Alexey, 454–455, 457 689, 720, 728, 752 Omega-3 fatty acids, 11, 256, 259 Newborns, 577, 579, 719 Omega-3 to omega-6 fatty acids Newts, 118, 475 imbalance of, 243 NF-κB, 334, 336–337, 398 Optic glands, 106, 140–141 Niche, cell, 445, 680 Orchiectomized men Niche exhaustion, 194 lower mortality rate of, 166 Niche(s), 395, 440, 443–447, 476, 500–501, Organelle testing, 760–761 588, 679–680 Organ mill, 734, 742, 744–747, 760, 770, 773, Niche, stem cell, 445, 680 778 Nicotinamide concentrations, 340 Organogenesis, 70, 74, 76–77, 441 Nitration, 588 Organ printing, 744–745 860 Index

Organs, 81, 104, 118, 139, 144, 162–164, Paraoxonase (PON), 287, 292, 295, 298–301 169, 171, 183, 195–197, 234, 237, Parkinson’s disease (PD), 338, 340, 348–349, 240–241, 283, 297, 376, 386–387, 370, 393, 396, 453, 474–475, 529, 389, 392, 439–447, 453–454, 505, 762, 819 507, 543–565, 589, 602, 607, Parthenogenesis, 471 646, 656, 679, 686–687, 689–690, Paternal age, 579 717, 723, 729–730, 734, 736–737, Pathological anatomical damage, 776 739, 742–747, 749, 755–756, 760, Pathologies, age-associated, 588, 614 770, 772–773, 775–778, 821–822, PCMT1, 595 833–834 PDK-1, 624, 627–628, 631 Orgel, Leslie Penis second law and, 88 cavernosal cells, 555 Ornithine, 594, 598, 657 erectile dysfunction, 554 Orthologs, 332–333, 359–360, 398, 401, 627, rabbit model of injury, 555 630 reconstruction of, 554–555 Osteoarthritis, 453, 589, 591, 599 PEPCK-C (mus) mice, 157–159, 186 Osteoblasts, 393, 590 Peripheral T cell pool, 496–502, 504, 509, 513 Oxidation, 154, 177, 253, 285–286, 291–294, Peritoneal cavity, 310, 313 298–301, 357, 398–401, 524, 588, Perls, T., 150, 575 592, 594–595, 599, 818 Permeability, 187, 319, 767 Oxidative damage, 93, 172, 182, 371, 378, 460, Personhood, 43–47, 55, 64–66, 71–79, 83 576, 607, 633, 680, 772 Petromyzon marinus, 142 Oxidative phosphorylation, 163, 320–321, 350, PGC-1α, 158, 186, 334, 336, 349, 397–401, 399, 410, 521–522, 524–526 403, 411 Oxidative stress (OS), 155–156, 182–183, Phagocytes, 313, 318, 717–718, 720–721, 727, 235–236, 243, 249, 286, 291, 293, 759, 767, 778 295, 298, 333, 335, 337, 393, 396, Phagocytosis, 547, 590, 599–600, 670, 718, 442, 576–577, 580, 602 720–721, 726, 729–730 Oxidized-LDL, 285–286 Pharmacological and nutritional interventions, Oxidized lipid, 285–294, 296, 299 in mammals, 159–165 Oxidized phospholipid, 288, 294, 298 Pharmacyte, 736, 739–740, 763, 767–768 Oxoaldehydes, 594 Phenformin, 159, 402 Oxygen, 17, 130, 156, 186, 234, 321, 403, 409, Phenotype, cancer killing, 316 460, 464, 524–525, 592, 613, 690, Phestilla sibogae, 131, 138 692, 695–696, 710–711, 727, 735, Phosphatidylinositide, 626 737–738, 749, 772, 810 Phospholipid, 286–288, 292, 294, 298–299, 592, 629, 752 P Phospholipid transfer protein (PLTP), 292 p15, 442–443 Photoaging, 588 p16, 443, 463 Phylogenic conservation, 369–370 p21, 442–443 Physical activity p27, 443 favorable responses to, 262 p38 kinase, 631 Physiological theory of aging p53, 334–337, 343–344, 390, 398, 459, 463, central hypothesis, 201 653 Phytochemicals, 253–254 p66shc gene knockout, 155 PI3 kinase, 624, 626 PABA, 604 Pimagedine, 603–604 Parabiosis, 187–188, 444 PIMT, 595 Paradigm shift rate, 30 Pineal gland, 174, 236, 247 Parameters, 110, 115, 228, 238, 245, 248, 321, and hypothalamic sensitivity to feedback, 372, 409, 412, 472, 575, 738–739, 247 757, 812 involution of, 174, 247 Paramutation, 314 Pineal polypeptide extracts, 247 Index 861 pKa, 605 Prophet of Pit-1 (Prop-1) mutation, Planaria, 118 153–154 Planetary gear, 692 Prostate cancer, 245–246, 253, 324, 343, 388, Plaque, atherosclerotic, 285, 732, 766, 769, 505, 514 818 Proteases, 189, 319, 392, 461, 592, 595–597, Plaques, beta-amyloid, 592, 601, 610, 767 600, 720, 764, 771 Platelet activating factor acetylhydrolase Protein(s) (PAF-AH), 287, 292–293, 298–299 Biological Value (BV) of, 256 Pleckstrin homology (PH), 627–628 extracellular, 320, 471, 588–589, 592, 597, Pleiotropic, 88, 94, 96–101, 136, 378–379, 614, 767, 821–822 443, 505 misfolded, 600 Pleiotropy, 96–104, 107, 136, 138, 463 recommended intake of, 255 as adaptation, 103–104 restriction, and lifespan, 378–379 strand breaks, 588, 595–597 Plethomnesia, 779–780 synthesis, 145, 151–152, 164–165, Pluripotent, 68–70, 80, 467, 472–473, 544, 177–180, 184, 244, 380, 390, 392, 548–551, 770 394, 400, 403, 530, 647, 724, 752, Poisoning, 737, 739–740 757 Polymerase gamma, 183, 523, 527 Protein kinase A, 629 Polymorphisms, 10, 13, 156, 339, 529, 656 Proteoglycans, 589, 591–592 Polymorphonuclear cells or PMN, 322 Protons, 336, 524 Popper, K.R., 358 Pseudomys fumeus, 144 Popular diets, comparison of, 260 PTB, 3-(2-phenyl-2-oxoethyl)-thiazolium Population dynamics, 95, 110–114 bromide, 607–608 Population genetics, 90, 109 PTEN, 324, 626–627 Population genetic theory, 97, 105, 115 PTEN knockout, LIFT treatment of malignancy Positional assembly, 702–704, 712–713 resulting from, 324 Positional navigation, 730 Pulmonary ﬁbrosis, 580 Postmenopausal, 237–238, 578 Puya raimondii, 145 Postmitotic, 148, 181, 381, 390–391, 397, 523, Pyridoxamine, 604–605 576, 628–629, 634, 676, 819 Pyruvate dehydrogenase, 630 PPAR-γ, 334, 336, 349 PPARδ, 158, 186 Q Predator-prey dynamics, 110, 114 Quackery, 28, 30–31 Predictions/predicting, 23–34, 43, 54, 88, 95, Quantum computer, 701 100, 115, 134, 236, 288, 410, 613, Quickening, 64 781–782 R Predictive genomics, 11–14 Rabbits, wild Preembryo, 65, 70 negative reproductive costs in, 175–176 Preventive settings, 322 Racemization, amino acid, 595 Prions, 759, 776 Radioactive, 323, 562, 759 Proapoptotic genes, 344 RAGE (receptor of AGEs), 598–599, 601, Probucol, 604 608 Procollagen, 590 Random damage, 89, 129,131, 135, 148–149, Progenitor cell, 188, 439–441, 444, 453, 176–177 467–468, 494–495, 527, 560–561, Rapamycin, 165, 403, 629–631 743, 752, 767 Rapiddeathofplants Progeria, see Hutchinson-Gilford syndrome hormones and, 145 Programmed aging, 89, 141, 152 RAS1, 629 Programmed death, 96, 105–109, 145, 453 RAS2, 629, 633 Programmed senescence, 107, 139, 232, Rational drug design, 16, 601, 612–613 246 Rattus fuscipes, 144 Prolongevity factors, 332 Raw food, 251, 602 862 Index

Reactive oxygen species (ROS), 92–93, 95, Retinopathy, 589 170, 286, 336, 338, 348–349, Retrotransposons, 777 523–529, 600–601, 603, 660, Retroviral components, 315 810–811 Retrovirus, 551 Recent thymic emigrants, 505, 509 Reverse cholesterol transport, 286 Receptors, 6, 15–16, 115, 150, 153, 155, Reversed development, 133 157, 175, 186–187, 197–198, 243, Reverse-engineer (the brain), 17–18 245, 285–287, 294, 301, 314, 336, RGD sequence, 590 375, 384–385, 389–390, 396–398, Rheumatoid arthritis (RA), 286, 291–292, 509, 400–401, 403, 405, 441–442, 589, 599 492–494, 496–497, 499–500, 504, Ribozymes, 643, 646–649 506–508, 511, 589–590, 592, RIM15, 629–630 596–600, 608, 611, 624–625, 627, Risk of dying, 150 631–633, 647, 657, 719, 727, 729, Risk-prediction models, 781–782 731, 761 RNA interference, 16, 19, 101, 146–147, 336, Recombination and mismatch repair, 653 646–650 Red cell, 323, 737–738, 740, 743, 746, 760 Robotic surgeries, 748 Red Queen hypothesis, 114 Rosettes, 313 Reductionism, 43, 56–59 ROS (reactive oxygen species), 92–93, 95, 170, Regeneration, 98, 115, 118–119, 143, 187, 190, 286, 336, 338, 348–349, 523–529, 192–195, 201, 439–445, 473–476, 600–601, 603, 660, 810–811 552, 558, 563, 596, 611–612, 656, Rupture, cell, 319 741, 752, 778, 814, 822, 832, 834 Regenerative competence S restored in old livers, 188 S180, 310–312, 324 restored in old muscle, 187–188 S6 kinase, 380, 630, 634 Regenerative medicine, 451–477, 544–545, Saccharomyces cerevisiae, 370, 397, 623–624, 810, 835 628–630 tissue engineering in, 544–545, 559 Salicylic acid, 604 Rejuvenation/rejuvenating, 27, 187, 241, Salmon, 106, 140, 142–145 444–447, 504–511, 513–514, 606, Sapience, 66, 76–79 612, 669, 764, 774–780, 809–823 SAP protein, 600 Remodeling of ECM, 590 Satellite cells, 187–188, 440–444, 563, 677 Repair by replacement, 199, 752–753 Scanning probe microscope (SPM), 704–707, Replacement mitochondria, 186, 773 709, 711–712 Replicative lifespan, 370, 398, 454, 458–459, Scanning rings, 733 461, 463–464, 477, 501, 512, 611, Scar formation, 592, 611–612 628–629 Scavenger receptor B1 (SR-B1), 287 Replicative senescence, 188, 456, 462, 464, SCH9, 629–630, 634 573, 576–580, 676 Schiff base, 593, 605 Replicometer, 454 SCNT, 68–69, 71, 470–473, 476, 549–550, 552 Reproductive costs Sea anemones, 136, 357 negative, 174–176 Seasonality, of cancer killing effect, 317–318 Reproductive cycling Second law of thermodynamics, 52–54, 90 reversal of cessation of, 160, 194–195, 386 α-Secretase activity, 349 Reproductive effects of CR Sedentary lifestyle, 7, 282, 577–578 in humans, 387 “Segmental aging reversal”, 176–198 in rodents, 385–386 Self-assembly, 702–703 Respirocyte, 17, 734–735, 737–739, 747, 782 ‘Self-destruct’ system, 117, 693, 723 Resveratrol (RSV), 7, 118, 158–159, 336, 340, Semaphores, 720, 729, 743 346–351, 382, 604 Semelparous, 106–107, 137, 139–146, 148, and metabolites of, 158, 336 167–169 See also Sirtuin activators Senescence, physiological, 588 Index 863

α-Secretase activity, 349 quercetin, 346 α-Synuclein, 338, 345, 396, 819–820 resveratrol, 340, 346–347 Senescent cells, 454, 461, 464, 471–472, 769, SRT1460, 348 821 SRT1720, 340, 347–350 SENS, 27, 669–671, 681, 764–773, 775, 778, SRT2183, 348 809–823, 835–837 Sirtuin-based therapies, 332 SENSE: Strategies for Engineering Negligible Sirtuin classes, 333–334 Senescence Evolutionarily, 358–359 Class I, 333 Senstatic activation, 461 Class II, 333 Sentience, 66, 76–78 Class III, 333 Serum proteins, 320, 592 Class IV, 333 Sex hormones Sirtuin inhibitors negative effects on immune function, 167 AC-93253, 344 Sexual maturation AGK2, 345 and aging phenotypes, 129–134, 169–174 cambinol, 341–343 prevention of, 142 in cancer therapy, 343–345 SGK-1, 632 chemotherapeutic properties, 343 Sickle cell anemia HR73, 345 correction of, 81 in other diseases, 345 Sickle cell disease, 284, 300 salermide, 340, 342, 344 Side effects, 77, 88, 90, 98, 108, 133, 136, sirtinol, 340–341, 343, 345 155, 164, 200–201, 234–235, 240, splitomicin, 340–341, 343, 345 308, 325, 361, 507–508, 512–514, suramin, 340, 342, 345 544, 559, 604, 608, 613, 671, 723, tenovin, 340, 344 729, 736, 739, 765, 768, 783, 810, Skeletal muscle, 157–158, 187–188, 262, 813–814, 836 334–337, 371, 375, 392, 399–401, Sigmoid function, 72, 74 403, 440–442, 467, 559, 576, 591, Signaling, hormonal, 100, 400 602, 676, 742, 759 Signaling pathways, 95, 149, 153, 314, 335, Skin, 53, 67, 81, 143, 171, 180, 184, 196, 350, 383–384, 390, 402, 441, 599, 230, 232, 239, 249, 297, 346, 611, 630, 632–634 387, 393, 462, 476–477, 490, Silent inﬂammation, 10–11 497, 508, 510–511, 545, 548, 552, Silent Information Regulator, 332–335, 556, 558, 563, 588–589, 591–592, 340–341, 398, 630, 632 596, 608–609, 612, 680, 725, 735, Sinclair, D.A., 117–118, 159, 332–333, 336, 739–741, 749, 752, 762, 768–769, 370 774 Single nucleotide modiﬁcation Smad, 442 engineered, 650–657 Small interfering RNAs (siRNAs), 337, 339, Single nucleotide polymorphisms (SNPs), 643, 649–650 12–13, 339 Smith, Kirby, 167–168 Single-stranded oligonucleotides (SSOs), 642, Smokers, 269, 315, 578 653–655, 657 Smokey mouse (Pseudomys fumeus), 144 SIR2, 332–335, 340–341, 398, 630, 632 Snell dwarf mouse, 154 SIRT1, 186, 332–336, 338–351, 397–399, 411 Social distance, 492 active regulator of, 334 SOD, 92, 182, 385, 396, 629, 633 SIRT3 variant Somatic cell nuclear transfer, 68–69, 71, in males older than 90 years, 338 470–473, 476, 549–550, 552 Sirtuin, 7, 158–159, 164, 174, 331–351, 398, Somatic cells, 67, 104, 116, 308, 452–464, 630 466, 469–470, 472, 549–551, 577, Sirtuin activation, 158, 174, 346 752, 771 Sirtuin activators Somatic involution, 170–174 butein, 346 Sorting rotor, 696–697, 699, 719–720, 728, piceatannol, 346 733, 737–738, 758, 763–764 864 Index

Specific nutrients and lifespan, 381–383 Survival, 161, 228–231, 626, 816 Speed reduction gear, 710–711 Survival time, 140–141, 161–163, 165, 402 Spinoza, 48–52, 55, 57–58 SV40 virus, 458–459 Spontaneous regression, 311–312 Swelling, 27, 319, 720, 740, 762 “Squaring the curve”, 228 Synaptic monitoring and recording, 778 SR/CR mice, 311–316, 323–324 α-Synuclein, 338, 345, 396, 819–820 SRT1720, 340, 347–350 Synvista Therapeutics, 607 See also Sirtuin activators Systemic lupus erythematosus (SLE), 286, Stanols and sterols, 258 291–292 Starch blockers, 6 Systemic sclerosis (SSc), or scleroderma, 292, Starfish, 118 297 Statin, 289, 608 Stem cells T adult, 68, 199, 439–440, 444, 446, 548 T cells, 118, 241, 371, 395, 463, 492, 494–495, amniotic fluid, 68, 548, 559 497–507, 509–513, 557–558, differentiation of, 466–467 579–580, 648, 719, 769, 821 embryonic, 63–83, 340, 344–345, 451–477, Tachigalia versicolor, 145 544–545, 548–549, 559, 817 Target cells, 246, 316, 319–320, 530, 611, 675, fetal, 545 730, 739, 755–756, 773 mesenchymal, 199, 559, 590 Target of rapamycin, 403, 629–631 placental, 548–549 Target structure (drug development), 612–613 Stem cell therapy, 64, 79, 118, 199, 558, 672, Technological evolution, 15 676, 682, 770, 833 Telemedicine, 748 Steric hindrance, 606–607, 610, 612 Telesurgery, 748 Stochasticity of aging, 91, 128, 135, 148–151, Telomerase, 96, 116, 188, 446, 455–460, 154, 166, 458, 464, 576, 810 462–465, 467–470, 472, 477, 512, Strength (resistance) training, 8–9, 266–267 577, 580, 672, 675, 677–682, Stress hormones, 316–318 773–774 Stress induced premature senescence (SIPS), activation, 456, 458–459, 462–463, 465, 460 467–469, 472 Stress-mediated cell death, 348 Telomeres Stretching, 9, 268, 597 attrition, 464, 576–579 Stroke, 7, 11, 17, 117, 150, 156, 233, 252, 269, dynamics, 454–460, 470–472, 573, 281, 349, 396, 464, 475–476, 522, 576–580 597, 726, 735–736, 744, 771, 776, erosion, 576–577, 579–580 821 extension in mice, 477 Strong inference, 358 40% extension of median lifespan by, Suffocation, 337–739 159, 188 Sugar, 7, 118, 251, 254, 261, 514, 588–589, length, 116, 452, 455, 459, 462, 464–465, 592–595, 601–602, 605, 607, 696, 467, 470, 472–473, 477, 573–574, 728, 768 576–580, 680, 776 Suicide, 42, 46–47, 142, 174, 252, 670, 715, shortening, 116, 134, 455–458, 460, 468, 736, 756, 769, 773, 780, 782 578, 580, 680 Sulfur, 253, 605, 692, 710–711 in vivo, 577–580 Sunburn, 596 Telomeric aging, 96, 115, 454–460 Supercentenarians, 369, 766 Telomeric erosion, 577 age-independent mortality rate of, 135 Telomeric G triplets, 576 Superoxide dismutase, 155, 247, 301, 338, 629 Telosome, 458, 472–473 Surface recognition, 313, 320–321, 324 Tendons, 8–9, 267, 589, 591, 602, 608, 614 Surgical microrobotics, 749–751 TERT, 458, 460, 462–463, 465, 469, 473, 611 Surgical nanorobot/surgical nanorobotics, Testosterone 685–783 and reduced mortality from all causes, 144, Surgical robot, 748, 751 167 Index 865

Tetrapeptides, 299 Totipotent, 67, 70, 465–466 FREL, 299 Toxic cells, 670, 769 KERS, 299 Tradeoffs, 97–104, 138, 145, 157, 176, 463 KRES, 299 evolutionary, 90 TGF-beta, 187, 439–447, 602 Tragedy of the Commons, 110 Theories of aging, 231–232 Transcriptional integrator p300, 335 accumulated damage, 90–93 Transcriptional programs adaptive theories, 104–114 in aged tissues, 337 antagonistic pleiotropy, 98–101, 103–104 Transforming growth factor beta, 187, 373, developmental, 201 612 disposable soma, 101–103 Transglycation, 604–606 evolutionary, 358 Transient ischemic attack (TIA), 735 mutation accumulation, 93, 97 Transition metals, 594 other, 232 Transmembrane potential, 319 Therapeutic modalities, 564, 575 Transposons, 314, 777 Therapeutic settings, 322–323 Transthyretin (TTR), 600–601, 657, 819–820 Therapeutic window, 325 Trauma, 81, 170, 198, 239, 255, 318, 345, 461, Thermodynamics, 52–55, 90, 262, 268 471, 475, 554, 720–722, 736–751, Thermogenesis, 170, 338–339, 386 776–777 Thiamine (vitamin B1), 605, 607 TREC (T cell receptor excision circle), 505, Thiazolium, 607–609, 614 507 Three dimensional (3D) printing, 745–746 TRF (telomere restriction fragment), 455–456, Thymic epithelium, 505, 508–510 462, 464, 469, 471, 477 Thymic hyperplasia, 191–192 Triglycerides, 11, 13, 157–158, 255, 257–258, Thymic involution 265, 287, 292, 371, 373 and aging, 170 Triplex DNA lack of, in hyperthyroid individuals, 191 homologous pairing of, 657–660 reversal of, 191–194 Trolox, 605 Thymic regeneration, 191–194, 504–510 Trophoblast, 67–68, 70 Thymocyte, 463, 494–496, 499, 507, 509 Tropism, 77 Thymosins, 241 Tryptophan, 163–165, 237, 255, 379–380, Thymulin, 191–192 411 Thymus deﬁciency, 163–165 as a controller of many aging processes, Tryptophan-deﬁcient diets, 163–165, 237 198 Tryptophan restriction and lifespan, 163–165, rejuvenation of, 191–194, 504–510 379–381 transplants, 170, 198 TTR (transthyretin), 600–601, 657, 819–820 lives extended by, 198 Tumor(s) Thyroxine, 191–192, 238 cells, 241, 335, 338, 343, 388–390, 410, Tissue(s) 456, 731 mill, 746, 778 promoter, 335 printer, 734, 742, 744–747, 760, 770, 778 suppressor, 338 t loops, 457–459, 462 Turnover, collagen, 591, 608, 611 T lymphocytes, 309, 313, 469, 497, 507, 558, Twins, monozygotic, 149 579 Type 2 diabetes (type II diabetes), 7, 12, 19, TNFα, 336 170, 240, 339, 349, 408, 411, 462, Tolerization, 718–719 477, 535, 605, 669, 736, 766, 769 Tooth replacement continuous throughout life, 199 U Tooth wear Ubiquinone, 92, 95, 162 as limiting for lifespan, 199 Ultrasound, 71, 700, 728, 738, 749, 756 TOR, 151–152, 165, 180, 380, 629–632, 634 Uncoupling protein (UCP), 186, 336, 404 Torpor, 579 United Therapeutics, 16 866 Index

Urethra Whole-body Interdiction of Lengthening of hypospadias repair, 553 Telomeres, 667–683, 730, 773–774, onlay replacement, 553–554 820 replacement of, 553–554 Wild rabbits stricture disease, 553–554 negative reproductive costs in, 176 tubularized repair, 553–554 WILT, 667–683, 730, 773–774, 820 Urinary bladder, 597 Winter, effect of on cancer killing, 317–318 Urine, 181, 247, 249, 557, 590, 605, 728 Wnt, 187, 441, 631 Uterus, 64, 68, 70, 77–78, 334–335, 549, 555 Women, 8, 13, 64, 68, 166, 168, 195, 197, Utility fog, 743–744 230, 237–238, 243–245, 247, 255, 258, 264–268, 288, 368, 373–374, V 406–408, 509–510, 577–578 Vaccination, 322, 395, 498, 507, 512, 514, 766 Worm drive assembly, 711 Vagina, 556 Worms, 95–96, 100–101, 106–107, 118, Value of life, 39–59, 716 129–130, 138, 146–149, 152–153, Valvular heart disease 155, 159, 163, 165, 332, 574, aortic valve, 283 625–627, 632–633, 635, 777 Varicella Zoster Virus (HHV-3), 502 Wound healing, 119, 232, 463, 588–589, 592, Vascular dysfunction, 284, 350, 476, 578 612, 737, 741–742 Vascular gate, 735, 742–744 Wright, Woodring, 454, 459–460, 465, 469, Vascular repair, 732 576–577 Vasculocyte, 732–735, 742–744, 766, 770, 776 Vaupel, 92, 103, 134–135, 321, 368, 574, Y 716–717 Y-chromosome deletions Vena cava filter, 744 human lifespan and, 166–168 Ventricular hypertrophy, 589, 609 Yeast, 95–96, 100, 118, 145, 153, 159, 165, Vesicoureteral reflux, see Cellular injection 332–334, 340–341, 346, 370, 378, therapy 380, 398, 401, 456, 623, 627–630, Vicious cycle, 588, 591, 597–598, 600 633–635, 644 Viroids, 759, 776 Vitamin Z vitaminB1(thiamine),604–605 Zero aging vitamin C, 243, 253, 603 in box huckleberry clones, 137 vitamin E, 190, 253, 382, 604 in Bristlecone pine, 137 Vitellogenin, 175 in C. elegans, 129–131 Vitronectin, 589, 598 in fish, 129 VPS34, 627 in Fusitriton oregonensis, 131 in giant fungus (Armillaria bulbosa), 137 W in golden corals, 137 War, 52–53, 228, 668, 688, 715, 725, 780, 782, in hydras, 136 833, 840 in naked mole rat, 137 Warburg effect, 321 in Phestilla sibogae, 131 Warburg, Otto, 321 in POSCH-2 mouse, 134 Watson, James, 12, 54, 455 in queens (insect), 136 WBC’s, 17, 241, 292, 316, 404, 574, 577–580, in sea anemones, 136 701, 729, 769, 771 in sea urchins (red), 136 Wear-and-tear, 92, 232, 234, 246, 252 in Sequoia, 137 Webster, George, 177–179 in Trogoderma glabrum, 132–133 Weismann, August, 92, 108, 453–454, 461, in Trogoderma tarsale, 133 463, 466 in tubeworms, 136 Werner syndrome, 456, 461–462, 464–465, in turtles, 137–138 477 Zinc finger nucleases (ZFNs), 642, 645, 677 West Nile Virus, 497 Zippocyte, 742 White blood cells, 17, 241, 292, 316, 404, 574, Zona reticularis, 170 577–580, 701, 729, 769, 771 Zygote, 65, 69, 73, 79, 528, 754