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article in BioEssays

Is human aging still mysterious enough to be left only to scientists?

 Aubrey D.N.J. de Grey,^1* John W. Baynes,² David Berd,³ Christopher B. Heward,⁴ Graham Pawelec,⁵ and Gregory Stock⁶

¹Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.

²Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208.

³Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107.

⁴The Kronos Group, Phoenix, AZ 85018.

⁵University of Tübingen Medical School, 2nd Deptartment of Internal Medicine, D-72072 Tübingen, Germany

⁶UCLA School of Medicine, Los Angeles, CA 90024-1759.

^*Correspondence to: Dr. Aubrey D.N.J. de Grey, Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK. E-mail: ag24@gen.cam.ac.uk

Summary

The feasibility of reversing human aging, at least within the next few decades, has traditionally been dismissed by all professional biogerontologists on the grounds that not only is aging still poorly understood, but also many of those aspects that we do understand are not reversible by any current or foreseeable therapeutic regimen.  This broad consensus has recently been challenged by the publication, by five respected experimentalists in diverse subfields of biogerontology together with three of the present authors, of an article (Ann. N.Y. Acad. Sci. 959, in press) whose conclusion was that all the key components of mammalian aging are indeed amenable to substantial reversal (not merely retardation) in mice, with technology that has a reasonable prospect of being developed within about a decade.  Translation of that panel of interventions to humans who are already alive, within a matter of decades thereafter, was deemed potentially feasible (though it was not claimed to be likely).  If the prospect of controlling human aging within the foreseeable future cannot be categorically rejected, then it becomes a matter of personal significance to most people presently alive.  Consequently, we suggest that serious public debate on this subject is now warranted, and we survey here several of the biological, social and political issues relating to it.

Introduction

In a recent article,⁽¹⁾ five eminent researchers with wide-ranging biogerontology expertise joined with three of the present authors (A. de G., C. H. and G. S.) to make an unprecedentedly bold forecast concerning mammalian life extension in the medium term.  They stated that, within about a decade, it might be possible to reverse (not merely retard) mouse aging.  Specifically, we might be able to take a mouse with a remaining life expectancy of six months and give it one of eighteen months, something that would require restoration of broadly youthful physiology.  The authors did not claim that this would occur in about a decade, nor even that it was probable.  They did state, however, that its possibility could no longer be considered remote, since no intervention considered necessary requires dramatic biotechnological advances.  It was further noted that the undoubtedly formidable obstacles to translating such technology (if developed) to humans are already being tackled, e.g. by gene therapy research, so might fall only a few decades thereafter.

Hayflick has energetically argued^(2-4) that many tumultuous challenges would confront civilisation were we greatly to extend human longevity.  However, few others have joined that debate, perhaps because of the apparently unanimous expert consensus that this scenario (which has been termed “engineered negligible senescence” or ENS⁽⁵⁾) is vanishingly unlikely to occur in the foreseeable future.  Such consensus no longer exists: it is now a matter of public record that several noted biogerontologists are highly optimistic about controlling mouse aging quite soon.

Here we examine several issues arising from the above.  We first propose some concrete definitions of key concepts.  Then we consider:

-       whether the range of cellular and molecular aspects of aging whose reversal was discussed in ref. 1 is comprehensive;

-       whether their translation from mice to humans is plausible on a comparable timescale;

-       whether such considerations call for a redistribution of our investment in anti-aging research and development versus other medical research; and

-       whether they motivate a readjustment of how biogerontologists present their work and its purpose to policy-makers and the public.

Can reversal and retardation of aging be rigorously distinguished?

A statement given great prominence in ref. 1 was that “reversing mammalian aging is not necessarily any harder than dramatically postponing it”.  Initially this assertion seems preposterous: for example, surely the postponement of mouse aging by caloric restriction (CR) qualifies as dramatic, and we can do that already.  Moreover, CR “mimetics” are under development.⁽⁶⁾

However, CR exerts progressively less effect on rodent lifespan the later in life it is imposed,⁽⁷⁾ and evolutionary theory suggests that any other inducible but endogenous life-extending metabolic adjustment would share this property.  Children will not be given such treatments, lest they have long-term side-effects (which, by definition, cannot quickly be ruled out).  Only those already concerned with their own aging (i.e., older people) are likely to consider such drugs, and for them the potential benefit is slight, even if CR works as well in humans as in rodents (which is unproven).  Only much more dramatic retardation of aging will be biomedically significant.

Several life-extending genetic and pharmacological manipulations of model organisms,^(8,9) including mice,^(10-12) have now also been reported.  Unfortunately, they have much in common with natural life-extending strategies of the organism in question (dauer, diapause, CR, etc.).  Hence, they may merely constitute crude approximations of these natural phenomena, rather than new mechanisms for postponing aging, and thus are unlikely to lead to interventions that postpone aging to a biomedically relevant extent.

Why is retarding mammalian aging so hard?  Mammals have had to tolerate the toxic side-effects of metabolism throughout their evolution, and have turned them to advantage: as signalling molecules, for example.⁽¹³⁾  Interfering in the pathways from metabolism to damage will thus tend also to interfere with these other, positive roles of the damaging agent.  Hence, the organism will tend to respond to such well-meaning interventions by compensatory adjustments to maintain the normal concentration of such agents—and if the intervention were powerful enough to overcome these homeostatic responses, the net result would generally be harm to the organism, not benefit (e.g. ref. 14).  Evolutionary pressure can select for retarded aging over thousands of generations,⁽¹⁵⁾ but the panoply of adjustments of gene expression and function that are probably involved is far beyond our present biotechnological (let alone biomedical) expertise to emulate.

Why might reversing aging be easier?  Reversing aging can be defined as removing the end-products of these side-effects of metabolism, as opposed to the reactive intermediates.  Thus, the above logic does not apply here: overcoming normal homeostatic responses should not be necessary.  The endpoints of oxidative and other damage are either the simple depletion of something (cells of a particular type, telomeric repeats…) or else stable, inert molecules, with no positive role to be balanced against their deleterious properties (Table 1).  Hence, removing such damage may have few deleterious side-effects, so reversing aging may indeed be easier than retarding it.  (Clearly this is logically impossible if retarding aging is defined to include reversing it more slowly than it is occurring, but that is not the definition used above.)

Can aging and age-related disease be operationally distinguished?

Great confusion surrounds the distinction (if any) between aging and age-related disease.  Many aspects of aging distinguish it from typical diseases, including its universality, intrinsic origin, post-pubertal onset and promotion of vulnerability to diseases.  However, none seems clear-cut.  All males over 70 have prostate cancer detectable at autopsy.⁽³¹⁾  Many age-related diseases result purely from side-effects of metabolism, not infection.  Arterial foam cells, the first stage of atherosclerosis, are present before puberty.⁽³²⁾  Some age-related diseases predispose to others, such as diabetes doubling the risk of heart disease.⁽³³⁾

Finding an operational definition of human aging that encapsulates its relationship to disease entails deciding what we mean by “disease” in the first place.  Though death certificates do not often use the term “natural causes” these days, the cause of death in the elderly often spans many organ systems and transcends our usual definitions of disease.  This leads us to suggest that, for purposes of clarifying how it relates to age-related diseases, human aging can be described as:

a set of early-onset, slowly progressive, mutually synergistic degenerative processes, whose later stages are fatal but tend to be given “disease” status only if they often kill or severely debilitate people before they reach their society’s life expectancy.

This description suggests that if we continue to raise the mean age of death from major age-related diseases, without postponing the aspects of aging that cause death by “natural causes”, we will take progressively more interest in the latter category.  This is because life expectancy will increase, so the age that we consider “a good innings” will increase, so increasingly many people will die of “natural causes” before that age, so we will want to study their specific cause of death, so we will name it.  Thereby, we would elevate progressively more causes of death to the status of “disease”.  The distinction between aging and age-related diseases is, in this view, highly fluid; similar conclusions have been reached concerning the post-genomic definition of “disease”.⁽³⁴⁾

Some aspects of aging that may be very hard to reverse

Here we address some important components of mammalian aging that merit more detailed analysis than they received in ref. 1.

The accumulation of random chemical modifications and cross-links termed advanced glycation and lipoxidation end-products, or AGE/ALEs, in long-lasting extracellular protein may be a major cause of age-related loss in extracellular matrix function and elasticity.⁽²¹⁾  Some such changes may be of limited consequence, but others may be significant contributors to age-related pathologies such as hypertension⁽³⁵⁾ and cataract⁽³⁶⁾ and age-related losses in renal and pulmonary function.  AGEs also accumulate in amyloid plaques in neurodegenerative diseases and dialysis-related amyloidosis.⁽³⁷⁾  Phenacyldimethylthiazolium chloride (PMTC) has been reported⁽³⁸⁾ to reverse this loss of elasticity, but its mode of action remains controversial, firstly because it would not cleave any AGE/ALE crosslink yet identified in vivo, and secondly because the proposed⁽²⁷⁾ cross-link cleaved by PMTC should be relatively reactive, i.e. transient.⁽³⁹⁾  However, impressive restoration by PMTC of elasticity in various tissues of several organisms, including humans, has been reported.^{(27,38,40,41)}  One possibility is that PMTC cleaves cross-links that have not been identified chemically, due perhaps to their lability to standard isolation procedures.  Another is that the apparent reversal of cross-linking is actually only a retardation of both enzymatic and non-enzymatic cross-linking, which appears as reversal because of turnover of proteins in the vascular wall.

Immunosenescence may be largely responsible for the diminished ability of older individuals to overcome infection and maintain anti-cancer surveillance.⁽⁴²⁾  It is principally a result of the declining efficacy of T cells and possibly NK cells: B cell decline is broadly a consequence of diminished T cell stimulation, and antigen presentation capacity appears well retained in the elderly.⁽⁴³⁾  The T cell population progressively shifts to a lower ratio of naive to memory cells, thereby shrinking the repertoire of cells available to respond to antigenic challenge from previously unencountered pathogens.  Those T cells remaining, especially the CD8⁺ (cytotoxic) subset, also show increased oligoclonality with age.⁽⁴⁴⁾  Memory cells can survive for at least two years in mice and possibly longer (though probably not as long as the memory itself) in humans; they, as well as naive cells, may thus face many of the intracellular maintenance challenges that affect postmitotic cells, such as accumulation of undegradable material.  This could underlie their progressively more sluggish activation in response to antigen, since cross-age transplantation experiments⁽⁴⁵⁾ indicate that many T cell functional deficits are intrinsic to the T cell rather than determined by the age of the host.  Naive (and hence, subsequently, memory) T cell functional decline is accompanied by involution of the thymus, which loses up to 90% of its cells by middle age (though with much inter-individual variation);⁽⁴⁶⁾ a causal link remains hypothetical but may now be testable using assays of T cell rearrangement excision circles.⁽⁴⁷⁾  Interleukin 7 (IL-7) injections have reversed thymic involution in mice,⁽²⁶⁾ but associated restoration of naive cell number was, at best, restricted to CD4⁺ (helper) cells.  Immune system function is an emergent property of a complex network of cell types in dynamic equilibrium; if the gross changes in this system (such as loss of naive cells) were reversed, endogenous homeostatic mechanisms might or might not restore its subtler aspects.

Cancer is unique among age-related pathologies in its ability to evade both endogenous and medical challenges (including denial of blood supply, immune attack and cell division-associated telomere shortening) by selection for additional mutations.  (Not all cancers are age-related, of course, but here we restrict consideration to those that are.)  Angiogenesis inhibitors have shown promise in mice⁽²³⁾ but their efficacy in humans remains unclear.⁽⁴⁸⁾  Telomere maintenance is usually (but not always⁽⁴⁹⁾) achieved by reactivating telomerase, whose inhibition is therapeutic only if selective enough to spare the many telomerase-dependent cell types, including T and B lymphocytes and diverse stem cells.  Immune stimulation also faces numerous difficulties, most fundamentally the relatively subtle antigenic difference between tumour cells and the non-tumour cells from which they arose.  Hence, it is perhaps unsurprising that attempts to induce tumour regression using specific peptides are often ineffective.⁽⁵⁰⁾  Immunising patients against whole cells from their own tumour elicits a response against many antigens without even having to identify them in advance, and has long shown encouraging results.⁽²⁴⁾  However, the tumour load against which it is effective remains limited.  The availability of such varied therapeutic approaches, many of them novel, which can potentially be used in combination, makes it plausible that the age at which cancer typically becomes life-threatening could be increased rapidly enough (in mice, then in humans) to achieve the goals set out in ref. 1.  However, the slow rate of progress hitherto warns us that this may not occur and that cancer may remain a formidable obstacle to dramatic life-extension for some time.

In summary, we caution that any one of the above aspects of aging, or of those discussed in ref. 1, could easily turn out to be so intractable that the one-year mouse rejuvenation goal is thereby thwarted.  One might infer that the chance of turning a two-year-old mouse into functionally a one-year-old one in ten years’ time is thus extremely small, since all key components of aging must be reversed simultaneously, an eventuality whose probability is the product of those of the component reversals.  But this does not follow, because of the synergistic interdependencies of these processes (which are only partly understood mechanistically^(51-53) but are decisively demonstrated by the fact that several single-gene mutations independently extend mouse lifespan^(10-12)).  If the most influential few processes can be robustly reversed, the others may be so retarded that the mouse will obtain the requisite extra year of healthy life.

Of mice but not men?

Let us now suppose that the proximate goal, rejuvenating a two-year-old mouse by a year, were indeed achieved within a decade.  How plausibly could translation of that technology to humans who are already alive be achieved relatively soon thereafter, and would this proportionally increase human healthy lifespan (roughly, giving a 60-year-old an extra 30 years)?

Many major age-related human pathologies do not afflict mice, so are tangential to the one-year mouse rejuvenation goal.  However, researchers in many such areas are working to “humanise” the mouse, causing it to develop these pathologies (such as atherosclerosis⁽⁵⁴⁾ and neural amyloid deposition⁽⁵⁵⁾).  If these mice were also rejuvenated by a year, the result would be correspondingly more relevant to humans.

Some interventions discussed in ref. 1 are transgenic, and the technique proposed there for applying them to two-year-old mice is not truly late-onset: drug-mediated induction of loxP recombination to activate transgenes introduced in an inactive configuration by germ-line transformation.  Truly late-onset transgenesis requires comprehensive somatic gene therapy.  Presently, transfection efficiency of gene therapy is limited, as is often the persistence of transgene expression.⁽⁵⁶⁾  However, progress is rapid in these areas.  In particular, vectors exist that can transfect non-dividing cells.⁽⁵⁷⁾

Nonetheless, a daunting amount of additional progress is required if somatic gene therapy is to become as sophisticated as seems necessary for anti-aging purposes.  Hence, if and when substantial aging-reversal were developed in mice and analogous transgenes were designed for humans, many individuals might seek to have children harbouring such transgenes.⁽⁵⁸⁾  This initially appears worrying in safety terms (irrespective of ethical or moral considerations).  However, it may not be so problematic.  Since (in this scenario) the interventions in question will reverse, rather than retard, aging, it will be preferable to construct these transgenes in the same inactive, drug-inducible form that has been advocated⁽¹⁾ for mice.  Then, an individual could choose to turn on his or her anti-aging genetic arsenal at age 50, say, if and only if his or her desire for extended life outweighed any side-effects that those transgenes had, in those 50 years, been found to possess.  In those same 50 years, however, huge advances would surely have been made both in somatic gene therapy and in what transgenes were available.  Accordingly, our 50-year-old might perceive greater aging-reversal benefit from contemporary somatic gene therapy than from the outdated (albeit ubiquitously expressible) technology with which he or she was born.  If so, germ-line therapy to reverse human aging might be implemented in inactive form, but never—at least, not purposely—activated.

Finally, it has been suggested⁽⁴⁾ that indefinite postponement of aging is incompatible with the retention of self, because it necessarily entails the periodical replacement of all body parts, including the brain.  However, a key distinction between animate and inanimate objects is that the former do indeed, autonomously, replace their components throughout life.  Most proteins, for example, have a half-life of only a few days, even in postmitotic cells.  This is a key reason why we live so long: for example, titanium is vastly stronger than cartilage, but titanium knees last only ten years.⁽⁵⁹⁾  Wholesale, en bloc replacement of the brain would be a different matter altogether, however.  There must, therefore, be a threshold granularity of replacement that is compatible with continued identity.  It seems plausible that the individual neuron is below this threshold, and thus that cell therapy (such as has already been used, albeit with serious side-effects in these early studies⁽⁶⁰⁾) is a legitimate component of brain rejuvenation that would not endanger the recipient‘s continued identity.

What do recent centuries predict?

One way to estimate the future pace of progress in combating aging is by extrapolation from the past.  A reasonable approach is to compare our present knowledge about how to combat aging with our past knowledge about goals that were subsequently achieved.  The most direct comparison is with infectious diseases, which accounted for 40% of US deaths in 1900 but only 3% in 1950.⁽⁶¹⁾  We do not obviously understand less today about aging and how to combat it than we understood in 1870 about infectious diseases and how to combat them: indeed, some would say we understand more.  Hence, one cannot dismiss as absurd the prospect of achieving the same degree of progress against aging in the next 80 years as was achieved against infection in the period 1870-1950.  Of course, one also cannot confidently infer that we will achieve such progress.  Doing so would, clearly, be much more dramatic than extending a two-year-old mouse’s lifespan by a year.  Indeed, it would constitute true “engineered negligible senescence” (ENS).

Recent data indicate that we are already accelerating the rate at which we postpone death of the most robust subset of the population.⁽⁶²⁾  The age of the oldest Swede rose by over one year per decade in the period 1969-1999, twice the rate during 1861-1969⁽⁶²⁾ and necessarily much more than that relative to the preceding millennium.  Although we may fail to continue this trend, or even to maintain the present rate of increase, there is no obvious reason why it should not continue.  To achieve ENS, “all” that is required is to continue this acceleration until the rate of increase reaches one year per year, which a logarithmic regression to the above data⁽⁶²⁾ predicts could happen this century (Figure 1).  This might be termed the “anti-aging escape velocity”, where aging still exists but is being postponed (by successive medical advances) faster than time is passing.

Anti-aging medicine for age-related diseases: who is missing the point?

Only 1% of the US National Institutes of Health (NIH) budget goes to research on the basic biology of aging, and the situation in western Europe is similar.  A frequent argument for increasing this proportion is that even a modest extension of healthspan would hugely impact the incidence of age-related diseases.  Thus, money should be spent on the effort to increase healthspan, despite the uncertainty of rapid progress.  This logic has consistently fallen upon deaf ears outside the biogerontology research community.  Why?

Various popular explanations seem inadequate.  The dictum that prevention is better than cure is easily accepted in other contexts, so it should be easy to communicate here, to government if not to the private sector.  Comprehension of the argument cannot be wholly lacking: those with influence in national government surely possess sufficient acumen.  Religious opposition may be an issue in the US, but is much less so in Europe.  The reallocation of funds from elsewhere in the system is not necessarily the issue, since total funding is not fixed.

Perhaps it is biogerontologists, not their interlocutors, who are guilty of a critical oversight.  Their focus on making aging less debilitating has given rise to phrases such as “successful aging” and “compression of morbidity” as goals towards which biogerontology strives.  However, diverse statistics show consistently that the period of late-life frailty is not being shortened by medical advances.^(63-66)  Its onset is being steadily postponed, but so is its conclusion (i.e., death).  For example, between 1982 and 1994 the proportion of Americans over 65 who were disabled (defined as chronically unable to perform at least one basic activity of daily living, such as cooking or bathing) declined impressively, from 24.9% to 21.3%,⁽⁶⁷⁾ but this was due to a later age of onset, not a shorter period, of disability (Table 2).

Thus, the non-biogerontologist may conclude that increased research into aging will not deliver the stated benefit of less age-related debilitation.  After all, why should medical advances that benefit robust people (delaying their frailty) not also, generally, benefit frail people (delaying their death)?  The biogerontologist may counter that future interventions into aging would differ in this respect from past ones addressing specific age-related diseases, but given the difficulties in distinguishing the two this is not convincing.  Two noted biogerontologists have recently voiced similar views.^(70,71)

Which is the greater risk—false hopes, or a false sense of security?

The 2000/2001 chair of the world’s largest biogerontology society stated recently⁽⁷²⁾ that the first 150-year-old human is probably already alive.  This prediction, with all that it implies for increases in average lifespan in the same timeframe, has been widely publicised on account of a wager to which it led.⁽⁷³⁾  However, what little comment has been forthcoming within the biogerontology community has usually been one of mild distaste.  This is noteworthy, because a prediction of what will happen over 100 years hence is scientifically just as meaningless as one with no timescale at all attached, and the latter is much more common in this field.

A major explanation for biogerontologists’ wariness regarding even such distant timescales may be the intrinsic inertia of scientific research funding.  A recent survey⁽⁷⁴⁾ found that only 8% of Americans expect to live to 100, and only 20% even expect the average lifespan of Americans born in 2010 to exceed 100.  Ultimately, the reason this is the prevailing view is that it is the consensus of public statements by those perceived—rightly or wrongly—as being most likely to know: namely, biogerontologists.  While governments and the public perceive human ENS as unachievable in their or their children’s lifetimes, they will not agitate for research directed at bringing it about.  Those who allocate research funds (be they funding agencies or peer reviewers) are thus reluctant to risk their reputations for prudence by favouring ambitious but expensive anti-aging research.  This, in turn, forces biogerontologists to focus on more conservative projects.  The circle is closed because such scientists cannot bite the hands that feed them by drawing attention to this chain of events, so they continue to avoid raising the public’s sights.  Additionally, many influential biogerontologists sincerely believe that human ENS really is unforeseeable,^(2,75) making this logjam even more immovable.

Another reason is that any positive remark about the feasibility of ENS risks two undesirable reactions: in the public the engendering of unwarranted optimism, and in the research community the pigeon-holing of oneself with snake oil-peddling charlatans.  Both are unjustified overreactions, but they still happen.

However, these arguments may be unsatisfactory.  Firstly, the alleged danger of unwarranted optimism is that it will rebound as a reduction in the field’s funding if today’s incautious predictions are not fulfilled.  If so, why has this not happened to cancer research, which was trumpeted in the 1960s as likely to yield results within a few years far exceeding what it has actually yielded even by today?  Surely funding of aging research would be similarly maintained if reasonable progress were made, even if that progress fell short of present-day predictions.  Secondly, however meaningless it may be in scientific terms to say that human ENS may be developed within a few decades, it is very significant in social terms.  Profound personal decisions, such as investment in life insurance and pension plans, are based on the perceived likelihood of events a few decades hence.  Governments are even more reliant on the best possible long-term predictions  In such circumstances, if a biogerontologist feels that the probability of a big anti-aging breakthrough within a few decades is non-negligible, can he or she justify keeping that view private?

This is not to say that the reasons given previously for remaining silent on these matters are wrong, only that they must be weighed against counterarguments.  In doing so, the biogerontologist must consider the wider social consequences of ENS and the extent to which debate on it now can influence those consequences.  A key consideration⁽²⁾ is whether society would eventually need to impose stringent population-limiting regulations upon itself.  This entirely depends on whether global population continues to grow, which is rendered uncertain by the present rapid decline in birth rates among affluent societies worldwide.  Nobody knows whether children will continue to become less popular, nor whether that trend is or will be influenced by perceptions of one’s remaining healthy life expectancy.  Our inability to predict future birth trends accurately, even presuming no medium-term anti-aging breakthroughs, is eloquently illustrated by the United Nations’ policy of publishing projections based on three different sets of assumptions, leading to world populations in 2050 differing by three billion.⁽⁷⁶⁾  (2050 is well before any anti-aging regimen could have this much effect on population.)  Other questions, such as whether life with ENS would be boring or shallow,⁽⁷⁷⁾ are if anything even more unanswerable, since answers rely on highly fragile assumptions about the retention of present cultural norms.  Apprehensions concerning political and distributive justice (tyrants reigning indefinitely, treatments being too costly to be universally available) cannot realistically restrain technological advance and must be solved as they arise.  The morality of ENS is perhaps the least knowable of all: until ENS is here, and new norms develop concerning what constitutes an appropriate length of life given the options available, we cannot morally evaluate it.⁽⁷⁸⁾

If social and ethical arguments concerning life with ENS are inconclusive, what of society’s transition to that state?  If ENS becomes widely perceived as achievable many years before it can actually be implemented, society has all those years to plan for the transition and make it as smooth as possible, without (for example) a long period when such medicine is only available to the wealthy.  A seductive conclusion is that we can safely delay public debate until mouse aging is well under control, because the time from then until the arrival of human ENS will be ample for society to prepare.  But we must also consider the immediate effects of ENS becoming widely perceived as foreseeable.  Many people would consider themselves likely to benefit personally from this anticipated breakthrough—but only if they survive until it is developed.  This might sharply increase the demand for health care, which already takes a large share of Western nations’ wealth.  The effects on the global economy could be severe.  Recruitment into dangerous but socially vital professions, such as fire and police services, might fall; improved financial rewards might adequately mitigate this, or they might not.

Present-day societal considerations

Whatever the strength of arguments that aging is actually a good thing, people do not like it.  In the same survey of public expectations mentioned earlier,⁽⁷⁴⁾ fully 63% of Americans said that they would like to live to 100.

Perhaps the only safe prediction about a post-aging world is the one that most deeply motivates the quest for it: the huge consequent reduction in chronic disability.  Consideration of society’s present attitudes towards ill health can and should influence what biogerontologists tell the public.  No society in history (to our knowledge) has experienced a sustained compression of morbidity; nor, as we have argued above, is there any realistic prospect of this.  Hence it may be misleading to promote it as our goal.  Conversely, essentially everyone agrees that postponing age-related diseases is desirable.  If society came to regard aging as it regards age-related diseases—that is, as potentially preventable—it would probably also regard it, again like age-related diseases, as an affront to human dignity whose prevention, however difficult, should be ardently sought.  Then the funding logjam described earlier would evaporate and research to develop human ENS would surely be much accelerated.  The effort that society invests in postponing specific diseases and/or postponing aging depends heavily on this issue, so it is one on which individuals and governments deserve to be better informed than at present.

One way to increase society’s understanding of biogerontology is to increase their interest in it.  The aforementioned wager⁽⁷³⁾ is an example.  Prizes are another approach—one that has historically attracted talent to hard problems at relatively little cost and reliably captures the public imagination.  One option⁽⁷⁹⁾ is to identify specific goals that experts believe are feasible within a decade or so and attach rewards to their accomplishment.  This might distort the field’s research priorities; also, many scientifically valid goals may be too esoteric to capture the public’s imagination.  Both problems are avoided by another proposal,⁽⁸⁰⁾ to award a prize for the oldest ever Mus musculus.  This has its own difficulties, however, including validation that a mouse is really as old as claimed and decisions on what types of intervention are permitted.  The two concepts are largely complementary: many key anti-aging questions are not best studied by making long-lived mice, and would be candidates for specific prizes.

The public include wealthy individuals, who may avoid investing in biogerontology because they feel that their dollars cannot yet make much difference to the rate of progress.  The repeated awarding of a prize whose goal such individuals understand may alter that perception, sidestepping the sometimes ponderous rate at which public funding policy responds to changed circumstances.

Conclusion?

This article has, purposely, drawn few conclusions.  Rather, we hope to stimulate debate on the issues raised by the prospect of ENS being developed soon enough to benefit many who are already alive—a prospect on whose likelihood experts (and we) are divided.^(1,2,75)  However, we do not identify any unambiguous, show-stopping obstacle to the development of a panel of interventions sufficient to rejuvenate a two-year-old mouse by a year (with all that that may entail for public expectations and demands concerning human aging) within about a decade.  We therefore submit that the possibility of that occurrence, although unquantifiable, is not remote enough to justify society’s prevailing complacency about it.

Some years ago, Rose predicted⁽⁸¹⁾ that eventually we will double human lifespan—and that, when we do, we will be ashamed that we did not do it much sooner.  Now is the time for society to prove him wrong, one way or the other: either to establish that human lifespan cannot be greatly increased, or to develop such technology without unnecessary delay.

Acknowledgements

We are much indebted to Jay Olshansky and Adelaide Carpenter for critical reading of the manuscript, and to David Gems, Len Hayflick, Rich Miller, Huber Warner and John Wilmoth for their invaluable contributions to the debate from which it arose.  The meeting at which that debate began took place at the UCLA Center for the Study of the Evolution and the Origin of Life, hosted by the Program on Medicine, Technology and Society of the UCLA School of Medicine and funded by the Maximum Life Foundation.

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