Escape Velocity: Why the Prospect of Extreme Human Life Extension Matters Now Aubrey D

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Book Review/Science in the Media Escape Velocity: Why the Prospect of Extreme Human Life Extension Matters Now Aubrey D. N. J. de Grey he biogerontologist David Kass retorted that science isn’t like Sinclair and the bioethicist that: modest success tends to place the TLeon Kass recently bit between our teeth and can often locked horns in a radio debate result in advances far exceeding our (http:⁄⁄www.theconnection.org/ expectations. shows/2004/01/20040106_b_main. Coping with Methuselah consists of asp) on human life extension that seven essays, mostly on the economics was remarkable for one thing: on the of life extension but also including one key issue, Kass was right and Sinclair essay surveying the biology of aging and wrong. Sinclair suggested, as have one on the ethics of life extension. The other experts, including his mentor Lenny Guarente and the National Copyright: © 2004 Aubrey D. N. J. de Grey. This is an open-access article distributed under the terms of Institute on Aging advisory council the Creative Commons Attribution License, which member Elizabeth Blackburn, that permits unrestricted use, distribution, and reproduc- tion in any medium, provided the original work is Kass and other bioconservatives properly cited. are creating a false alarm about life extension, because only a modest (say, Abbreviations: AEV, actuarial escape velocity 30%) increase in human life span is Aubrey D. N. J. de Grey is in the Department of Genet- achievable by biomedical intervention, ics at the University of Cambridge, Cambridge, United Kingdom. E-mail: [email protected] whereas Kass’s apprehensions concern extreme or indefi nite life extension. DOI: 10.1371/journal.pbio.0020187 PLoS Biology | http://biology.plosjournals.org June 2004 | Volume 2 | Issue 6 | Page 0723 economic issues addressed are wide anything beyond this degree of life The second oversight made both ranging, including detailed analysis of extension is inconceivable. by the contributors to Coping with the balance between wealth creation by I agree with these predictions in Methuselah and by other commentators the employed and wealth consumption two respects: that the degree of life is demographic. Life expectancy is in pensions and health care; most extension achieved by fi rst-generation typically defi ned in terms of what chapters focus on the United States, drugs of this sort may well approach the demographers call a period survival but the closing chapter discusses these (currently unknown) amount elicitable curve, which is a purely artifi cial issues in a global context. Each essay by caloric restriction itself in humans, construction derived from the is followed by a short commentary and that it is unlikely to be much proportions of those of each age by another distinguished author. exceeded by later drugs that work the at the start of a given year who die Within their own scope, all of these same way. In two other ways, however, I during that year. The ‘life expectancy’ contributions are highly informative claim they are incorrect. The fi rst error of the ‘population’ thus described and rigorous. Dishearteningly, is the assumption of proportionality: I is that of a hypothetical population however, all echo Sinclair’s views about have recently argued (de Grey 2004), whose members live all their lives the limited prospects for life extension from evolutionary considerations, with the mortality risk at each age in the coming decades. In my opinion, that longer-lived species will show that the real people of that age they make three distinct oversights. a smaller maximal proportional experienced in the year of interest. The fi rst concerns current science. life-span extension in response to The remaining life expectancy of Sinclair and several other prominent starvation, probably not much more someone aged N in that year is more gerontologists are presently seeking than the same absolute increase seen than this life expectancy minus N for human therapies based on the in shorter-lived species. The second two reasons: one mathematical (what long-standing observation that error is the assertion that no other one actually wants, roughly, is the age lifelong restriction of caloric intake type of intervention can do better. In to which the probability of survival considerably extends both the healthy concert with other colleagues whose is half that of survival to N) and one and total life span of nearly all species areas of expertise span the relevant biomedical (mortality rates at each in which it has been tried, including fi elds, I have described (de Grey et al. age, especially advanced ages, tend rodents and dogs. Drugs that elicit the 2002, 2004) a strategy built around the to fall with time). My spirits briefl y gene expression changes that result actual repair (not just retardation of rose on reading Aaron and Harris’s from caloric restriction might, these accumulation) of age-related molecular explicit statement (p. 69) of the latter workers assert, extend human life span and cellular damage—consisting of just reason. Unfortunately, they didn’t by something approaching the same seven major categories of ‘rejuvenation discuss what would happen if age- proportion as seen in rodents—20% therapy’ (Table 1)—that appears specifi c mortality rates fell by more is often predicted—without impacting technically feasible and, by its nature, than 2% per year. An interesting quality of life, and even when is indefi nitely extensible to greater scenario was thus unexplored: that in administered starting in middle age. life spans without recourse to further which mortality rates fall so fast that They assiduously stress, however, that conceptual breakthroughs. people’s remaining (not merely total)

Table 1. Strategies for Engineered Negligible Senescence

Type of Age-Related Damage Suggested In Proposed Repair (Or Obviation)

Cell loss, cell atrophy Brody 1955 Stem cells, growth factors, exercise (Rao and Mattson 2001)

Senescent/toxic cells Hayfi ck 1965 Ablation of unwanted cells (Barzilai et al. 1999)

Nuclear mutations/epimutations Szilard 1959, Whole-body interdiction of lengthening of telomeres (only cancer matters) Cutler 1982 (de Grey et al. 2004)

Mitochondrial mutations Harman 1972 Allotopic expression of 13 proteins (Manfredi et al. 2002)

Extracellular cross-links Monnier and AGE-breaking molecules (Kass et al. 2001) Cerami 1981

Extracellular aggregates Alzheimer 1907 Immune-mediated phagocytosis (Schenk et al. 1999)

Lysosomal aggregates Strehler 1959 Transgenic microbial hydrolases (de Grey 2002)

The seven categories of accumulating molecular or cellular side effects of metabolism whose possible contribution to age-related mammalian physical or cognitive decline is an established school of thought within contemporary biogerontology, and the foreseeable therapies that can repair or obviate them. DOI: 10.1371/journal.pbio.0020187.t001

PLoS Biology | http://biology.plosjournals.org June 2004 | Volume 2 | Issue 6 | Page 0724 life expectancy increases with time. Is this unimaginably fast? Not at all: it is simply the ratio of the mortality rates at consecutive ages (in the same year) in the age range where most people die, which is only about 10% per year. I term this rate of reduction of age- specifi c mortality risk ‘actuarial escape velocity’ (AEV), because an individual’s remaining life expectancy is affected by aging and by improvements in life- DOI: 10.1371/journal.pbio.0020187.g002 extending therapy in a way qualitatively very similar to how the remaining life Figure 1. Physical and Actuarial Escape Velocities expectancy of someone jumping off a Remaining life expectancy follows a similar trajectory whether one walks off a cliff or merely ages: the time scales differ, but one’s prognosis worsens with time. Mild cliff is affected by, respectively, gravity mitigation of this (whether by jet propulsion or by rejuvenation therapies) merely and upward jet propulsion (Figure 1). postpones the outcome, but suffi ciently aggressive intervention overcomes the force of The escape velocity cusp is closer gravity or frailty and increasingly distances the individual from a sticky end. Numbers than you might guess. Since we are denote plausible ages, at the time fi rst-generation rejuvenation therapies arrive, of people following the respective trajectories. already so long lived, even a 30% increase in healthy life span will give the fi rst benefi ciaries of rejuvenation whenever they arrive, will surely rejuvenation therapies for humans for therapies another 20 years—an build on a string of prior laboratory at least 25 years, and it could certainly eternity in science—to benefi t achievements. Those achievements, be 100 years. But given the present from second-generation therapies it seems to me, will have progressively status of the therapies listed in Table 1, that would give another 30%, and worn down humanity’s evidently we have, in my view, a high probability so on ad infi nitum. Thus, if fi rst- desperate determination to close its of reaching the mouse life extension generation rejuvenation therapies were eyes to the prospect of defeating its milestone just described (which I call universally available and this progress foremost remaining scourge anytime ‘robust mouse rejuvenation’) within in developing rejuvenation therapy soon. The problem (if we can call it just ten years, given adequate and could be indefi nitely maintained, these that) is that this wearing-down may focused funding (perhaps $100 million advances would put us beyond AEV. have been completed long before the per year). And nobody in Coping with Universal availability might be thought rejuvenation therapies arrive. There Methuselah said so. This timeframe economically and sociopolitically will come an advance—probably a could be way off, of course, but as implausible (though that conclusion single laboratory result—that breaks Wade notes (p. 57), big advances often may be premature, as I will summarise the camel’s back and forces society occur much sooner than most experts below), so it’s worth considering the to abandon that denial: to accept expect. Even the most obvious of these same question in terms of life-span that the risk of getting one’s hopes lifestyle changes—greater expenditure potential (the life span of the luckiest up and seeing them dashed is now on traditional medical care, avoidance people). Figure 1 again illustrates outweighed by the risk of missing the of socially vital but risky professions— this: those who get fi rst-generation AEV boat by inaction. What will that could severely destabilise the global therapies only just in time will in fact result be? I think a conservative guess economy; those better versed in be unlikely to live more than 20–30 is a trebling of the remaining life span economics and sociology than I would years more than their parents, because of mice of a long-lived strain that have doubtless be even more pessimistic they will spend many frail years with a reached two-thirds of their normal life about our ability to negotiate this short remaining life expectancy (i.e., a span before treatment begins. This period smoothly. Overpopulation, high risk of imminent death), whereas would possess what I claim are the key probably the most frequently cited those only a little younger will never necessary features: a big life extension, drawback of curing aging, could not get that frail and will spend rather in something furry and not congenitally result for many decades, but the same few years even in biological middle sick, from treatment begun in middle cannot be said for breadth of access age. Quantitatively, what this means age. irrespective of ability to pay: in a post- is that if a 10% per year decline of It is the prospect of AEV, of course, 9/11 world, restricted availability of mortality rates at all ages is achieved that makes this juncture so pivotal. rejuvenation therapies resembling and sustained indefi nitely, then the It seems quite certain to me that the that seen today with AIDS drugs would fi rst 1000-year-old is probably only 5–10 announcement of such mice will invite violence on a scale that, shall we years younger than the fi rst 150-year- cause huge, essentially immediate, say, might be worth trying to avoid. old. society-wide changes in lifestyle and Am I, then, resigned to a future in The third oversight that I observe expenditure choices—in a word, which countless millions are denied in contemporary commentaries on pandemonium—resulting from the many decades of life by our studied life extension, among which Coping anticipation that extreme human life reluctance to plan ahead today? Not with Methuselah is representative, is the extension might arrive soon enough quite. The way out is pointed to in most signifi cant because of its urgency. to benefi t people already alive. We Lee and Tuljapurkar’s (1997) graph First-generation rejuvenation therapies, will probably not have effective of the average wealth consumed

PLoS Biology | http://biology.plosjournals.org June 2004 | Volume 2 | Issue 6 | Page 0725 and generated by an individual as a References Kass DA, Shapiro EP, Kawaguchi M, Capriotti function of age, reproduced in Alzheimer A (1907) Uber eine eigneartige AR, Scuteri A, et al. (2001) Improved arterial Coping Ehrankung der Himrinde. Allg Z Psychiatr compliance by a novel advanced glycation end- with Methuselah (p. 143). Once AEV is Psychish-Gerichtliche Med 64: 146–148. product crosslink breaker. Circulation 104: achieved, there will be no going back: Barzilai N, She L, Liu BQ, Vuguin P, Cohen P, 1464–1470. Lee R, Tuljapurkar S (1997) Death and taxes: rejuvenation research will be intense et al. (1999) Surgical removal of visceral fat reverses hepatic insulin resistance. Diabetes 48: Longer life, consumption, and social security. forever thereafter and will anticipate 94–98. Demography 34:67–81. and remedy the life-threatening Brody H (1955) Organization of the cerebral Manfredi G, Fu J, Ojaimi J, Sadlock JE, Kwong JQ, et al. (2002) Rescue of a defi ciency in degenerative changes appearing cortex III. J Comp Neurol 102: 511–556. Cutler RG (1982) The dysdifferentiation ATP synthesis by transfer of MTATP6, a at newly achieved ages with ever- hypothesis of mammalian aging and longevity. mitochondrial DNA-encoded gene, to the nucleus. Nat Genet 30: 394–399. In: Giacobini E, editor. The aging brain: increasing effi cacy and lead time. This Monnier VM, Cerami A (1981) Nonenzymatic Cellular and molecular mechanisms of aging will bring about the greatest economic browning in vivo: Possible process for aging of in the nervous system. New York: Raven Press. long-lived proteins. Science 211: 491–493. change of all in society: the elimination pp. 1–19. Rao MS, Mattson MP (2001) Stem cells and aging: of retirement benefi ts. Retirement de Grey ADNJ (2002) Bioremediation meets Expanding the possibilities. Mech Ageing Dev benefi ts are for frail people, and there biomedicine: Therapeutic translation of 122: 713–734. microbial catabolism to the lysosome. Trends won’t any frail people. The graph Schenk D, Barbour R, Dunn W, Gordon G, be Biotechnol 20: 452–455. Grajeda H, et al. (1999) Immunization with just mentioned amply illustrates how de Grey ADNJ (2004) The unfortunate amyloid-beta attenuates Alzheimer-disease-like much wealth will be released by this. infl uence of the weather on the rate of aging. pathology in the PDAPP mouse. Nature 400: Gerontology. In press. 173–177. My hope, therefore, is that once policy de Grey ADNJ, Ames BN, Andersen JK, Bartke Strehler BL, Mark DD, Mildvan AS, Gee MV makers begin to realise what’s coming A, Campisi J, et al. (2002) Time to talk SENS: (1959) Rate and magnitude of age pigment they will factor in this eventual windfall Critiquing the immutability of human aging. accumulation in the human myocardium. J Ann N Y Acad Sci 959: 452–462. Gerontol 14: 430–439. and allocate suffi cient short-term de Grey ADNJ, Campbell FC, Dokal I, Fairbairn LJ, Szilard L (1959) On the nature of the ageing resources to make the period of limited Graham GJ, et al. (2004) Total deletion of in process. Proc Natl Acad Sci U S A 45: 35–45. availability of rejuvenation therapies vivo telomere elongation capacity: An ambitious but possibly ultimate cure for all age-related brief enough to prevent mayhem. This human cancers. Ann N Y Acad Sci. In press. will, however, be possible only if such Harman D (1972) The biologic clock: The Book Reviewed resources begin to be set aside long mitochondria? J Am Geriatr Soc 20: 145–147. Aaron HJ, Schwartz WB, editors (2004) Coping Hayfl ick L (1965) The limited in vitro lifetime of with methuselah. Washington (District of enough in advance—and we don’t human diploid cell strains. Exp Cell Res 37: Columbia): Brookings Institution Press. 296 pp. know how long we have.  614–636. ISBN (paperback) 0-8157-0039-3. US$19.95.

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