The foreseeability of real anti-aging medicine: Faith, rational design, and our duty to abandon dogmatism just this once Aubrey D.N.J. de Grey Department of Genetics, University of Cambridge Website:

Structure of this talk 1) some unpleasant truths about our rhetoric 2) human calorie restriction and its emulation 3) an alternative with a “paradigm problem” 4) why something must be done

Yes, Huber authorised this quote The difficult political climate for a major [life extension research] branch within the NIA is reflected by recent correspondence with Huber Warner, Associate Director of NIA’s Biology of Aging Program, in which Warner wrote, “our NIA Director does not look forward to having congressmen ask him during testimony sessions about whether our goal is to extend the human life span”. Mackey T, Rejuvenation Research 7:211

Was this wise, in the long run? “Aging is not a disease” “Add life to years, not just (!) years to life” “… one-hoss shay …”

What Jim Fries actually wrote “Present data allow calculation of the ideal average life span, approximately 85 years. Chronic illness may presumably be postponed by changes in life style, …. Thus, the average age at first infirmity can be raised, thereby making the morbidity curve more rectangular. Extension of adult vigor far into a fixed life span compresses the period of senescence near the end of life.” Fries 1980, NEJM 303:130

The desperate discernment of compression of morbidity Manton 1997, PNAS 94:2593; Hodes testimony 2001

The desperate discernment of compression of morbidity Year Mild disability5.7%6.2%4.8%4.4%3.2% Moderate disab.6.9%7.0%6.7%6.1%6.0% Severe disability6.7%6.5%6.7%6.4% Total 26.2% 24.2%22.5% 19.7% National Long-Term Care Survey (Manton 2001, Fries 2003) Proportion of US over-65’s disabled reduced by 25% !!! Hm, but proportion severely disabled reduced by only 5%

The desperate discernment of compression of morbidity Year Life expec. at Mild disability0.94 y1.04 y0.82 y0.77 y0.57 y Moderate disab.1.14 y1.17 y1.15 y1.06 y Severe disability1.11 y1.09 y1.15 y1.11 y1.13 y Total 4.32y 4.38 y4.14 y3.91 y 3.49y Average time spent disabled reduced by 19% Time spent severely disabled increased by 2%

The desperate discernment of compression of morbidity Himsworth/Goldacre 1999, BMJ 319:1338

Has this rhetoric served gerontology well? Institute1993 budget2003 budget NCI$1981m$4592m NINDS$600m$1456m NHLBI$1215m$2794m NIA$400m$994m Does this parity match our media exposure?

A radical new theory: politicians are not as dumb as they look Might it conceivably be that: - politicians see no convincing evidence for sustained compression of morbidity? -nor for biogerontology’s potential to deliver it in the foreseeable future? -rhetoric better supported by real data would elicit more positive reactions?

Are bioconservatives exploiting our fear of discussing extreme life extension? “Beyond Therapy”: 311 pages “Ageless Bodies”: 46 pages Biogerontologists who discuss foreseeable, extreme life extension in the media: 1 Biogerontologists who don’t: N-1, N >> 6… Interpretation: our failure to educate the public out of their ambivalence about real anti-aging medicine gives bioconservatives a foothold via which to turn people against ES cells etc.

A modest proposal: evidence-based rhetoric Biogerontologists Voters, shareholders Government, industry Media Ballot box Peer review, short-termism

A modest proposal: evidence-based rhetoric Biogerontologists Voters, shareholders Government, industry Media Ballot box Peer review, short-termism Philanthropy and Vision

A modest proposal: evidence-based rhetoric Biogerontologists Voters, shareholders Government, industry Media Ballot box Peer review, short-termism Philanthropy and Vision

How should we approach serious life extension? Three sincerely-held views 1) Denial -- e.g. Hayflick, Olshansky 2) Faith -- e.g. A 4 M, Miller, Guarente 3) Rational design -- e.g. de Grey

Denial: are the arguments robust? “Proposals to circumvent aging by replacing all parts as they age with new or younger parts are unlikely to be tenable.... When everything is replaced in a car, it is no longer identical to the original. … In parallel with the dilemma of replacing all parts in an aging inanimate object, doing so in humans would result in a different person.” Hayflick 2004, JG:BS 59A:573

Denial: are the arguments robust? “… slow development at any age is viewed universally as a serious pathology. If retarding the mental and physical development of someone from birth to age 20 years for, say, 10 years, in order to gain a decade of additional life is unattractive, then slowing one’s aging processes in later life will not be attractive for the same reasons.” Hayflick 2004, JG:BS 59A:573

Faith: the hype and the reality “A 4 M believes that the disabilities associated with normal aging are caused by physiological dysfunction which in many cases are [already?] amenable to medical treatment, such that the human life span [mean? max?] can [already?] be increased, and the quality of one’s life improved as one grows chronologically older.” American Academy of Anti-Aging Medicine

Faith: the hype and the reality “CR typically produces in rodents an increase in mean and maximal longevity of about %. [if begun at weaning] Similarly, [mouse dwarf mutants, small dog breeds -- prenatal CR?]. Thus one can, with some confidence, expect that an effective antiaging intervention [begun when??] might increase the mean and maximal human lifespan by about 40%” Miller 2002, Milbank Q 80:155

Proportionality: the null hypothesis? OrganismManipulationMax. life ext. C. elegans Genetic and anatomical 5 months Drosophila Temperature, photoperiod Several months to a year GrasshopperDesiccationSeveral months Mus musculus (relative to non-obese controls) 53% CR~14 months Dog (avg. life 11 y)25% CR~14 months

Proportionality: the null hypothesis? Okinawans versus same-age mainland Japanese: - half the dementia - half the breast, colon and prostate cancer - less than half the cardiovascular disease (just like bona fide CR in rodents) times as many centenarians …. i.e. a maximum lifespan ~1.5 years more than mainland Japan. Mean lifespan was only 1.3 years more.

Evolutionary theory supports the data, not the hype “the extent of the evolutionary pressure to maintain adaptability to a given duration of starvation varies with the frequency of that duration.... The pattern of starvation that the weather imposes is suggested here to … cause all terrestrial animals, even those as far apart phylogenetically as nematodes and mice, to possess the ability to live a similar maximum absolute (rather than proportional) amount longer when food is short.” de Grey 2005, Gerontology 51, in press

Rational design of real anti-aging medicine Damage rising with ageIt or its effects reversible by Cell loss, cell atrophyExercise, cell therapy, growth factors Extracellular junkPhagocytosis by immune stimulation Extracellular crosslinksALT-711, other AGE-breakers Cell senescenceImmune ablation of senescent cells mtDNA mutationsAllotopic expression of 13 proteins Lysosomal junkTransgenic microbial hydrolases Nuclear [epi]mutations (only cancer matters) Telomerase/ALT gene deletion plus periodic stem cell reseeding de Grey , various

Impossibly piecemeal? An analogy

Response of the establishment: an instructive comparison “Intervention to remove the accumulating damage would sever the link between metabolism and pathology, so has the potential to postpone aging indefinitely. We survey the major categories of such damage and the ways in which, with current or foreseeable biotechnology, they could be reversed. Such ways exist in all cases, implying that indefinite postponement of aging … may be within sight.” Aubrey de Grey, Bruce Ames, Julie Andersen, Andrzej Bartke, Judy Campisi, Roger McCarter

Response of the establishment: an instructive comparison “I think it would be irresponsible to publish the work as it stands, because it could engender quite unwarranted optimism in readers.” Anonymous review of de Grey, Ames et al “Rae laments that he "has yet to hear a cogent rejoinder …" from the anti-aging skeptics; in my view it's because we skeptics have yet to see [anything] even remotely convincing from de Grey and his ilk, and don't wish to draw further public attention to this fringe movement” Anonymous review of letter to JG:BS

What is at stake? - Some large egos (including mine) - Some chunk of today’s modest budget - 100,000 lives per day that we delay success of the right research

“100,000 lives a day? Who’s hyping now?” My axiom: Extending healthy lives = saving lives Old people are people too Any challenge?

Escape velocity: why “saving lives” is, if anything, an understatement de Grey 2004, PLoS Biology 2:723

Whose duty is it to act? Biogerontologists Voters, shareholders Government, industry Media Ballot box Peer review, short-termism

Conclusion - Our traditional rhetoric has failed utterly - If anyone can break the logjam, we can - Instead, we are cravenly distorting biology - This is costing thousands of lives each day Now is the time to take risks for life