What should actuaries be doing in the run-up to a post-aging world? Aubrey D.N.J. de Grey Department of Genetics, University of Cambridge Reprints, general info:

Structure of this talk - definitions, milestones and strategies - why the “War On Aging” may be only a decade away - why it may be a very short war - why we may also “win the peace” very quickly - what this means for those projecting population trends: what CMIB et al. can do to make (4) a reality

Definitions Senescence (Anon): the process that progressively reduces an organism’s remaining life expectancy Negligible senescence (Finch 1990): absence, in a population, of a degree of senescence sufficient to be statistically detectable by examining its age distribution Engineered negligible senescence (de Grey 1999): the biotechnological conversion of a population that exhibits statistically detectable senescence into one that does not

t 1 t 2 t 3 t 4 t 5 t 6 : late-onset human ENS (LOHENS) ubiquitous A brief “history” of engineered negligible senescence (ENS)

Q: What do people need, to start caring about life extension? A: Laboratory results that they can identify with: - life extension in mammals - treatment initiated late in life

t 1 : important components of human aging all known to be so t 2 : feasible plan for “Robust Mouse Rejuvenation” described t 3 : RMR developed: remaining LE of 2yo mice trebled LOHENS widely seen as foreseeable, WOA begins t 5 : LOHENS developed, some people are in “clinical trials” t 6 : late-onset human ENS (LOHENS) ubiquitous A brief “history” of engineered negligible senescence (ENS) t4:t4: t5:t5: t6:t6:

Three paradigms for intervention Gerontology Engineering Geriatrics Metabolism Damage Pathology Claim: only the “engineering” approach can achieve substantial extension of human healthspan any time soon

2. Why the War On Aging may be only a decade away

Metabolism Damage Pathology: The seven deadly things -- or, t 1 was 1982 Respiration (oxidation) Carbohydrate metabolism (glycation) Cell turnover (mutations, telomere shortening, dysregulation, stem cell depletion) Etc, etc, etc Cell loss/atrophy Nuclear mutations and epimutations mtDNA mutations Cell senescence AGE crosslinks Extracellular junk Lysosomal junk Er.... that’s it! Neurodegeneration Atherosclerosis Cancer Diabetes Hormone decline Blindness Immune decline Etc, etc, etc

t 2 is now Damage rising with ageReversible or obviatable 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 ****** t 2 : feasible plan for “Robust Mouse Rejuvenation” described

A brief “history” of engineered negligible senescence (ENS) t 1 ~ 1982: important components of human aging all known to be so t 2 ~ 2002: feasible plan for “Robust Mouse Rejuvenation” described t 3 ~ ????-????: RMR developed: remaining LE of 2yo mice trebled t 4 ~ ????-????: LOHENS widely seen as foreseeable, WOA begins t 5 ~ ????-????: LOHENS developed, people are in “clinical trials” t 6 ~ ????-????: late-onset human ENS (LOHENS) ubiquitous ????-????:

Biogerontologists Voters, shareholders Government, industry Media Ballot box Peer review, short-termism t 3 = t y: RMR developed: remaining LE of 2yo mice trebled t 4 = t y: LOHENS widely seen as foreseeable, WOA begins Will WOA begin in one decade, or two? 3-5y:

A brief “history” of engineered negligible senescence (ENS) t 1 ~ 1982: important components of human aging all known to be so t 2 ~ 2002: feasible plan for “Robust Mouse Rejuvenation” described t 3 ~ : RMR developed: remaining LE of 2yo mice trebled t 4 ~ : LOHENS widely seen as foreseeable, WOA begins t 5 ~ ????-????: LOHENS developed, people are in “clinical trials” t 6 ~ ????-????: late-onset human ENS (LOHENS) ubiquitous : ????-????:

3. Why it may be a very short war

How long will the war on aging last? t 5 = t ???y: LOHENS developed, people are in “clinical trials” t 1 ~ 1982: important components of human aging all known to be so t 2 ~ 2002: feasible plan for “Robust Mouse Rejuvenation” described t 3 ~ : RMR developed: remaining LE of 2yo mice trebled t 4 ~ : LOHENS widely seen as foreseeable, WOA begins t 5 ~ 2020-????: LOHENS developed, people are in “clinical trials” t 6 ~ ????-????: late-onset human ENS (LOHENS) ubiquitous : 2020-????: ????-????: 5-???y:

Q: Aren’t there lots of aspects of human aging that mice don’t get? A: yes -- but as soon as something is implemented in mice, it can be translated incrementally to humans: to suitably humanised mice, to dogs, to monkeys. With late-onset interventions (and ample funding -- remember WOA is in progress at this point), this is relatively quick.

Q: How could LOHENS (complete control of human aging) possibly arrive so soon after WOA begins? A: bootstrapping We age very slowly. Even a doubling of the remaining life expectancy of 60-year-olds, such that at 80 they are still physiologically 60 but then they decline at present rate, allows 20 years (a very long time in science!) to develop a doubling of the remaining life expectancy of those same people at 80, etc, etc.

Q: But won’t life-extended people be at risk from yet-unknown causes, which will take time to research/cure? A: monkeys It is very unlikely that humans will ever suffer at age N from anything that monkeys don’t get by at least age N/2 given the same medical care. We will thus have a long (and increasing!) lead time to develop cures for as yet unknown age-related problems before any human ever exhibits them.

Q: But aren’t small-looking steps sometimes surprisingly hard? (e.g.: we had Concorde and moon walks 30 years ago, but we still lack space tourism and Mars walks) A: Progress ceased only when we couldn’t be bothered. This seems unlikely with aging once we have the bit between our teeth

4. Why we may also “win the peace” very quickly

How long will it take to “win the peace”? t 6 = t y: late-onset human ENS (LOHENS) ubiquitous t 1 ~ 1982: important components of human aging all known to be so t 2 ~ 2002: feasible plan for “Robust Mouse Rejuvenation” described t 3 ~ : RMR developed: remaining LE of 2yo mice trebled t 4 ~ : LOHENS widely seen as foreseeable, WOA begins t 5 ~ 2020-????: LOHENS developed, people are in “clinical trials” t 6 ~ 2025-????: late-onset human ENS (LOHENS) ubiquitous : 2020-????: 2025-????: 5-???y:

With infinite funds and infinitely many medical personnel... the situation would be simple enough: nothing would stop us from providing rejuvenation therapy for free, to everyone, without delay. Arguments stressing the dangers of doing so (overpopulation, boredom, tyrants reigning forever) will be unpersuasive, to say the least. But funds and expertise will be finite

The history of distribution of medical care: not a useful precedent Difference #1: public pressure will force the compulsory purchase of any patent that risks retarding universal access Difference #2: in the long term, rejuvenation therapy pays for itself, however expensive it is, by wealth produced by the beneficiary

Inference: the sooner we start setting funds aside and training more medics, the better Danger: un-meetable demand (starting at t 4, the start of the WOA) for traditional medical care to help people make the cut Danger: strife between wealthy “immortal” nations and poor “subhuman” nations in a post-9/11 world

Conclusion, for biogerontologists Straw polls at IABG 10, 22/9/03: 1) Most of you think I might be right about t 3 2) Most of you think we shouldn’t discuss t 5, t 6 Are these views compatible?

Conclusion, for actuaries The best possible scenario will only occur with: 1) luck with the science 2) wisdom of policy-makers 3) forward planning to provide enough resources How many people will demand rejuvenation in year X? How many people will demand traditional medicine? How much will it cost and how soon will it be repaid?