Arguing the scientific feasibility of defeating aging Aubrey D.N.J. de Grey Chairman and CSO, Methuselah Foundation Lorton, VA, USA and Cambridge, UK MF site: Science site: Prize site:

Shameless plug #1 The SENS conferences: a unique synthesis of research on technologies to repair the molecular and cellular damage of aging - SENS 3 - Cambridge UK, Sept

Shameless plug #2 Out Sept 4

Background - Focus on “giving life to years” is >60y old - It hasn’t delivered adequate public funding - Even when absurdly exaggerated (“C of M”) - Or illogically described (“HA”, “A not a D”) - It’s high time we tried something different - Is the Longevity Dividend initiative the answer?

Why I’m pessimistic about LD (though I do strongly support it!) Since the mid-1960s, the USA has seen: - ~7y increase in life expectancy - improvement in public health - extension of the period of health and vigour - reduction in frailty and disability at all ages - no compression of severe morbidity - a subtler LD than Olshansky et al describe

“How’s it going to be done?” Len Hayflick, Australia, 2006 (rhetorically?) “We don’t know; we don’t need to know” SJO’s response Correct - up to a point…

What if…… - a demographer, - a geriatrician, - a lobbyist, - and a biogerontologist uniformly described by his colleagues as problematically dogmatic …are wrong about what’s realistic?

As I claim… The first 1000-year-old is probably less than 20 years younger than the first 150-year-old

Similarly… The first 1000y-LE cohort is probably less than 20 years younger than the first 100y-LE cohort

Radical LE: Topics - The key credibility challenges: - Argument from personal incredulity - Argument from self-serving authority - The key solutions - Demystifying the task - Achieving interim results

Radical LE: Topics - The key credibility challenges: - Argument from personal incredulity - Argument from self-serving authority - The key solutions - Demystifying the task - Achieving interim results

Aging in a nutshell Metabolism ongoingly causes “damage” and Damage eventually causes pathology

Options for intervention Gerontology Engineering Geriatrics Metabolism Damage Pathology Claim: unlike the others, the “engineering” approach can probably achieve substantial extension of human healthspan quite soon

Age Reserve 0 0 max frail The simple logic of LEV Fixing half the damage, then 3/4, then 7/8…. - outpaces the so-far-unfixable damage… - maintains healthspan indefinitely

Robust human rejuvenation (RHR) Addition of 30 extra years of healthy life (and total life) to people who are already in middle age when treatment is begun

Longevity escape velocity (LEV) The rate at which rejuvenation therapies must improve (following achievement of RHR) in order to outpace the accumulation of so-far-irreparable damage

Is this rate of progress plausible? Data

Simulating aging (Phoenix & de Grey, AGE, in press) Metabolism ongoingly causes “damage” and Damage eventually causes pathology So…. Simulations of aging (and intervention) should simulate damage accumulation

Simulating damage: model Structural parameters N_CAT: The number of damage categories each person hasN_MECH: The number of mechanisms in each category MECH_WEIGHT m : The contribution of a mechanism to a category Fitting parameters BASAL_M: The mean basal damage rateBASAL_SD: The standard deviation of the basal damage rate BASAL_H: The homogeneity of basal damage rate in a single personEXP_M: The mean exponential damage rate EXP_SD: The standard deviation of the exponential damage rate EXP_H: The homogeneity of exponential damage rate in a single person FATAL_M: The mean yearly challengeFATAL_SD: The standard deviation of the yearly challenge Values set for each person at initialisation: PB: Basal rate for the person: lognorm(BASAL_M, BASAL_SD) PE: Exponential rate for the person: lognorm(EXP_M, EXP_SD) MB c,m :Basal rate for each mechanism: lognorm(BASAL_M, BASAL_SD)*(1-BASAL_H) + PB*BASAL_H ME c,m : Exponential rate for each mechanism: lognorm(EXP_M, EXP_SD)*(1-EXP_H) + PE*EXP_H D_M c,m : Cumulative damage for each mechanism: 0D_C c : Cumulative damage for each category: 0 Variables updated for each person at each time step (year): Total damage: PD(t) = [SUM c=1..N_CAT] D_C c (t) Damage increment: DI_M c,m (t) = MB c,m + ME c,m *PD(t-1) Cumulative damage: D_M c,m (t) = DI_M c,m (t) + D_M c,m (t-1) Cumulative category damage: D_C c (t) = [SUM m=1..N_MECH] DI_M c,m (t) Fatality challenge: FATAL(t) = |norm(FATAL_M, FATAL_SD)| If D_C c (t) > FATAL(t) for any c, the person dies at age t

Results: LEV in practice Therapies doubling in efficacy every 42 y

Question When simple and unchallenged logic leads to counterintuitive conclusions, is it more effective in the long run to ignore/suppress/deny those conclusions, or to point them out?

LD’s key vulnerability - yes, modest LE sounds realistic - yes, modest LE sounds un-scary BUT - maybe not un-scary enough - hard questions will precede money - “won’t this just fuel the LE fire?” - “what happened to ‘aging not a disease’?”

Radical LE: Topics - The key credibility challenges: - Argument from personal incredulity - Argument from self-serving authority - The key solutions - Demystifying the task - Achieving interim results

Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation Damage rising with ageIt or its effects reversible by Cell loss, cell atrophyCell therapy, mainly Extracellular junkPhagocytosis by immune stimulation Extracellular crosslinksAGE-breaking molecules/enzymes Death-resistant cellsSuicide genes, immune stimulation Mitochondrial mutationsAllotopic expression of 13 proteins Intracellular junkTransgenic microbial hydrolases Nuclear [epi]mutations (only cancer matters) Telomerase/ALT gene deletion plus periodic stem cell reseeding

7-KC degradation - presented at meetings

First MF-funded paper submitted

Radical LE: Topics - The key credibility challenges: - Argument from personal incredulity - Argument from self-serving authority - The key solutions - Demystifying the task - Achieving interim results

Which is the odd one out? “laughable claim...arrant nonsense” “this is worthless nonsense” “It can’t be done”

“The BBC … earnestly reported a few months ago the laughable claim that the first human who will live to 1,000 years is 60 already. If even Auntie, as the BBC is affectionately known, can succumb to such arrant nonsense, what hope is there for the more excitable sections of the media?” Tom Kirkwood, 2005, writing in Nature

“There are four stages of acceptance: i) this is worthless nonsense; ii) this is an interesting, but perverse, point of view; iii) this is true, but quite unimportant; iv) I always said so.” J.B.S. Haldane, 1963

“New ideas pass through three periods: 1) It can’t be done. 2) It probably can be done, but it’s not worth doing. 3) I knew it was a good idea all along!” Arthur C. Clarke, 1968

Hypothesis “the SENS agenda is easily recognized as a pretence by those with scientific experience” 28 eminent gerontologists, November 2005 EMBO Reports 6:1006

Experimenters

Experiment - Induce critics to give their reasons in writing - Ask a panel of neutral experts what they think Craig Venter (needs no intro) Rod Brooks (head, MIT AI lab) Nathan Myhrvold (ex-CTO, Microsoft) Vikram Kumar (Harvard/MIT medic) Anita Goel (Harvard medic/physicist)

Reagents Life Extension Pseudoscience and the SENS Plan (7000 words) Preston W. Estep, Matt Kaeberlein, Pankaj Kapahi, Brian K. Kennedy, Gordon J. Lithgow, George M. Martin, Simon Melov, R. Wilson Powers III, Heidi A. Tissenbaum “1) SENS is based on the scientifically unsupported speculations of Aubrey de Grey, which are camouflaged by the legitimate science of others; 2) SENS bears only a superficial resemblance to science or engineering; 3) SENS and de Grey’s writings in support of it are riddled with jargonfilled misunderstandings and misrepresentations; 4) SENS’s notoriety is due almost entirely to its emotional appeal; 5) SENS is pseudoscience.”

Result “They are too quick to engage in name-calling, labeling ideas as ‘pseudoscientific’ or ‘unscientific’ that they cannot really demonstrate are so.” “SENS is a collection of hypotheses that … cannot rise to the level of being scientifically verified. However, by the same token, the ideas of SENS have not been conclusively disproved.” “I have no confidence that they understand engineering, and some of their criticisms are poor criticisms of a legitimate engineering process.”

Hypothesis “the SENS agenda is easily recognized as a pretence by those with scientific experience” 28 eminent gerontologists, November 2005 EMBO Reports 6:1006

Question Why are grandees, others skeptical? - evidently not for scientific reasons - sustained refusal to learn key data - fixation on own prestige, funding - grandees espouse one’s prior view - grandees espouse comforting view

Question How are grandees skeptical? - lunge for cerebral off-switch “they stress my failure to note that no SENS intervention—in isolation—has ever been shown to extend any organism’s lifespan. I do not recall Henry Ford alerting potential customers that the components of a car—in isolation—remain obstinately stationary when burning petrol is poured on them, nor do I recall his being castigated for this omission.”

A familiar exchange “Where’s your data?” “I just showed you my data” “That’s not relevant data” “Who says?” “Well it’s just you saying it’s relevant” “No, I’m also saying why” “Well I want lifespan data” “Bzzzt! - API, ASA”

Will 7y LE bring a dividend? - 40 years ago, Western LE was ~7 years shorter - Medical expenditure has not precisely fallen - Why should the next 7y rise be different? - NOT because we’ll combat “aging” - frailspan has held steady. Slope vs intercept not the issue - However, the economy benefited anyway! - Hence, focus should be on what WON’T work

LD’s key vulnerability - yes, modest LE sounds realistic - yes, modest LE sounds un-scary BUT - maybe not un-scary enough - hard questions will precede money - “won’t this just fuel the LE fire?” - “what happened to ‘aging not a disease’?”

Unavoidable, and useful, facts - Lack of speed (in combating aging) kills - Aging will be just as bad when LE is 90 - The demystification option is working - Warm words are cheap; ultimately policy follows, not leads, the electorate - Fear of the facts (API, ASA) never works

Back to first principles - Most people are irrational about aging - This was for good psychological reasons - Thus, mealy-mouthed messaging is futile - Demystification is a serious alternative - It will be hastened by experts’ objectivity

“I want the old Aubrey back” Jay Olshansky “Do You Want to Live Forever?” “Old Aubrey”: harmless theoretician who wasn’t even thinking about intervention, let alone talking about it, so wasn’t threatening grandees’ quiet lives “New Aubrey”: dangerous activist who exposes grandees’ dirty little secrets about how little they really know (or care?) about options for intervention Which is really preferable???

Age Reserve 0 0 max frail LEV decreases with time Fixing half the damage, then 2/3, then 3/4…. - still good enough… - just like gravitational escape velocity

Data