Defeating aging
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The document discusses strategies for achieving indefinite life extension in humans through addressing the biological processes and damage that cause aging. It outlines seven major types of age-related damage and proposes engineering approaches ("SENS strategy") to repair each type of damage, arguing this approach could substantially extend human healthspan. It acknowledges challenges but argues emerging therapies that extend life by 30 years could allow continued progress if recipients survive to benefit from subsequent therapies.
![Defeating aging: Why the prospect of dramatic life extension matters now Aubrey D.N.J. de Grey Department of Genetics, University of Cambridge Email: [email_address] Reprints, general info: http://www.gen.cam.ac.uk/sens/](https://image.slidesharecdn.com/defeating-aging2713/85/Defeating-aging-1-320.jpg)
![Plausible ways to avoid dying, and why Aubrey D.N.J. de Grey Department of Genetics, University of Cambridge Email: [email_address] Reprints, general info: http://www.gen.cam.ac.uk/sens/](https://image.slidesharecdn.com/defeating-aging2713/85/Defeating-aging-2-320.jpg)
![We know how to fix all of them (in mice, in principle!) Strategies for Engineered Negligible Senescence (SENS) * * * Allotopic expression of 13 proteins mtDNA mutations Transgenic microbial hydrolases Lysosomal junk Exercise, cell therapy, growth factors Cell loss, cell atrophy Ablation of senescent cells Cell senescence Phagocytosis by immune stimulation Extracellular junk AGE-breaking molecules/enzymes Extracellular crosslinks WILT: telomerase/ALT gene deletion plus periodic stem cell reseeding Nuclear [epi]mutations (only cancer matters) It or its effects reversible by Age-related damage](https://image.slidesharecdn.com/defeating-aging2713/85/Defeating-aging-10-320.jpg)
![20 years is an instructively long time to find nothing out Harman (1972) Mitoch. mutations Strehler (1959) or earlier Lysosomal junk Brody (1955) or earlier Cell loss, cell atrophy Hayflick (1965) Senescent cells Alzheimer (1907) Extracellular junk Monnier and Cerami (1981) Extracellular crosslinks Szilard (1959) and Cutler (1982) Nuclear [epi]mutations (only cancer matters) Proposed as contributing to aging by Damage rising w/ age](https://image.slidesharecdn.com/defeating-aging2713/85/Defeating-aging-12-320.jpg)
![Let’s roll [email_address] http://www.gen.cam.ac.uk/sens/ http://www.mprize.org/](https://image.slidesharecdn.com/defeating-aging2713/85/Defeating-aging-47-320.jpg)
Defeating aging
- 1. Defeating aging: Why the prospect of dramatic life extension matters now Aubrey D.N.J. de Grey Department of Genetics, University of Cambridge Email: [email_address] Reprints, general info: http://www.gen.cam.ac.uk/sens/
- 2. Plausible ways to avoid dying, and why Aubrey D.N.J. de Grey Department of Genetics, University of Cambridge Email: [email_address] Reprints, general info: http://www.gen.cam.ac.uk/sens/
- 3. Structure of this talk Modest mouse, human life extension Indefinite human (but not mouse) LE Infinite LE, risk and cryonics Desirability: surprising advances
- 4. Aging in a nutshell Metabolism ongoingly causes damage whereas Damage only eventually causes pathology This turns out to be very useful
- 5. Paradigms for intervention Gerontology Geriatrics Metabolism Damage Pathology
- 6. Paradigms for intervention Gerontology Engineering Geriatrics Metabolism Damage Pathology Claim: only the “engineering” approach can achieve substantial extension of human healthspan any time soon
- 9. Metabolism Damage Pathology: The seven deadly things Neurodegeneration Atherosclerosis Cancer Diabetes Hormone decline Blindness Immune decline Etc, etc, etc Cell loss/atrophy Nuclear mutations and epimutations mtDNA mutations Senescent cells Protein crosslinks Extracellular junk Lysosomal junk Er.... that’s it! Respiration (oxidation) Carbohydrate metabolism (glycation) Cell turnover (mutations, telomere shortening, dysregulation, stem cell depletion) Etc, etc, etc
- 10. We know how to fix all of them (in mice, in principle!) Strategies for Engineered Negligible Senescence (SENS) * * * Allotopic expression of 13 proteins mtDNA mutations Transgenic microbial hydrolases Lysosomal junk Exercise, cell therapy, growth factors Cell loss, cell atrophy Ablation of senescent cells Cell senescence Phagocytosis by immune stimulation Extracellular junk AGE-breaking molecules/enzymes Extracellular crosslinks WILT: telomerase/ALT gene deletion plus periodic stem cell reseeding Nuclear [epi]mutations (only cancer matters) It or its effects reversible by Age-related damage
- 11. Isn’t this list certain to be incomplete? Won’t our solutions be very imperfect at first?
- 12. 20 years is an instructively long time to find nothing out Harman (1972) Mitoch. mutations Strehler (1959) or earlier Lysosomal junk Brody (1955) or earlier Cell loss, cell atrophy Hayflick (1965) Senescent cells Alzheimer (1907) Extracellular junk Monnier and Cerami (1981) Extracellular crosslinks Szilard (1959) and Cutler (1982) Nuclear [epi]mutations (only cancer matters) Proposed as contributing to aging by Damage rising w/ age
- 13. Isn’t this list certain to be incomplete? YES Won’t our solutions be imperfect at first? YES But that doesn’t mean we’re all doomed, because . . . . .
- 14. Three sorts of “cure” of diseases: which is relevant here? Total removal of the disease-causing agent Periodic, partial removal of an inert agent Ditto of an increasingly resistant agent Difficulty: 1) 2) 3) Goal: indefinite avoidance of age-related frailty ==> Cure (3) is enough if we outrun the problem
- 15. How fast must we run to stand still? Goal of powered flight: prehistoric First powered flight: 1903 First transatlantic flight: 1927 First commercial flight: 1949 First supersonic airliner: 1969 Commercial space travel: 2004 Treatments that extend healthy life by ~30 years will be the cusp: recipients will mostly survive to receive treatments giving a further 30 years, etc.
- 16. Q: But won’t life-extended people have yet-unknown problems, which will take time to research/cure? A: monkeys It is very unlikely that humans will ever suffer at age N from anything that no primate species get by at least age N/2 given the same lifestyle and medical care. We will thus have a long ( and increasing! ) lead time to develop cures for new age-related problems before any human ever exhibits them.
- 17. Life extension escape velocity Conclusion: the first 1000-year-old is probably only ~10 years younger than the first 150-year-old
- 18. So we’ll have a half-life!
- 19. So we’ll have a half-life! NO
- 20. Ever-increasing half-life: interesting numbers 1/2 survive 1 half-life 1/4 survive 2 half-lives: (1/2 of 1/2) = 1/4 die 1/8 survive 3 half-lives: (1/2 of 1/4) = 1/8 die … None survive forever if half-life is fixed
- 21. Ever-increasing half-life: interesting numbers 1/2 survive 1 half-life 3/8 survive 2 half-lives: (1/4 of 1/2) = 1/8 die 21/64 survive 3 half-l’s: (1/8 of 3/8)=3/64 die … 28% survive forever if half-life rises like this!
- 22. So this is immortality!
- 23. So this is immortality! NO Immortality means immunity from death -- everyone living forever This is just some people living forever
- 24. So this is immortality! NO Immortality means immunity from death -- everyone living forever This is just some people living forever But hey, it’s better than aging….
- 25. Risk: a big, big problem Lots of risky activities are fun Without aging, the risk is far bigger DRIVING WILL BE OUTLAWED!
- 26. Or will it? Well, maybe… Two ways to avoid risk: avoid risky activities stop them being risky (sensors, etc) In practice, though, this can only be partial
- 27. Cryonics: a good solution? Pro: arbitrarily advanced technology can repair you Con: you come back in a very different world Con: you might well never be brought back Con: you might even never be cryopreserved
- 28. Another big problem Aging is SLOOOOOOOW -- especially dementia When Reagan died, he was already nonexistent What good is cryopreservation for such people? Only real solution is suicide -- but what if medicine improves in time?
- 29. Resuscitation: the options thaw the body, repair it, warm it, hope wait until safer -- and wait, and… scan and copy. Identity …. So what?
- 30. Scan and copy…. Hm…. Why wait to be frozen?
- 31. Solving three problems in one - aging is gradual - death is “too late” cryopreservation is a gamble risky activities are fun And the solution is …… Regular (monthly?) backups, reconstruction as needed!!!
- 32. Desirability Convincing the world that aging is bad: futile until we really rejuvenate mice?
- 33. Desirability breaking the global trance
- 34. Trance? Consider some standard excuses for condemning 100,000 people to death, every day, forever: “ Wouldn’t it be crushingly boring?” “ How would we pay the pensions?” “ What about starving African children?” “ Dictators would rule forever!” Claim: nobody is really that dumb -- they MUST be in a trance
- 35. A heartening convert Who's Afraid of Life Extension? Harry R. Moody, Institute for Human Values in Aging, International Longevity Center-USA When I began to prepare to write this article, I was clear and confident about my direction. Anti-aging technologies, I was sure, are a snare and a delusion … It is a line of thought I have held for many years … But the more I thought about my skepticism and hostility to life-extension technology, the more uneasy I became. Gradually, as I reflected on my uneasiness, I found it more and more difficult to rationalize my strong rejection of life extension .
- 36. Yes, Harry Moody said this … within mainstream gerontology, anti-aging medicine is widely viewed with hostility and skepticism (an incipient form of “gerontological correctness”?). But we are entitled to wonder: Are the arguments against anti-aging medicine valid, or are the opponents of anti-aging medicine (including me) simply gerontological Luddites? If one lifelong opponent can wake HIMSELF up, there is hope yet…
- 37. Another unexpected ally (eventually…): the wisdom of repugnance “ Offensive.” “Grotesque.” “Revolting.” “Repugnant.” “Repulsive." These are the words most commonly heard regarding the prospect of human cloning. .... Even Dolly's creator has said he "would find it offensive" to clone a human being. Revulsion is not an argument; and some of yesterday's repugnances are today calmly accepted -- though, one must add, not always for the better. In crucial cases , however, repugnance is the emotional expression of deep wisdom, beyond reason's power fully to articulate. Would anybody's failure to give full rational justification for his or her revulsion at these practices make that revulsion ethically suspect? Not at all. On the contrary, we are suspicious of those who think that they can rationalize away our horror Leon Kass, 1997, “The Wisdom of Repugnance”
- 38. Why is this useful? Fundamentally barbaric Keeps the numbers down Traditional Human aging Fox hunting
- 39. Why is this useful? Leon Kass said it Our wisdom about aging is precisely a wisdom of repugnance -- well, mine is… Repugnance can go down as well as up
- 40. Another unlikely ally in the making: A 4 M - Business: promoting “anti-aging” products - Policy: “open-mindedness” -- anyone can buy a stall at the expo right next to the meeting, sell magnetic water or whatever, and they do - Interpretation: profit first, efficacy second - Resulting reputation: oiliest of the snakes
- 41. My abstract and introduction at three A 4 M-funded conference last year “ Anti-aging medicine does not currently exist , in the sense in which the term ‘medicine’ is generally used. Medicine is biomedical technology that, at least for most recipients, effectively treats the primary symptoms of the condition against which it is claimed to act. The primary symptom of aging is indisputably death, and no existing product appreciably delays death from aging.” And what happened?
- 42. - Bob Goldman cornered me for an hour to discuss how we can work together - I was asked to give a similar talk at A 4 M in Las Vegas in December Ditto an A 4 M-sponsored conference in London in September One simple interpretation: I am in the ascendancy, hence a good ally to have Why did I accept (“academic suicide”)?
- 43. Why am I taking this risk? The anti-A 4 M movement (Olshansky, Hayflick) is backfiring, because everyone who sells anything downplays its flaws - hence their criticism is not considered fair The “A 4 M community” are in much less of a pro-aging trance than most people They are numerous and their customers quite affluent They want their business to last long-term
- 44. The rational theist Points to be carefully noted: 1) Fundamentalists (very numerous, very powerful) do, in the end, follow the doctrine as it evolves 2) God deprecates hastening death, however good the afterlife is claimed to be 3) God also deprecates apathy The most unanswerable retort to the life-extension crusade is “Yes, we should cure aging ASAP, but I don’t feel like it”
- 45. The hope that dare not speak its name Little known fact: Len Hayflick looks after his health Phenomena not to be ignored: - Death penalty abolished throughout Europe - Vietnam war slightly less popular than WWII - Britain banned gun ownership after one mass murder - No war in Western Europe for 60 years - not seen since Roman times - Canada, Norway, etc -- lots of guns, little gun crime
- 47. Let’s roll [email_address] http://www.gen.cam.ac.uk/sens/ http://www.mprize.org/