香港六合彩

Mechanisms for extending lifespan

(SENS): genetic aspectsAubrey D.N.J. de Grey

Department of Genetics, University of Cambridge

Email: [email protected]

Reprints, general info: http://www.gen.cam.ac.uk/sens/

“Is he nuts?”http://

www.technologyreview.com/articles/05/02/issue/mag_toc.asp

Aging in a nutshellMetabolism (the hugely messy network of homeostatic processes that keep us alive)

causes

Pathology (the hugely messy network of anti-homeostatic processes that kill us)

This is not controversial -- indeed, it is why most biogerontologists think there’s

little hope of curing aging for ages

Paradigms for intervention

Gerontology Geriatrics

Metabolism Pathology

An oft-neglected observationAging is indisputably a side-effect of essential

biochemical and cellular processesBUT

Its functional effect (loss of performance) is delayed

Putting it another way:

Being alive must have immediate side-effects, since metabolically active molecules are short-lived

BUTThose effects must accumulate, and have a

threshold level below which they are harmless

Aging in slightly less of a nutshell

Metabolism ongoingly causes “damage”

whereas

Damage only eventually causes pathology

This turns out to be very useful

Paradigms for intervention

Gerontology Geriatrics

Metabolism Damage Pathology

Paradigms for intervention

Gerontology Engineering Geriatrics

Metabolism Damage Pathology

Claim: unlike the others, the engineering approach can achieve a large extension of

human healthy lifespaspan quite soon

Metabolism Damage Pathology:

The seven deadly thingsRespiration (oxidation)

Carbohydrate metabolism (glycation)

Cell turnover (mutations,

telomere

shortening,

dysregulation,

stem cell

depletion)

Etc, etc, etc

Cell loss/atrophy

Protein crosslinks

Extracellular junk

Death-resistant cells

mtDNA mutations

Lysosomal junk

Nuclear [epi]mut’ns

Er.... that’s it!

Neurodegeneration

Atherosclerosis

Cancer

Diabetes

Hormone decline

Blindness

Immune decline

Etc, etc, etc

FAQ #1:

How do you know that this list is complete?

20 years is a suspiciously long time to find nothing out

Damage rising with age Proposed as contributing to aging by

Cell loss, cell atrophy Brody (1955) or earlier

Extracellular junk Alzheimer (1907)

Extracellular crosslinks Monnier and Cerami (1981)

Cell senescence Hayflick (1965)

Mitochondrial mutations Harman (1972)

Lysosomal junk Strehler (1959) or earlierNuclear [epi]mutations (only cancer matters) Szilard (1959) and Cutler (1982)

FAQ #2:

OK… How close are we to fixing these things?

Damage rising with age It or its effects reversible by

Cell loss, cell atrophy Exercise, cell therapy, growth factors

Extracellular junk Phagocytosis by immune stimulation

Extracellular crosslinks AGE-breaking molecules/enzymes

Death-resistant cells Cell ablation, reprogramming

Mitochondrial mutations Allotopic expression of 13 proteins

Lysosomal junk Transgenic microbial hydrolasesNuclear [epi]mutations (only cancer matters)

WILT: Telomerase/ALT knockout plus periodic stem cell reseeding

We know how to fix all of them (in mice, in principle!)

See www.gen.cam.ac.uk/sens/ for detail (lots of it, including all my publications)

Damage rising with age It or its effects reversible by

Cell loss, cell atrophy Exercise, cell therapy, growth factors

Extracellular junk Phagocytosis by immune stimulation

Extracellular crosslinks AGE-breaking molecules/enzymes

Death-resistant cells Cell ablation, reprogramming

Mitochondrial mutations Allotopic expression of 13 proteins

Lysosomal junk Transgenic microbial hydrolasesNuclear [epi]mutations (only cancer matters)

WILT: Telomerase/ALT knockoutplus periodic stem cell reseeding

We know how to fix all of them (in mice, in principle!)

See www.gen.cam.ac.uk/sens/ for detail (lots of it, including all my publications)

SENS components cover the genetic bases (no pun intended…)

Allotopic expression: insert many genes

Xenohydrolases: insert foreign genes

WILT: target genes, in vitro and in vivo

Q: How could these therapies ever undergo clinical trials?!

Q: How could these therapies ever undergo clinical trials?!

A: Robust Mouse Rejuvenation

Definition of RMR: trebling of the remaining lifespan of a cohort of 2yo mice that normally die at 3yo

Q: what’s so important about mice?

A: the other milestones1)Robust Mouse Rejuvenation - proves

plausibility of:

2)Robust Human Rejuvenation - give 30 extra healthy years to 55yo’s

3)Longevity Escape Velocity - indefinite youth

Indefinite youth????!!!!

Gerontology Engineering Geriatrics

Metabolism Damage Pathology

Damage can be kept sub-pathogenic indefinitely by repair that only

asymptotically approaches perfection

Longevity escape velocity

Conclusion: RHR gives LEV. The first 1000-year-old is probably only ~10 years

younger than the first 150-year-old

RMR’s probable impact on clinical trial policy

- Timeframe: I predict RMR will be achieved within 10 years

- How achieved: I predict all 7 SENS strands will be necessary for RMR or seen by then to be necessary for RHR

- Moreover: not just necessary, but sufficient

- Consequence: global “War On Aging”

War on Aging?- The “War on Cancer” was a misnomer:

- limited life-extension if successful- economically imperceptible to voters

- RMR will make RHR unarguably feasible- RHR should give longevity escape velocity

- indefinite youth- huge economic impact will be accepted

My inference: public (hence political) response to RMR will be unlike any previous biomedical situation, and more like wartime