Moonshots for the Treatment of Aging: Less Incrementalism, More Ambition

There is far too much incrementalism in the present research and development of therapies to treat aging. Much of the field is engaged in mimicking calorie restriction or repurposing existing drugs that were found to increase mouse life span by a few percentage points. This will not meaningfully change the shape of human life, but nonetheless costs just as much as efforts to achieve far more. If billions of dollars and the efforts of thousands of researchers are to be devoted to initiatives to treat aging, then why not pursue the ambitious goal of rejuvenation and adding decades to healthy life spans? It is just as plausible. There are just as many starting points and plausible research programs aimed at outright rejuvenation via repair of molecular damage, such as those listed in the SENS approach to aging, as there are aimed at achieving only small benefits in an aged metabolism. The heavy focus on incremental, low yield programs of research and development in the present community is frustrating, and that frustration is felt by many.

As the global population ages, there is increased interest in living longer and improving one's quality of life in later years. However, studying aging - the decline in body function - is expensive and time-consuming. And despite research success to make model organisms live longer, there still aren't really any feasible solutions for delaying aging in humans. With space travel, scientists and engineers couldn't know what it would take to get to the moon. They had to extrapolate from theory and shorter-range tests. Perhaps with aging, we need a similar moonshot philosophy. Like the moon once was, we seem a long way away from provable therapies to increase human healthspan or lifespan. This review therefore focuses on radical proposals. We hope it might stimulate discussion on what we might consider doing significantly differently than ongoing aging research.

A less than encouraging sign for many of the lifespan experiments done in preclinical models, namely in mammals such as mice, is that they have modest effect sizes, often only having statistically significant effects in one of the genders, and often only in specific dietary or housing conditions. Even inhibiting one of the most potent and well-validated aging pathways, the mechanistic target of rapamycin (mTOR) pathway has arguably modest effects on lifespan - a 12-24% increase in mice. This is all to ask, if the mTOR inhibitor rapamycin is one of the potential best-case scenarios and might be predicted to have a modest effect if any (and possibly a detrimental one) in people, should it continue to receive so much focus by the aging community? Note the problems in the aging field with small and inconsistent effects for the leading strategies aren't specific to rapamycin.

Treating individual aging-related diseases has encountered roadblocks that should also call into question whether we are on the optimal path for human aging. Alzheimer's is a particularly well-funded and well-researched aging-related topic where there are still huge gaps in our understanding and lack of good treatment options. There has been considerable focus on amyloid beta and tau, but targeting those molecules hasn't done much for Alzheimer's so far, leaving many searching for answers. The point is when we spend collectively a long time on something that isn't working well, such as manipulating a single gene or biological process, it should seem natural to consider conceptually different approaches.



Every exponential technologies are incremential. SpaceX made space incremential, yet progress are faster than ever. Anti-aging will just follow this trend, but that does not mean it is bad news. Senolytics will just get better and better every two years or so, instead of a big upgrade once in a decade. Insillico medicine will make drug development cycle down from 15 years to 1 or 2 years. We will get a new generation of treatments every 2 years not 15 years, this is good incrementation. This will be like a moore's law for anti-aging.

Posted by: Jonathan Weaver at January 4th, 2021 6:31 AM

Hi there! Just a 2 cents. I commend the efforts to try defeat aging but there needs change of optic/doing.

I think people need to understand that currently, just from my POV, there is nothing that is capable of making true 'anti-aging', only 'anti-health decripiting'...not even anything from SENS.

(I read a great article, don't remember, but I think it was a biogerontologist saying: ''people need to stop saying 'anti-aging'...and start saying 'pro-lifing/pro-longevity'...anti-aging is riddled with negativism...some people love 'to age' negative/not helping; obviously, it's 'against aging'..the bad thing being aging...but, many peolpe don't see it as bad...but as normal/natural...even age; so, instead of anti-aging, it should be 'spinned' positively..into 'pro-longevity/pro-life'....which has a nicer (positive) ring to it and then people are like ' you can live/you can live longer - pro-longer...Prolong my life...yes...not 'anti' age can age...the whole point is you age slower/nill so you can prolong life; so that anti-aging, is just 'put another way/spinned differently' 'to sound' nicer/more likeable/more aggreable/more long as you don't say anything about 'aging'...because people have a love/hate relationship with that word - so you don't want to fragment/divide the population and make them hate the whole point of longevity; which is to stop aging...-but some people want to age; so that's a problem. Pro-longevity does not talk of 'age/aging'..only living longer (obvioulsy, it is 'anti-aging' just put another way/nicer wording'')

The confusion (that lingers ever) is that we confound aging and health; they are together but Now, it is 100% clear, they are not the very same thing, or put another way,if nuancing we see that they relate of each other but work independently.

How so? Aging is an intrinsic mechanism that you can't do anything about (so far), it is 'written' in your cells - 'signed/cell signature'...from my view no amount of 'damage repair/reversal' will make any difference. Not even removal of junk. That is why the whole medical field/biogerontological field needs to get it.

Here is stuff that will improve your health and make you possible reach the ±122 years MLSP - but will never make you live much above MLSP:

- Senolytics
- DNA damage repair
- Telomere attrition rate reduction
- Anti-oxidants
- Mitochondrial tinkering (ROS control/expression of genes/so forth, remain a health effect)
- Residu removal (lipofuscin, progerin, drusen, MDA, TBARs, AGEs, ALEs, and the whole rest)

Now, for the only things, right now that might make LEV/go above MLSP:

- Epigenetic (clox) reprogramming in all cells/organs/fluids (blood/plasma...); transcription tinkering, splicing tinkering, transposon tinkering, histone tinkering, chromosome tinkering might do it, but I doubt it because epigenetic switch controls them - they are downstream and do not command gene expression/(de)activation (gene silencing/unsilencing), epigenetic clocks do.

- Organ replacement (the brain is problematic, because we have to keep the person's identity/(in) neuron memories but organ replacement means 'erasure of former by new slate/new organ' brain is the knot/we can't get a 'new brain' empty of nothing, we have to 'transfer' the 'old self' - identity/soul/memory to the new memory-free brain...other organs can be replaced if they are not rejected by body during transplant). The key is all organs must be of age 0 or very low signature.

- Stem cell injection (stem cells much be with a 0 age signature, like embryonic stem cells), I put it but so many studies of stem cell in mouse made weak results (20% extension lifespan)...because it is not enough and because the mechanistic properties (of aging) are 'in the cells' not the new surrounding/ECM (it is why sometimes transplanting old cells into a young body - makes nothing, the old cells Do Not reverse to a young cells - despite transplanted in a younger body), but maybe this can be honed better to replace our Own adult stem cells (like mesenchymal adult stem cells) and make them be younger (of course that means epiclock tinkering of the very stem cells/niche itself).

- I am not sure but if telomere are too small than epigenetic reversal will be 'overcomed' by telomere shortening; in essence, your cells will commit replicative senescence - Even If they are epigenetically younger (becase, we know, that telomere shortening causing replicative senescence is a Different thing, than epigenetic aging (was shown/demonstrated by Horvath in regular cells); as in, short-telomere cells that senescence Exit the 'regular course of epiaging' they simply 'butt out' of the regular aging program (epiprogram) by stopping to cycle/divide/replicate (cell cycle Exit -> senescence). So, it means that replicative senescence and inflammation/DNA damage/senescence are a '2nd layer' 'exit program'...of the 'main program ('normal epiaging/normal 'written aging' in your cells')'. If you do not have replicative senescence (no short telomeres/no DDR/DNA damage response).. then you are -Bound by the regular course of epiaging. DNA damage only 'hastens' the premature-exit of cells that cycle/ does not Change anything about epiaging. Again, Horvath demonstrated DNA damage does Nothing to the epigenetic clock.

What it does, though, by SSBs/DSBs (DNA fragmentations strand-breaks) is that it hastens senescence entry/accelerates telomers shortening --- but does not hasten the epiclock - at the same time that the damage happens.

Because aging is 'written in the cells/memorized/methylation 'imprinted'' is from the very start since you are born; 'inscribed' in your cells since then. That is what controls the longevity of an animal/human. It is why I am so adamant to epigenetic researchers to find ways to reprogram (safely without cancer, because cancer will happen) our cells - that is, True the purest sense of the word. For now we have to make do with 'anti-bad health' or 'pro-health'...or 'pro-aging', I hate that word...'healthy aging'...that is waht is possible with the therapies so far (if excluding epireprogramming); not pro-longevity-'above-MLSP/LEV, that is clearly the clocks' domain.

Just a 2 cents.

PS: I hope more funding goes toward reprogramming/clocks research (all along we thought damages were the be all end all..not so/more nuanced), the key lies there. The 99% of other therapies are sadly dead ends, in terms of longevity/to live beyong our maximum as humans...while, in terms of health/inflammation reduction and 'healthy aging-healthy dying' (/s)..they can help on that point.I prefer the 'not dying/LEV' therapy.

Posted by: CANanonymity at January 4th, 2021 2:39 PM

@CANanonymity The best term is rejuvenation. Pro-longevity means you will still die of aging in the end. Rejuvenation is making old people revert to when they were 20 or 30, and periodically rejuvenate them every 5 years or so. I understand some people love to age but some don't. We need to build those therapies and let people pick them or not. People shouldn't make choice because of negativity of something. Even if aging is viewed positively by 99% of the world I would still want to be young. Making a choice from the majority means you don't know what to do with your life. Every choice should be independant from others choice.

Posted by: Jonathan Weaver at January 5th, 2021 9:52 AM

Hi Jonathan! Thank you for that. Just a 2 cents.

I agree that Pro-longevity is still 'limited' in the sense of one day 'it ends'...but the most important thing is not we still die of age is When we still die of age. If we can die of age in a 1000 years, then I am sold - on Pro-longevity, any day any time; because there is a huge differential between: living 15 years (HGPS/fast progeria), 50 years (Werner Syndrome/low progeria), 60-95 years (regular avg modern life), 100-110 years (centenarians/exceptional genetic/avoiders of diseases/survivors), 115-120-122 or possibly 125-130 or so (maximal human longevity, 1 person out of 7.5 billion, that's low (er than low) odds; you got more chances of being hit by a car, by thunder lightning 'while outside Under a tree', or sinking in your baththub with the electric toaster plugged in), 111 years (blue amazon Parrot), 130-140 years (yellow rougheye rockfish), 120 years (red lobster), 175 years (giant sea/galapagos islands tortoise), 211-268 years (bowhead whale maximum, maximum longevity of all mammals so far; this whale is a mammal like humans and is the longest living existing mammal animal found), 300-400+ years Groenland Sharks, 500-600 years Icelandic quahogs bivalves clams oysters/mollusks...those pretty pearls Inside those clam Oyster shells took a long time to happen (some, centurieS). Not just pearls they hold, they fig. hold the key to living this long.

Thus, pro-longevity is we still die, but if we can post-pone death, then we do still die, one day - just much much much much much much much...........farther. That is the point that medical litterature/biogerontology oftenly skimps/skips/skims on, always staying in the 'safe 120' because that's all they aim for,, 'yeah we die one day' not much we can do so far about That point, we die. But what if we died, like, extremely much post-poned in our future, like late late, Later than late(r). It would give a new meaning to 'procrastination' in, we'd never have 'it done' 'the dying' part...dying would be so 'reculé'/push back 'to square 1' that for it 'to happen' it would take you a 'small eternity'. You still die, just 'in never (ever)'. If we can do this 'loop-d-loop-d-loop...' thing and repeatedly 'push back/post pone' 'time of death'...then yes you still die but if you push it back 'forever'; dying would become moot/nearly nill in that sense, in forever how long/forever what time you live - by pushing it back on and on and on and on....

I know you might be thinking, 'but that supposes we can push it back ever and forever'...that is true. And I hope that it becomes true..then...we will have to solve the 'other' problems (100% all ethical problem) overpopulation on earth (no one dies anymore, we live 100000 years ...everyone, so lacking space as newcomers arrive and they too 'live forever'), drought of resources (feeding an ever living and ever growing population of 'never dying people (your great-great-great-great-great-great-great....great-great..grand-ma will be alive - while you are alive too)...we lack resources to feed all mouths), those problems will have/will be solved in time...we will Have the Time (thousand years...) to think it through and find some solution...not gonna miss any time. That is the Problem now, we die, and 'lack time' to solve these problems. IF we had more time we could devote our time 'plenty of it/not lacking any' to 'finding a solution' it might take 100 years to find that solution but in that time, aging will have be solved, we still will die 'one day' (far future), but no one we will want to die (except people that Want to die/bored of life, no reason to live, no Will, think life ends at 100 or less, think living 20 years is very very Long and 20 is enough no more, think we will decripit for thousand years, ethics/people stubbornly say not natural/artificial rigging/Against god-sentient being/overpopulation/earth will explode and humanity extinct// dictators/ prisoners/murderers/homicidal maniacs...

will live forever if no death sentence to stop them 'from living forever (because who wants criminals living forever)'...and any other reason Under the faint dying sun to not live but say 'die is good' etc...), if we can post-pone death for an infinity. I prefer a Bright Lit Sun - that Lives and Shines, Sun Star will live for 4 billion years after our death. Lots of stuff will happen after we are gone, but do we need to be? For ethical people, yes, we must. Stars when they die emit powerful energy/radiation 'in a blaze' and form a supernova, the giant 'blowing up death' of star is kind of a metaphor to humans microcosm internal cell deaths/and normal body death...out there in the giant macrocosm cosmos, it happens too; but some stars live forever; like the/our sun basically; it will die one day too. But, the differential of aging, is that we will live 90-100 years while it will live 4,000,000,000 more years; that gives a new meaning to delay(ing) things. Why should I/you/we/us be the former and not like the latter. Because order of things/god said so?...right now it's more our bioclocks say so.

But 'say it ain't so' those clocks need riggging and throwing a monkey wrench in their figurative mechanical cogwheels so that we don't end up the former anymore (well at least for Quite a Few more years). But sadly, as I said before (that's my view), eternity of living handed on a silver plate 100% free - to some - is aberrant/insult/ can you dare ofter eternal life, 'humans die' after all that's what they do.

Just a 2 cents.

PS: I Absolutely agree with you, that it should be a choice, personal choice of living or not any longer (it is why many modern countries are now 'giving choice of people to die/ assisted suicide'...or such' for example someone suffering and Wanting to die/end it because of me..I know this, I suffered (fro atherosclerosis and nearly died of it)...but I stuck to the will to live...and endured my pain/still do, otherwise I would be dead/given up...but that is a personal choice/personal 'body' choice of that person...if they want to end it...then they should have that choice/personal decision on their body/life -Their body/Their one else's life/body but theirs (because, no one else lives in them/in their body - than themselves). But govs have decided they Want to decide of your body/ see for example China curbing number of kids...or 'abortion' laws...all this goes back to these ethical problems...Should a gov decide 'when' you die (like if you live 122 lived too long..the gov Must terminate you/you are past due..and will cause overpoulation and resources you must terminate yourself...I am saying this like that..but it would not surprise me in the least bit...because this sci-fi future vision might happen...when you see dictatorship govs...they might do that 'to control population numbers', population curbing is Something the govs like to have a hold on by instating whatever law to abolish/ban whatever - like maybe living 'too long' so you 'must sacrifice yourself your life 'for the other''

...that would not soound so farfetched because we live in society and society asks you 'to chime in' for others and not be 'individualistic/egotistical/nonaltruist/antisocietal by 'just wanting yourself your own thing to you'...scary like that (but What's scarier is that people sometimes don't even realize that this whole point of prolongevity is that is it for all and not a very 'rich person becoming an *mmortal person' only by virtue of being the richest person that 'can afford it' alone and the others/poor ones...too bad (harsh like that) they will die - can't afford it (capitalism 101 in all its flaws, no money, no candy, poor people are affected and die quicker because no cash/no resource to 'obtain longevity therapy'.

It's why societies are trying to be more 'social/societal' by spreading the wealth to all - 'à la robin hood stealing from the rich to redistribue to the poor or communism/communautarism (everyone makes same salary no one oerson alone - making billions of salary rich person privilege- while a poor on the street is living on 30cents a day and soone will die of hunger ..but 'not my problem' in capitalistic society, individualistic society does not care what the next one suffers of, only the self alone/individual)'; well, in social countries it means 'social services' (tax paid by tax payers))). But, these models of society are not perfect, none are, they have their + and - (from democratism, republicanism, communism, fascim, dictatorialism, capitalism, marxism, socialism, meritocratism, conservationism, abolitionism, etc. etc and everyother -isms....and the new one Automatism/Robotomatism/the future).

PPS: It is hard to 'segment' the text I write, like I can make paragraphs...but it's much harder now (like I must segment 50 times to make it readable), I apologize for it being 'very condensed' post 'wall of text'.

Posted by: CANanonymity at January 5th, 2021 12:07 PM

I agree with CANanonymity: reprogramming DNA will extend life beyond 125 years for humans.

Posted by: Nicholas D. at January 12th, 2021 3:50 PM
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