It is Faintly Ridiculous to Propose that Human Life Span Cannot be Increased by Altering Metabolism

Today's open access commentary is, I think, an overreaction to present challenges in engineering greater longevity via metabolic manipulation. I would be the first to say that altering the operation of metabolism is not a good path forward, at least if the goal is to engineer greater healthy longevity in our species. Cellular metabolism and its intersection with aging is ferociously complex and poorly understood in detail. Those details matter greatly: there are many feedback loops and switches based on protein levels that will change from beneficial to harmful for reasons that only become apparent after years of painstaking research. The best-studied mechanisms that link cellular metabolism to individual and species longevity have been under investigation for decades, and are still at a point at which related interventions are haphazardly beneficial and poorly understood.

Further, those best studied mechanisms, linked to the response to calorie restriction and other stresses, cannot greatly increase life span in long-lived species. They work quite well in short-lived species. That is well demonstrated: calorie restriction itself boosts mouse life span by as much as 40%, and certainly does not do that in humans. Thus we should not be looking to altered metabolism as a path that can add decades to the healthy human life span in the foreseeable future.

Arguing that this line of development is hard, and that all of the specific approaches examined so far appear to be capable of producing only low yields at best, in terms of healthy years added, is one thing. Arguing that it is impossible to ever achieve meaningful gains via this line of development is quite another. It is ridiculous to argue that it is impossible in principle to engineer humans to be very long-lived by changing the operation of cellular metabolism. We only have to look at the wide range of life spans in mammals to note that some concrete collection of differences must be enabling naked mole-rats to live nine times as long as mice, or for whales to live for centuries. Making significantly longer-lived humans through the approach of altered cellular metabolism is scientifically plausible - it just isn't a viable project at this time, and probably won't be for a lifetime yet.

This is why many people who have looked into the field in detail support the damage repair approach to rejuvenation, as first put forward by Aubrey de Grey and presently championed by the SENS Research Foundation and its network of allies and researchers. This is explicitly a strategy to work around the inability to make near term progress in altering metabolism. Instead we keep the metabolism we have, and target the periodic elimination of the various well-described forms of cell and tissue damage that cause aging. Remove the damage, and rejuvenation results, as illustrated in animal studies in which senescent cells are selectively destroyed via senolytic therapies.

The Zugzwang Hypothesis: Why Human Lifespan Cannot Be Increased

Lifespan is one of the most variable life history traits in the animal kingdom, lasting from days to centuries. Despite intensive investigation, there are still many grey areas in our understanding of the factors which contribute to the variability of lifespan. Humans are among the fortunate animals which have an unusually long lifespan compared to their similar sized mammals. On the flip side, the long lifespan of humans and large genetic heterogeneity are important reasons why it is very difficult to use humans as models to study ageing or longevity or test the efficacy of anti-ageing interventions. Ageing studies on humans often require a very large cohort of people and can potentially be affected by many confounding factors. As a consequence, most studies involving ageing, lifespan, and anti-ageing interventions are based on model systems.

In the evolutionary history after divergence from the great apes, the most recent of our primate ancestors, humans have completed almost 300,000 generations. During this period, the lifespan of H. sapiens has almost doubled. The increased longevity of humans is, in part, attributable to environmental changes; improved food, water, and hygiene; reduced impact of infectious disease; and improved medical care at all ages. However, the above factors had an opportunity to play some role in increasing lifespan only in the last 2 centuries. The dramatic increase in human lifespan compared to our nearest ancestors, should, therefore, must have other valid explanations. It is highly conceivable that forces of natural selection may have played vital role in increasing the basic longevity of humans.

Zugzwang is a German word with the literal meaning "compulsion to move." This word is frequently used in chess to describe a situation when a player gets a disadvantage because it is his turn to play, but all the available moves are bad. In Zugzwang position, any move the player makes will clearly weaken his position. Here, I propose that at this stage of evolution, humans may face the Zugzwang problem. Scientific research and the understanding of the hallmarks of ageing now provide humans with more than a dream to extend lifespan. However, it must be taken into consideration that natural selection has already played its part in extending human lifespan much beyond the expectation. All possible mechanisms which can increase longevity in lower animals have already been exploited by natural selection to stretch human lifespan. Any artificial attempt to tinker, through any possible intervention, with the signalling pathways or transcription factors to achieve a longer lifespan may actually be disadvantageous to humans.

Humans may thus be considered to be in the Zugzwang state. Humans may have already achieved or approached the maximum lifeĀ­span, and further lifespan extension may be very difficult or impossible. Documented record of human longevity for the last 100 years (with a conservative estimate of data from 8 billion individuals) shows that the limit of human lifespan is around 122 years; the fact that no individual has lived beyond this limit is a clue to the validity of the Zugzwang hypothesis.

Comments

Hi there! Just a 2 cents.

''Humans may thus be considered to be in the Zugzwang state. Humans may have already achieved or approached the maximum lifeĀ­span, and further lifespan extension may be very difficult or impossible. Documented record of human longevity for the last 100 years (with a conservative estimate of data from 8 billion individuals) shows that the limit of human lifespan is around 122 years; the fact that no individual has lived beyond this limit is a clue to the validity of the Zugzwang hypothesis.''

Clue does not make true. They should get a clue (another).

Mouse/rat - Naked Mole Rat; 3-5 years vs 35 years
Progeria HGPS - Jeanne Calment; 15 years vs 122 years

It is a fact that (most probably) no human has outlived her (or, if indeed there was 'another Jeanne before Jeanne' at some point (because things repeat themselves/history repeats itself - Her siblings lived 90-100 years -like her; so there was a genetics familty ultra-longevity element there, that allowed her to reach that age), not by much let's say). maybe 130-140, since other people did reach 115, 116, 117, 120...so it Could be possible someone made it to 125..126...127..130? (it does not mean that, necessarily, because it was not recorded in the literatture that it Never happened. I.e. Many things are Never reported -doesn't mean they never happened. Some stuff did/does happen and never heard about it, does not make it any less true/real, was 'unreported/unhead of' - for All this time, you would think someone 'would have found out/noticed by now (and reported it)'; apparently, not)..by 140 it's a miracle and mostly likely no one (or maybe 1 Single Person in entire humanity's history) ever saw the '150 light of day. That would be the unicorn (like her, Jeanne) 1 out-of-dozen billions people over 3 million years.

In the future when we reach 150 (and we will (be optimistic, or just don't, and accept that it ends before), we will be Supercentanarian-halfcenturists (150).

ZugZwang has a zigzag twang (sound-pitch/or just, 'the Pitch') that I don't like, which is one that is pitching that we are doomed.

Ok I'll conced them the : ''humans May thus be considered zugzwang state''...''humans May have already achieved or approached the maximum lifespan, and further lifespan May be very difficult or impossible...''.

That may, is one may too many; but at least they are being realistic, semi-optimistic &
semi-pessimistic; so not ''a Glass Half-Full''...nor ''a Glass Half-Empty''...just, a ''Glass sort of filled, kinda''.

I wonder how many points your get in Scrabble when you put zugzwang - probably you win the game.
Cause the opponent never saw it coming (it's like the 3-of-Aces Flush up your sleeve in poker).

Ok...being serious, I know they write this seriously and mean well...like I kind of:
''Accept it...most likely, you will die, and no you won't outlive Jeanne or even maybe, not even your grand-ma..''.

Or..even worse, not even your parents, or your siblings, could outlive you. They are still alive even if older.

Being older is a testament that you are 'Reaching'...as in, your Reached It - The Old Age...you 'made it'...many people don't.

The Older you are, the More Likely, you will reach Even Higher..because you reached that Old Age - in the 1st Place.

In other words, it is survival, survival bias, 'resilience', keeping in shape/healthy/no disease - living long - ..Long -er.

Living in old age is a sign that health was kept enough for function and 'continuing to age - Healthy/Healthily - ''Healthy Aging''.

The worse wording ever. Total misnomer.

Studies like this one are ethically/morally/moral conscience axed; they mean well, to not make up 'have false hopes' about a 'fake antiaging treatment' that 'will save us' from..death.
I understand that. The statistics don't lie (much)...you have 1 chance out 7,000,000,000 of reaching her age.

''So you're saying there is a chance!''

Yeah....1 chance out of planetary sized population.

''Slim pickings....I'll take my chances...erh...I mean my (1) chance''.

Look, we can't be blind, and innocent-like....oblivious you know...we can't; we have to realize that if we can't make it (with rejuvenationTM) well, we can't.

But studies like this though are sincere in intent, kind of break the mood. ''party pooper''.,not to say negative nelly, but not far.

''Any artificial attempt to tinker, through any possible intervention, with the signalling pathways or transcription factors to achieve a longer lifespan may actually be disadvantageous to humans.''

it may indeed, but I think, actually, it is worth trying; because we never tried. We will learn something, a gift for the future (generations). The Knowledge of Whether we Can Outwit death (of aging) or not. Whether we Do (and can) have a choice or we don't (like right now). Whether it is an Irreversible and Irrefutable Order; or a suggestion (when we 'may' die if we 'want' to...,or not). Not a biocoercion as it is.

Any attempt to not do anything, which is what many people do and simply accept it comes, accept death/that we age and die, may also be disadvantageous to humans.

As in, they are dead.

Just a 2 cents.

PS: For some people; dead/dying = good; I used to be that people, I realized I was wrong, I did not fear death then, you could say I was more 'mature' younger...and now older I turned immature (inverse) and 'scaredy cat'/fearing - death; fear keeps you alive. When you have lived near-death, you fear death. Otherwise, you don't know and can 'talk macho - I am not scare of dying'. Ok...we you feel pain (ike I felt it), you mind will change, and you will thankful to be alive, because the pain - kept you so. ''I prefer dying than torture''. I understand that and it's only normal, nobody wants to feel godly-torturelike pain that wich you die on the spot because your body 'fragments' into little pieces and you life goes away, while feeling the pain of it being teared apart.

PPS: This study does not realize that aging is reversable, or does, but thinks it will amount to nothing; and nothing wrong with being skeptic; it's important to be. Lots of BS is peddled around so only normal to avoid snakeoil/false hopes.

PPPS: IT's not sci-fi anymore, it's science, and yes some of it is flawed and gives poort results, but were are getting there.

PPPPS: No the maximum lifespan is not 'set in stone' it is pretty much the 'gradual' process of 'natural/healthy aging' (taking it's course), in other words telomeric and egigenetic changes etc...and one day it halts; that's around the 120ish; what If it doesn'tanymore? Exactly, aging is NOT unstoppable or irreversible; it IS reversible. Now, I think we will have much difficultyies and we may not obtain the best result (like living to 150)...heck even less reaching 400 years...but at least...we are aiming HIGHER to fall 'Not Too Low'...cause we will fall, but not so low, because we Aimed High -Enough (''Aim for the Moon...and if you don't make it...you'll be dancing among the stars'').

Posted by: CANanonymity at April 16th, 2021 9:28 PM

@CANanonymity
If you change the wording you can say that this story is absolutely correct ... at the current state medical and scientific progress... Yes with all the medical and social advances we still cannot beat 122 years record. Hell , we don't even have a second best contender. Out of billions off people. On the other hand, if there's a treatment that can let at least 10 people out of all supercenteriana alive today to reach 122 that would mean that it really works and slows down the aging at the hardest part. So we have an easy statistical test/indicator to look for. The bucket off people alive above 120. 122 and 125.

Posted by: Cuberat at April 17th, 2021 12:15 AM

It was unimaginable to reprogram fully differentiated cells into pluripotent stem cells before Yamanaka. Just saying.

Posted by: laguy at April 17th, 2021 8:31 AM

Oh those of little faith (not that kind)! Throughout human history, many have said of many things, "That can not be done", only to be proven wrong in future generations.

Simplistically, I've always thought of any thing's potential lifetime as a battery - that runs down. Some start with bigger or smaller batteries. Regardless, most succumb to "battery faults", disease, malnutrition, injury, etc., that short circuits available life potential. Only a few run the battery to natural exhaustion without problems. Today, as with true battery technology, battery life, energy density, expense, and deeper understanding of the chemical processes bring significant improvements. So to will further understanding of life's battery.

I see hope in extending our lifespan through the emerging understanding of the molecular workings of the human cell, the mitochondria, the power sources, the catalysts that make it all possible, to name a few. Keeping these processes running longer (or forever) and at full tilt will reap for us as yet unseen benefits. Human kind has never had the tools before to delve into these intricacies - as we are presently doing. What may appear (nearly) incomprehensible right now, at the present state of knowledge, will likely come into clearer focus to future knowledge seekers. The future always hold surprises. Never say never.

Posted by: Randomwalk at April 17th, 2021 8:48 AM

"Further, those best studied mechanisms, linked to the response to calorie restriction and other stresses, cannot greatly increase life span in long-lived species. They work quite well in short-lived species."

That's interesting that life span (and presumably health span) interventions do not translate all that well from mice to humans. If the Harold Katcher and Steve Horvath experiment with E5 turns out to be real (i.e., the claimed 54% age reversal in epigenetic age in mice), one has to wonder how much of this benefit, if any, would translate over to a long lived species such as humans.

Posted by: Brad at April 17th, 2021 9:37 AM

@Brad
A lot of things that work in mice translate poorly to humans. Cancer and Alzheimer's treatments to name a few...

Posted by: Cuberat at April 17th, 2021 4:30 PM

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