Back to Debating Limits to Human Life Span Again

While it is self-evident that longevity is limited in the practical sense, in that one or more degenerative processes of aging eventually make it so unlikely for survival to continue that everyone dies somewhere before age 120, that doesn't mean that longevity is limited in any other sense. If we alter the consequences of the underlying processes of aging, by repairing the damage that they cause, by changing the process, and so forth, then longevity will increase. While the authors of today's open access paper make generally sensible statements about the nature of aging, they seem far too skeptical that anything of practical use can be achieved in the near future in the field of rejuvenation research. They mount an argument from complexity, against the ability to increase maximum life span from any single intervention into processes of aging, that doesn't seem at all sound to me.

If anything, the demonstrated network of interactions between processes of aging, and between processes and cellular metabolism, is an argument for addressing any one process to be broadly beneficial, eliminating harmful effects throughout cellular biochemistry and tissue function. That evolution has not produced this outcome in any given species is not an argument against the benefits of, for example, removing senescent cells from aging tissues. It is more an argument against the idea that evolutionary selection operates strongly on matters relating to later life. Species lifespan is most likely a consequence of evolutionary pressures operating on the early life environment, a byproduct of that tooth and nail competition, not a selected outcome.

Why Gilgamesh failed: the mechanistic basis of the limits to human lifespan

Thus far, geroscience has been remarkably successful in increasing our insight into aging and convincingly demonstrating that lifespan, at least mean lifespan, as well as healthspan, can be modulated, based on interventions targeting the molecular pathways first discovered in the worm. What it has not done, however, is demonstrate that the maximum lifespan of a vertebrate can be radically extended. The possibility of doing just that, however, is suggested by the large diversity of mortality curves across species.

Confidence in technological progress has now become so high that it has been argued that new medical interventions will soon emerge and radically increase human longevity. Such optimism is the driving force behind the very large sums of money recently donated by billionaires to new organizations active in geroscience. These include: the Methuselah Foundation, which has set up a series of prizes to demonstrate longevity extension in mice; the SENS Research Foundation, which has funded research into aging and rejuvenation; Calico, launched by Google, has engaged in multiple collaborations with academic and commercial researchers; Human Longevity, founded by Craig Venter of human genome fame, and largely focused on a concierge longevity service; and Altos Labs, a newcomer with $3 billion of funding.

Despite their impressive rosters and large cash flows, these organizations face great difficulty in achieving their lofty goals. Currently, there is little consensus as to the cause, or causes, of aging. Most would agree that aging is the result of damage, that is, deleterious changes, that are ultimately molecular in nature. Although preventative measures can be useful, a damage-repair approach, like the one advocated by the SENS Research Foundation and others, will be necessary

While in theory targeting cellular defense systems, including systems for DNA repair, detoxification, immune response and programmed cell death, to boost the quick removal of damage to biological macromolecules, protein aggregates, and senescent cells, should be feasible in the long term, singular causes of aging are conflicting with evolutionary theory. Indeed, if there would be one highly conserved central cause of aging, possibly going back in evolutionary time to the early replicators, multicellular organisms would fall prey to the late-life adverse effects of mutations that accumulate in the germline due to the age-related decline in efficacy of natural selection. This would mean that, independent of any hypothetical central cause of aging, a host of additional adverse late-life effects have to be taken into account.

This would essentially mean that any fix of the limits to lifespan would require interventions at many choke points. Such multipoint targeting would also need to be fine-balanced so as to avoid side effects. Indeed, there are few if any gene regulatory pathways exclusively involved in somatic maintenance and it is this complexity that essentially rules out successful interventions aiming to exclusively extend maximum lifespan of a species. In essence, what needs to be done is to mimic evolution as to how this gave rise to extremely long-lived species, such as those mentioned above, but in real time. As this would involve possibly millions of genetic variants, this seems an impossible quest.

Based on the above, geroscientists should clearly distinguish between mean and maximum lifespan and not give the impression that their research can substantially increase the current limits to human lifespan. Their focus should be on improving life expectancy and healthspan, that is, bringing more people closer to the maximum lifespan possible for members of Homo sapiens and improving the quality of those years.


Brandon Milholland... had another such paper a couple of years ago:
Evidence for a limit to human lifespan
Xiao Dong , Brandon Milholland , Jan Vijg
Nature (2016) pubmed: 27706136 doi: 10.1038/nature19793

People had opinions about it:

'How could an article with numerous shortcomings be published in top-tier journal Nature?'

'We respond to claims by Dong et al. that human lifespan is limited below 125 years. Using the log-linear increase in mortality rates with age to predict the upper limits of human survival we find, in contrast to Dong et al., that the limit to human lifespan is historically flexible and increasing. This discrepancy can be explained by Dong et al.'s use of data with variable sample sizes, age-biased rounding errors, and log(0) instead of log(1) values in linear regressions. Addressing these issues eliminates the proposed 125-year upper limit to human lifespan.'

'A cohort is not representative of humanity'
'Summing up, the presented evidence does not clearly "suggest that the maximum lifespan of humans is fixed and subject to natural constraints". I believe, we better put faith in the results of demographers (e.g. Vaupel [4] or Vallin & Meslé [5]), who draw much more optimistic projections based on the population-wide analyses.'

and last but not least my favorite:
'Like analogous, disproven publications over the past 100 years, Vijg et al. and Olshansky add nothing to scientific knowledge about how long we will live. The publications are advocates' arguments based on selective use of data, with one-sided conclusions not supported by the data.'

There were a couple more like those.

Anyways, I'm sure this time is different. Milholland learned from past mistakes and delivered sound science this time. Lulz!

Posted by: Jones at October 25th, 2022 3:08 PM

It is patiently clear that at the current state of affairs the human lifespan of limited. And is also quite clear extending it is not an easy challenge either.

And yet there's no theoretical block , no no law of nature prohibiting such an extension to an arbitrary age.

Such an extension might need quite unnatural. But our natural fate is to procreate around the age of 20 ( as early as 13 was considered acceptable in some societies not that far ago), coast for about 20-30 years and die more or less quickly. Our bodies are overbuilt to survive stresses and abuse. So if we can avoid the worst of the abuse, body stress and have some luck, we can easily move to to 60-70 with minimal medical help. With good medical services that can resume to 70-90.

So no news here. Our bodies just sent meant to last over 100 years. There was zero evolutionary pressure for lockdowns over 60. It was good enough. Almost 4 generations, if you take the youngest reproduction age.

So living above the age of 60 is not natural. Having enough food all the time is not natural. Not being exposed to deadly pathogens and predators is unnatural.

So life extension is unnatural. Yet possible, albeit hard

Sorry for the long rant. I feel getting old and grumpy

Posted by: Cuberat at October 25th, 2022 10:23 PM

Perhaps it is not as interesting debating maximum life span as it is to debate how much intervention/ modification needs to occur to realize increased health span and eventually productive life expectancy. There may indeed be significant trade-offs with the early stages of rejuvenation work: from easy issues of significant medical attention time and money over time -to- actual alteration of traditional episodes of development, reproduction, survival-maintenance within a human life span -to- substantial 'switch-out' of organs/ systems/ molecular eco-systems (whatever that means). We may not be the same physical being that was birthed many decades previous. Beyond simple navel-gazing this may have impact on how money is spent, how research is coordinated/ initiated, how regulation is lobbied, etc., etc. - i.e the best 'fruitful' path.

Posted by: Jer at October 26th, 2022 6:24 AM

I disagree with this paper's claim that there has never been a radical extension of lifespan in a vertebrate animal model. Here is a study reporting an extension of maximum lifespan in mice of 28%. In this study, old mice received bone marrow cells from young mice:
Extension of Maximal Lifespan and High Bone Marrow Chimerism After Nonmyeloablative Syngeneic Transplantation of Bone Marrow From Young to Old Mice

Although 28% may not sound very radical, the old mice only began receiving the treatment at an old age. The actual survival time of the mice from the beginning of the experiment increased by a whopping 2.8-fold. In addition, a relatively low bone marrow chimerism was achieved (only 28%), and the results could have been much better if a higher bone marrow chimerism was achieved (ideally 100%) via the administration of G-CSF or other stem cell mobilization agent to recipient mice prior to their receiving the young bone marrow cells. Plus, the old mice received the treatment only once and did not receive young bone marrow cells on an ongoing basis.

Similar results were achieved in earlier studies that transplanted bone marrow cells from young to old mice.

We should start paying attention to studies that extend maximum lifespan, particularly in mammals, vertebrates, and other higher life forms. Those studies can teach us a lot.

So I strongly disagree with the pessimistic tone of the above article by Brandon Milholland, which basically conveyed a sense of hopelessness and despair that biological aging is too difficult and that we (humanity) will never figure it out.

Posted by: Andrew Lee at October 30th, 2022 10:05 PM

I'm surprised that no one is commenting on the very welcome improvements in this paper relative to the 2016 one from the same group that is noted in Jones's comment. Specifically, in this new paper they go out of their way to speak in the language of damage, and they even make clear that damage repair is the way to go: "Although preventative measures can be useful, a damage-repair approach, like the one advocated by the SENS Foundation and others, will be necessary". All in all, while I of course lament the pandering to deathism in the soundbites (such as the title), I am happy that they got the messge.

Posted by: Aubrey de Grey at November 1st, 2022 4:25 AM
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