Arguing Against the Appearance of a Limit to Human Life Span in Historical Data

Today I'll point out the latest paper in a debate over whether there are limits to human life span. As everyone in the audience here is no doubt aware, human life expectancy is gently trending upward. Life expectancy at birth is rising at about two years with every decade, while life expectancy at 60 is rising at about a year with every decade. The evidence in support of this trend is robust, thanks to the enormous demographic databases collected over the past few decades. Is this trend approaching any sort of limit to human life span, however? Can historical data even be used to answer that question? This is a much more challenging proposition, as the available data for the oldest humans, the population of supercentenarians older than 110, is sparse. Very, very few people survive to these ages, to the point at which statistical methods operating on this data become ever more dubious with each additional year of age.

Still, people crunch the numbers and try to extract meaning. You might recall that last year, Jan Vijg's group put forward their argument for the data to show there to be a limit to human life span over the years in which that data was collected. It was coupled to some unexpectedly pessimistic commentary on the future development of longevity science, given that Vijg has for some time been counted among those researchers openly in favor of extending healthy life spans by treating aging as a medical condition. The paper sparked some occasionally heated discussion. I don't think the researchers expressed their argument all that well in their publicity materials, and the popular science press then generated more than the usual degree of mess and confusion when they pitched in.

So to the casual observer, it was a little difficult to see whether Vijg and company were making the obvious point, which is that human life span is effectively limited by the present level of medical technology, or whether some more subtle argument was being made. I think it is hard to disagree with the statement that medical technology determines limits to human life span. Where we can debate, given the sparse nature of the evidence to hand, is whether or not there exists one or more mechanisms of aging that have not been impacted in any meaningful way by improvements in medical technology over the past century, and which, on their own, can produce a very high rate of mortality in late life. That circumstance would look a lot like a limit when examining the consequent demographic data.

One mechanism that springs to mind here is the accumulation of transthyretin amyloid, found in one small study to be the majority cause of death in supercentenarians, but which appears to have only a smaller impact on mortality in younger old age - it is implicated in something like 10% of heart failure cases, for example. Can we argue that advances in medicine and public health over the past century have had little to no impact on the accumulation of misfolded transthyretin deposits in tissues, and thus this mechanism acts as a limit on life span? Or do some of these improvements in fact produce an small, incidental reduction in amyloid burden in later life? I think that the evidence to support any of the possible positions on these questions is presently lacking.

Whatever the state of effective limits on life span today, however, the limits on life span tomorrow are determined by progress towards rejuvenation therapies. There are treatments under development that can clear transthyretin amyloid from tissues, for example. The same is true for many of the other forms of molecular damage and waste accumulation that cause aging. Thus any debate over what the present demographics do or do not show is more academic than it might otherwise be. The natural state of human aging, already largely paved over by medicine, will be buried completely, made irrelevant in the decades ahead by the advent of means to repair the damage, restore youthful function, and eventually to indefinitely postpone all of the symptoms of aging.

No detectable limit to how long people can live

Supercentenarians, such as Jeanne Calment who famously lived to be 122 years old, continue to fascinate scientists and have led them to wonder just how long humans can live. A study published last October concluded that the upper limit of human age is peaking at around 115 years. Now, however, a new study comes to a starkly different conclusion. By analyzing the lifespan of the longest-living individuals from the USA, the UK, France and Japan for each year since 1968, researchers found no evidence for such a limit, and if such a maximum exists, it has yet to be reached or identified.

"We just don't know what the age limit might be. In fact, by extending trend lines, we can show that maximum and average lifespans, could continue to increase far into the foreseeable future." Many people are aware of what has happened with average lifespans. In 1920, for example, the average newborn Canadian could expect to live 60 years; a Canadian born in 1980 could expect 76 years, and today, life expectancy has jumped to 82 years. Maximum lifespan seems to follow the same trend. Some scientists argue that technology, medical interventions, and improvements in living conditions could all push back the upper limit. "It's hard to guess. Three hundred years ago, many people lived only short lives. If we would have told them that one day most humans might live up to 100, they would have said we were crazy."

Many possible maximum lifespan trajectories

A recent analysis of demographic trends led to the claim that there is a biological limit to maximum human lifespan (approximately 115 years). Although this claim is not novel - others have also identified a biological 'barrier' at 115 years - the methodology that the authors used is. Here we show that the analysis does not allow the distinction between the hypothesis that maximum human lifespan is approximately 115 years and the null hypothesis that maximum lifespan will continue to increase. The central difficulty with this exercise is accurately extrapolating onwards from a limited, noisy set of data.

Beyond a plateauing of maximum life span, there are other different trajectories that maximum lifespan could follow over time if the null hypothesis (that maximum lifespan will continue to increase) were true, with maximum lifespans continuing to increase to an eventual future plateau or continuing to increase indefinitely. All three models appear equally consistent with the known maximum lifespan data used. How the authors differentiated between these possibilities is important. Their claim rests on their identification of a plateau in the ages of maximum lifespan beginning around 1995. They separated the data into two groups, 1968-1994 and 1995-2006, and modelled each group using linear regression. While the first partition shows a trend for increasing maximum lifespan, the second partition does not. It is this latter partition upon which their conclusions are largely based. This is problematic, because, even within a dataset showing an overall trend for an increase with time, normal variability can generate apparent plateaus and even temporary decreases over small intervals.

Furthermore, the authors do not describe how they identified the lifespan plateau, nor the partition site, indicating that these were products of casual visual inspection. This is a critical point for the validity of their argument because even slight changes to the assumptions that they made can notably alter the results of their analysis, with markedly different outcomes. In conclusion, the analyses do not permit us to predict the trajectory that maximum lifespans will follow in the future, and hence provide no support for their central claim that the maximum lifespan of humans is "fixed and subject to natural constraints". This is largely a product of the limited data available for analysis, owing to the challenges inherent in collecting and verifying the lifespans of extremely long-lived individuals.

A reply from Jan Vijg's research group

The authors of the accompanying comment disagree with our finding of a limit to human lifespan. Although we thank them for alerting us to other work reporting a limit of around 115 years, we disagree with the arguments presented and remain confident in our results. We feel that the scenarios presented, although imaginative, are not informative. They argue that their three different models (which they extrapolate until the year 2300) are not statistically differentiable based on the data available. We used a data-driven approach to identify the trend in the maximum reported age at death (MRAD) by analysing actual data rather than arbitrary simulations; although the authors criticize us for visually inspecting our data, graphing data in order to evaluate the choice of model has long been acknowledged as a useful and important technique by statisticians. Taken together, and in the absence of solid statistical underpinning of various possible future scenarios, we feel that our interpretation of the data as pointing towards a limit to human lifespan of about 115 years remains valid.

This is, it has to be said, exactly the sort of exchange one might expect to see between researchers who are working with a very sparse set of data. It is always interesting to watch the ongoing efforts to better refine, mine, and interpret this data, but it is of limited relevance to the near future of therapies to treat aging. All of the present well-known demographics of later life will be changed greatly for the better as therapies capable of addressing the causes of aging emerge.

Comments

"It was coupled to some unexpectedly pessimistic commentary on the future development of longevity science, given that Vijg has for some time been counted among those researchers openly in favor of extending healthy life spans by treating aging as a medical condition. "

The real problematic argument he produced.
And unfortunately no one is specifically interested in arguing it, at least not officially like they did with the meaningless demographic study.

Posted by: Anonymoose at June 28th, 2017 11:40 PM

Hi, just a 2 cent.

MSLP (Maximum Lifespan Potential) is, technically, an anomaly and like they say in that study we don't really 'know' what is the limit - Possible; with that said, currently, is stops around 120-122; that's about the slowest speed of aging right now (of course with new technologies and therapies aging could be slowed, or just simply, reversed altogether (though that will be the hardest)).

''Can we argue that advances in medicine and public health over the past century have had little to no impact on the accumulation of misfolded transthyretin deposits in tissues, and thus this mechanism acts as a limit on life span? Or do some of these improvements in fact produce an small, incidental reduction in amyloid burden in later life?''

They definitely have helped and surely, would retard, this transthryretin amyloid problem - which is tied to the near-same mechanism as brain amyloid accumulation. Any reduction of aging - Earlier - in life will manifest later on because it orchestrated 'concert' (i.e. what you did before left 'some mark' (epigenetics, etc) and this shows later on in life).
That'S also why I say these therapies must be started the Youngest possible - sooner the better (for the most part, certain therapies must be more helpful in elderly because they need it while the young ones don't; but damages accumulate - At All Ages - so, better Earlier than Later.)

But to go on on what they said, currently, as the speed at which we age; yes, they are about right that, indeed, certain slow-aging humans hit a brick wall around 120.

But, there is a but; it's not 'the end' of it : some animals live 500 years (Greenland Sharks, ok not mammal; Mammal : Bowhead Whale MLSP 200+ years - ok, it's not a human; but you see where I'm going; it's not a finality but in order to Live About 120 - we must Keep Young a Lot Longer than what we do right now (so for example, a chronologically aged person with 100 years (old) has the biological body of a 50 year old; and one study showed that Centenarians were 8 years younger (epigenetically) at all times of their lives than regular people who die below 100)),
So :

That means what, it means that we keep biologically younger - Sooner - Earlier...so down the line, later on we 'are less damaged'...and continue to live on - until, we hit the 120 wall.

There are way too many things that show that, for humans of regular aging and slow aging (centenarians)), they accumulate many things that Stop them from being able to go above 122-130 years old.

Ex:
-Mitofused mitochondrias in centenarians, they are mitofused but that does not mean they are 'perfect' they have damage and as such, bound to fail anytime soon.
-Centenarians accumulate lipofuscin - too, just less of it - at the start; their accumulation rate is the same, they just have Less to Begin with - and keep that Lesser AMount for longer because they started with less of it (for they have slow aging phenotype)). If you have a 'baby face' (plump-skinned, plumpness is a marker of aging by collagen levels (babies have immense levels of collagen (we lose that as we age, and that's what gives the 'old' look vs soft plump skin of baby) right now, you could have a chance of making it to a 100 (it'S not certain of course) but it's a good indicator (collagen is a good marker vs MLSP; you can detect it in the depth of sub-scattering in the skin (when light penetrates the collagen scaffolds, by looking at face pictures gradient)).
If you look at photos of certain centenarians like Jeanne Calment, at 40 years old she looks basically like 20 (it means her collagen levels were full pin and, indeed, it Was Not something like she 'ate olives/olive oil' or some other thing; she had a genetic predisposition for slow aging (yes her olive oil did help (monounsaturate-rich) - a bit (for accumulated a large amount of unsuscpetible monounsaturates (oleic acid 18:1) in her membrane phospholipids thus protected from peroxidation of PUFAs (polyunsaturates)) and she ate tons of dark chocolate (she got high levels of Polyphenols from cocoa polyphenols in dark chocolate, dark chocolate has high ORAC/TAC values; and it's full of fat (cocoa butter) of palmitic acid (16:0)/stearic kind(18:0)) this was incorporated too in her Mitochondrial and Triglycerides membranes in small amounts (for lipids are controlled by Deltas-Saturase/Desaturase/Lipase/Phospholipase/Sphingolipidpase...) and made them more Peroxidizable Resistant - and she Smoked from 20 to a 100 years old (Smoking is contributes to cancer and oxidative stress - and paradoxically, in certain instances, like her; it can actually Increase Health because it increases the NRF2/ARE/Redox response; which means the body responds in 'hormesis/hormetic' way and thus protects from the oxdative insult (this 'stress resistance' 'stress priming' of her system nullified much the negative effects of cigarette she smoked FOR 80 YEARS and on top of the fact, the real reason she lived to a 122 was FAMILY inherited GENETIC, her sisters, mother etc...ALL of them Lived Long (90 years old and over...so no, this is not some 'oliveoil+chocolate' cure...she had a Family-Given Lucky Genetic that allowed her a very slloow aging phenotype in her young years in order to reach 122 (remember she looked biologically (Biological Age) Much Younger in (bioyears) than her Chronological Age (real-Time years) - as I explained, you must Uncouple Them To Live Longer); and so yes your skin is great determinant of how long you Could live. If it's deathly looking, it's a bad sign that oxidative stress is immense in you and you age at the speed of light (For skin is an Organ in itself)). Of course, it's not the entire picture, for many organs don'T age exactly at the same speed; but, overall, if healthy, than yes, aging is pretty equal is most organs. Sorry for typos, I'm starting to 'hit the sack soon' (which means my mental abilities are becoming foggy/sleepy).
-Replicative Senescence, there is a limit there; of course, in her case, she had More Replicative Rounds because the cell works like that; if you grow slower (developmental growth), you allow more replicative rounds (by reduced mTOR levels), her replicative senescence was greatly diminished compared to the rest - her telomeres were Taller and she experienced less damage over all - but not necessarily (she smoked), she just had Less To Begin With. She was born with a younger biological body (this was seen with babies from older fathers, they have longer telomeres; due to telomere elongation in male's sperm over the years; so aged fathers can give more mutations and problems to the child - but also, Longer Telomeres to the baby. This 'chunk' of extra telomerric DNA - She Got it at Birth, as such she had 'more Life' right from the start. Analogy : She started at 20 kb Telomere. You started at 16 kb Telomere; she 4 kb extra right there). So, she's technically not aging necessarily Slower - But She is Younger Biologically Than You; this is Behind in (Biological) Time than you (by taller telomeres).
So she's a 'Head Start Ahead (or should we say 'Behind' in this case, because she was just 'born younger' than you; your were born 'biologically' older (smaller telomeres DNA im chromonsomes))'

It,s just a downhill slope, what happens when someone's start 'half-way' the slope, they get to the bottom much quicker than that person that started at the top of the slope (Jeanne Calment).

I say Younger biologically because Telomere length was shown as replicative 'counting' mechanism - and humans are bound by Replicative (senescence/rounds) of somatic cells; centenarians have more consecutive rounds available to them - in the alloted replications before the cell reaches Hayflick Limit. This means slower accumulation of lipofuscin, for lipofuscin is cell cycle diluted residue that is undegradable, can only be diluted through cell cycle mechanism; and lipofuscin in lysosomes (especially) is an 'age marker'. Higher TElomeres = More Replicative Rounds = Less Lipofuscin Accumulated so far in cells.
Werner fibroblast cells can make 15-20 PDs (population doublings) and become chock-full of lipofuscin and senesce there. SV40-infected Werner fibroblasts can make 265 PDs and become 'void' of lipofuscin (seen on FACS fluorescence); they harbor immortal quality like cancer cells - whomm, too, don't accumulate lipofuscin and can be replicatively immortal - their Telomeres never go below 2Kb either, thus never Senesce.

-Redox, Centenarians keep their redox, animals who live 500 years keep redox, same thing. people who die before 80 don't.
-Epigenetic TRanscriptional Drifting : centenarians are epigenetically 8 years younger than rest. They don'T drift as much in their epigenome - they keep sufficient global DNA methylation (we lose methl count, like 5-methylcytosine total loss). Their genes are far more 'silent' (like young people), they have gene silencing, while people dying below 80 have mega mutations (cancer, diabetes,..etc) going on and lots of 'gene activation' (to try to compensate for cataclysmic downhill fail by - Closer to final death point (we have to remember they are lower down the 'telomere' ladder, as such gene activation at low Telomere length starts to be very strong (the telomere signal and DDR/telomeric DNA damage signals activate inflammation genes p53/p16); thus, Spontaneous senscence happens more in those age from diseases whom die below 80 yaers old; while Centenarians are far more affected by Replicative Senescence.

- Studies like this are good but are mostly conjecture and some stats verifying but notthing 'iron-clad' (their results are 'decently-accurate' but not the Utter Truth either, there is a trend - the chances of reaching 122 are 0,0000000001% (1 out of 8 billions (ofpeople)) when aging 'normally' without any therapy, CR or anti-aging supplement etc.....so no point holding your breath you have more chance of dying in a plane crash even if you never take planes and should be Utttter Zer-0), But We Rejuvenation Therapies that will then Increase Odds - Millions (if billion maybe) of Times)) Maximum lifespan is 'maleable' depending on many factors (environmental, evolutionary, biological, nutrition/diet, social...) - but one thing is near sure, trying to save a 80 year old human whom is on his/her death bed and to make it live 500 years will be near Nigh impossible; especially, if we can't pin everything 'sufficiently' to allow Robust Rejuvenation. How Robust ? I think it will be robust enough for living aroud 120-150. But not that much more, because of the many enumerated problems. I, sincerely, hope that damage reduction to a 'good enough' level would Be ENough to retard aging and could be repeatable to live indefinite life; but I hold great reservation on that. I could be/am (many times) very wrong (too) that is very sure. Just a 2 cent.

Posted by: CANanonymity at June 29th, 2017 1:08 AM

I agree that taking a historical interval of 35 years and dividing it manually in 26+9 years intervals is highly unconvincing, statistically, even more so when the data is so sparse.

Posted by: Antonio at June 29th, 2017 2:35 AM

@CANanonymity centenarians definitely have a "regenerative reserve" in comparison to other people but don't forget aging is without a doubt a function of time. So a simple reserve isn't going to beat the problem, while adding to your pool on intervals might.
There is no hard limit, but there are definite hard soft limits caused by technological incompetence and lack of infrastructure in healthcare.

I still can't wrap my head around the problem of providing truly young, genetically identical stem cells of every type, to the right places, even for a single person. With our current state of stem cell medicine that is simply not possible or even plausible.

I believe Aubrey made a mistake when he didn't go into stem cell research 10 years ago, that field seems to have reached a standstill both on the side of regulation by government agencies and on the scientific side which has almost entirely changed it's aim from doing more basic science (which is needed) to trying to make the quick buck by selling half baked stem cell therapies which comply with the current regulatory systems. Almost every stem cell product being sold or being developed currently is either - an autologous product made from barely reprogrammed cells which still carry many signs of aging regardless of their epigenome, or alternatively heterologous products which ... I'm not sure what those are supposed to do besides increasing your inflammatory burden down the road when they stop spewing good cytokines.

Posted by: Anonymoose at June 29th, 2017 10:50 AM
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