23 replies to this topic

[albedo]

When considering SENS and the more conventional disease-centered approach, one of the many objections to SENS is that no radicalism is needed due to the progresses in medicine as shown when comparing life expectancy  (LE) say between 1840's and present times.

 

Indeed, an outstanding 42 years for women are gained (from 45 to 87) over 170 years (ref here and here)

 

However, a point Dr. David Wood did not fail to miss in his truly excellent book “Abolishing Aging” (see chapter 2, Q2), is that, when taking into account childhood health improvements, the mature LE gain reduces to a less impressive 15 years over the same 170 years (from 64.6 to 79.2 in women, ref here). So passing the 1840’s dangerous childhood years seems to be a reasonable explication to the substantial 42 years rise in LE. Wood then argue that a more radical approach, possibly à-la-SENS or “rejuveneering” (from the contraction of rejuvenation and engineering) would be needed if we want to do more.

 

I hazard a comparison with what looks to happen in the very last stages of life of supercentenarians but still struggle to find an explication.

 

It looks like that the exponential increase of mortality rate slows down starting at about 115 (e.g. see Dr. Aubrey de Grey’s presentation here).  Technically this is a deviation from the Gompertz-Makham’s “law”. What can be the explication assuming this effect is real as Aubrey convincingly argues?

 

In other words, I wonder what could be the equivalent of letting passing the dangerous childhood years, likely by the progress of medicine against infections, in the case of supercentenarians. It is just like the very old starts be to “forgotten” by Nature.

 

Can an explication be found in that, just as that passing the infection driven dangers of childhood years increased substantially the life expectancy in the 1840’s, passing the killing cancers before the very old age picks up slows down mortality. Eventually death will take back its toll much later in age by late cancers disruption or, ironically, by the same increased susceptibility, this time for the very old, to infections. Would this make sense?

[Turnbuckle]

It looks like that the exponential increase of mortality rate slows down starting at about 115 

 

 

There are presently only 17 people in the world who have been verified to live past 115. So I'd say the statistics are shit. Besides, when people get that old, there's more interest in verifying them and putting them on the list. Thus there's a selection bias in the data of the very old.

[albedo]

I realize data set is very limited but that is the all point Aubrey is doing in his talk (by the way, it is very new material from him and I normally listen well when he comes up with something new).

 

The effect is quite impressive graphically when you plot it removing the background (done by Monte Carlo simulation). The effect was noted, reportedly by Aubrey, by the Gerontology Research Group keeping the deaths log: http://www.grg.org/SC/SCindex.html. In his peculiar style, Aubrey also referred to “pompous academics” who dismissed the value of these data.

 

Maybe it will turn to be a statistical fluke but still I am not convinced as per today. It looks like also this deceleration is quite well known, e.g. see Gravilov & Gravilova “…At advanced ages (after age 80), the “old-age mortality deceleration” takes place: death rates increase with age at a slower pace than expected from the Gompertz-Makeham law. This mortality deceleration eventually produces the “late-life mortality leveling-off” and “late-life mortality plateaus” at extreme old ages (Curtsinger et al., 1992; Economos, 1979, 1983; Gavrilov & Gavrilova, 1991; Greenwood and Irwin, 1939; Vaupel et al., 1998). Actuaries— including Gompertz himself—first noted this phenomenon and proposed a logistic formula for mortality growth with age in order to account for mortality falloff at advanced ages (Beard, 1959, 1971; Perks, 1932)...”

 

From Aubrey's talk I also understood lot depends how you bin your data (exactly to alleviate the small statistics) yet retain some insight to what data are potentially telling and the degree of precision: e.g. I realized the number of days (vs only reporting years) is important (e.g. Mrs. Calment died at 122 years and 164 days).

[Never_Ending]

It's almost surely not a fluke.  The reason is because of the force of natural selection is tight when selecting for youth and adult stages but it gets looser and looser as age increases after adulthood. There comes a point where the base level of biological functioning/integrity (or level of bad faulty genes) is reached and it remains stable even in the absence of selection forces. This makes sense and also it's seen in many animals not just humans.

 

The explanation that you are mentioning about it being like moving past a "risk phase" would be more applicable if the mortality goes down past a certain old age, which from what I presume it doesn't (it only stops increasing it doesn't reverse back to a younger mortality rate).

Edited by Never_Ending, 05 October 2017 - 09:33 PM.

[albedo]

Yes, various evolution based explications might be provided as well as others:

 

"Several causes are proposed for late-life mortality:^[1]

• Population heterogeneity (first proposed in (Beard 1959)), is by far the most common explanation of mortality deceleration. Even if individual hazard rate follows a Gompertz law, if the population is heterogeneous, the population hazard rate may exhibit late-life deceleration.
• Redundancy exhaustion – in the reliability theory of aging, an organism's redundancy (reserves) are exhausted at extremely old ages, so every random hit results in death. In more detailed accounts, this only holds in relatively simple organisms – in more complex organisms with various subsystems, deceleration is less present or entirely absent.
• Less risky behavior and more sheltered environment for older people (Greenwood & Irwin 1939).
• Various evolutionary explanations."

https://en.wikipedia...ty_deceleration

 

Population heterogeneity seems attractive:

 

"...Whichever model best fits the data for survival to extreme human ages, the phenomenon of the apparent plateau in late-life mortality requires explanation. One attractive solution to this enigma is population heterogeneity [39,47,48]. If the population comprises a set of individuals who differ in the inherent robustness or rate of ageing, the frailest individuals tend to die soonest, leaving the most robust individuals to predominate at the oldest ages. In such a scenario, it is possible for a late-life mortality plateau, or even a decline, to be seen at the population level, even if the various individuals that comprise the population all experience an increasing probability of dying with advancing age...."

 

Kirkwood TB. Deciphering death: a commentary on Gompertz (1825) 'On the nature of the function expressive of the law of human mortality, and on a new mode of determining the value of life contingencies'. Philos Trans R Soc Lond, B, Biol Sci. 2015;370(1666)

[Never_Ending]

I think it's more likely an evolutionary related reason (or some reason inherent to the life cycle). It just seems that such a trend would not be due to a less profound reason.

 

The population heterogeneity does not seem to make much sense if you really picture what it's meaning to say. The way life is maintained requires the cohesive functioning of many genes so it would take more and more beneficial genes stacked on top of each other to further add each additional ounce to the life span compared to the norm(all else being equal, lifestyle etc). So heterogeneity could just as well apply in continuously accelerating mortality. For their explanation, it would require an almost unnatural distribution of a very thorough selection of "good" genes unto a certain group of individuals. Realistically I don't see how that would ever be the case.

 

It's definitely still one possibility (despite my doubts on it) , further analysis and research on the topic would be interesting to see. It would be particularly interesting to see ones regarding how much of the deceleration (if related to life cyle /aging) is able to be altered whether through controlled selection or on an individual level.

Edited by Never_Ending, 07 October 2017 - 02:10 AM.

[albedo]

I think it's more likely an evolutionary related reason (or some reason inherent to the life cycle). It just seems that such a trend would not be due to a less profound reason.

...

 

You seem to be standing on the shoulders of the evolutionary biologist, Prof. Michael Rose, one of the very well known figures in the field who says about aging "It's a transitional phase of life between being amazingly healthy and stabilizing". The stabilization or leveling off is what we might see as the deviation to the Gompertz-Makham's law and mentioned by Gravilov & Gravilova in my previous post:

http://uk.businessin...016-4?r=US&IR=T

 

 Rose's concept.PNG   58.91KB   0 downloads

http://www.longecity...lity-naturally/

 

 Rose's concept 2.PNG   105.52KB   0 downloads
 

Rose MR, Rauser CL, Mueller LD, Benford G. A revolution for aging research. Biogerontology. 2006;7(4):269-77.

https://link.springe...0522-006-9001-6

 

(edits:links)

Edited by albedo, 05 November 2017 - 09:32 PM.

[Robert Seitz]

I would suggest that a search on "supercentenarians" and "transthyretin" will say that 70% of supercentenarians die of a buildup of transthyretin plaques in artery walls. The transthyretin protein (TTR) transfers thyroxene and retinol through the blood and the cerebrospinal fluid (like cholesterol transports lipoproteins?). With age, this protein degrades and clogs arteries. The drug tafamidis (or Vyndaqet) has been approved in Europe but not in the U. S. for treatment of an inherited form of this disease (familial amyloid polyneuropathy)

[albedo]

I would suggest that a search on "supercentenarians" and "transthyretin" will say that 70% of supercentenarians die of a buildup of transthyretin plaques in artery walls. The transthyretin protein (TTR) transfers thyroxene and retinol through the blood and the cerebrospinal fluid (like cholesterol transports lipoproteins?). With age, this protein degrades and clogs arteries. The drug tafamidis (or Vyndaqet) has been approved in Europe but not in the U. S. for treatment of an inherited form of this disease (familial amyloid polyneuropathy)

 

Interesting. However I do not understand in what this might be an explication of the flattening and possibly the decrease of mortality rate.

 

Also, I just realize my previous post did not link correctly to the picture, so I repeat it here:

 

 Rose's concept 2.PNG   105.52KB   1 downloads

 

 

Rose MR, Rauser CL, Mueller LD, Benford G. A revolution for aging research. Biogerontology. 2006;7(4):269-77.

https://link.springe...0522-006-9001-6

 

[Robert Seitz]

Albedo, You're right, of course. I'm thinking about ways to extend this late-in-life plateau rather than trying to explain why it exists.

[albedo]

Marck A, Antero J, Berthelot G, et al. Are We Reaching the Limits of Homo sapiens?. Front Physiol. 2017;8:812.

https://www.frontier...2017.00812/full

 

 life span.PNG   307.2KB   1 downloads

 

"Figure 2. Maximal lifespan trends have shown a plateau for the oldest supercentenarian and the oldest Olympian. Since Jeanne Calment, who currently holds the lifespan record at 122.4 years in 1997, no one has lived more than 120 years and data suggest a plateau around 115–117 years that may indicate the potential biological upper limit of our species in terms of longevity. Oldest supercentenarian trends have shown a plateau for both women (purple) and men (blue). Similarly, maximal lifespan trends for oldest Olympians have shown a plateau for both women (red) and men (orange). Data for supercentenarians are available at the Gerontological Research Group (GRG; http://www.grg.org/). Data for Olympian athletes came from the most authoritative source of Olympian biographies (Clarke et al., 2012; Antero-Jacquemin et al., 2015)."

 

 

 

[Never_Ending]

Yes I think what Prof. Michael Rose was explaining makes a lot of sense. If it is true, which it likely it,  it does give a lot of insight into the nature of aging.

[albedo]

An impressive deviation from Gompertz's law:

 

"...But Buffenstein says the data simply do not show the typical aging pattern seen in mammals or any other animals. “If you look at any rodent aging study, 100 animals is all you need to see Gompertz aging,” she says. "Here we have 3000 data points and we're not seeing it.”...

 

"...After they reached sexual maturity at 6 months of age, each naked mole rat’s daily chance of dying was a little more than one in 10,000. It stayed the same the rest of their lives and even went down a little, Buffenstein reports this week in elife. “To me this is the most exciting data I’ve ever gotten,” says Buffenstein. “It goes against everything we know in terms of mammalian biology.”

 

http://www.sciencema...gical-law-aging

 

Ruby JG, Smith M, Buffenstein R. Naked Mole-Rat mortality rates defy gompertzian laws by not increasing with age. Elife. 2018;7

 

[albedo]

Just seen, adding to an seemingly endless debate:

 

There’s no limit to longevity, says study that revives human lifespan debate

https://www.nature.c...ontent=20180629

 

The original paper concludes:

 

"...Our findings further provide fundamental knowledge about the biodemography of human longevity. By using clean data from a single nation and straightforward estimation methods, we have shown that death rates, which increase exponentially up to about age 80, do decelerate thereafter and reach or closely approach a plateau after age 105. Thus, these well-estimated hazard curves share the qualitative pattern observed for extreme ages in widely differing species (8, 18), regularities calling for common structural and evolutionary explanations. An important structural contributor to mortality rate deceleration must be the impact of selective survival in heterogeneous populations. The fixed-frailty proportional hazard model of Vaupel et al. (19) [with precursor (20)] implies approach to plateaus (5, 8, 18), and Gamma-Gompertz distributions for deaths arise naturally in the framework (21–24). Enhanced care for the extremely old may help to mitigate increases in mortality. Evolutionary theories of senescence, including the mutation accumulation theory and age-dependent effects of genetic load (25), also offer promising ingredients toward a joint explanation of both the phases of exponential increase and extreme-age plateaus. Ongoing theoretical progress depends on empirical clarity, and we hope to promote such clarity with the data and estimates reported here."

Edited by albedo, 30 June 2018 - 02:15 PM.

[Nate-2004]

I saw this and none of it makes any sense to me. How is that information useful at all? Of course things plateau at that point, you can die at any point for any reason. What else is there?

[albedo]

Well Nate, these things matters if you are interested to theoretical and evolutionary biology and to try and distinguish the many different theories of aging out there. The paper of the Italian group tried to clarify using a better statistics. I am not an expert of these matters but find the all debate interesting. There are many places where this is discussed on LC, even a bit in relation to a very exciting topics of epigenetic aging, kind of programmed theory of aging, vs. damage-induced theory, due to therapeutic potentials and we all have our skin in (see here). Also, if the claimed plateaus is not real, many demographic models need to be changed, so it is important.

 

Also:

Burger O, Missov TI. Evolutionary theory of ageing and the problem of correlated Gompertz parameters. J Theor Biol. 2016;408:34-41.

https://www.ncbi.nlm...pubmed/27503574

 

[albedo]

Here is a recent publication explaining the subject effect as based purely on errors and statistics without calling on biology or evolutionary models:

 

"...Here, I demonstrate that apparent late-life mortality decelerations and plateaus can be generated by low-frequency errors. I then reveal how indicators of demographic data quality predict the magnitude of late-life mortality deceleration and the existence of late-life plateaus in human populations. These findings suggest that human late-life mortality plateaus are largely, if not entirely, artefacts of error processes..."

 

"...This finding has immediate consequences for demographic modelling, evolutionary biology, and the projected upper limits of human and nonhuman life..."

 

Newman SJ. Errors as a primary cause of late-life mortality deceleration and plateaus. PLoS Biol. 2018;16(12):e2006776.

[albedo]

Another blow to the reality of the "effect" from well renowned researchers?

 

"Knowledge of true mortality trajectory at extreme old ages is important for biologists who test their theories of aging with demographic data. Studies using both simulation and direct age validation found that longevity records for ages 105 years and older are often incorrect and may lead to spurious mortality deceleration and mortality plateau. After age 105 years, longevity claims should be considered as extraordinary claims that require extraordinary evidence. Traditional methods of data cleaning and data quality control are just not sufficient. New, more strict methodologies of data quality control need to be developed and tested. Before this happens, all mortality estimates for ages above 105 years should be treated as unreliable." (bold mine)

 

Gavrilov LA, Gavrilova NS. Late-life mortality is underestimated because of data errors. PLoS Biol. 2019;17(2):e3000148.

[albedo]

Reading back a bit more on this. I wonder if you have a clue how to reconcile these two statements (italic mine) of the longevity implication of a plateau in mortality which to me seems opposing each other. The 1st statement implies that a (supposedly real) plateau implies a limit, while the 2nd implies a no-limit. I must be missing something !

 

"...data suggest a plateau around 115–117 years that may indicate the potential biological upper limit of our species in terms of longevity..."

https://www.frontier...2017.00812/full

 

"...An immediate consequence from the mortality deceleration phenomenon is that there is no fixed upper limit to human longevity ...This conclusion is important, because it challenges the common belief in the existence of a fixed maximal human lifespan and biological limit to longevity. However, new results discussed in this article challenge the existence of late-life mortality plateau in humans when data are of better quality..."

https://doi.org/10.1...al.pbio.3000148

 

 

 

[QuestforLife]

I guess contradictory conclusions are what we should expect from weak statistical data - the 'law of small numbers' we get from the few people that reach extreme ages.

Jerry Shay has some interesting things to say about the healthiest centenarians and the low percentage of short telomeres they have (compared to controls).



This and other things, suggests to me that telomeres will put a cap on maximum human lifespan.

[albedo]

Thank you QuestforLife.

 

Regarding the two statements, I am concerned by (surely) me falling in a logical fallacy: I am not discussing the poor statistics, which might bring to wrong conclusions, but rather how is it possible, assuming I am not mixing with the logic, that under the assumption that the plateau is real, two nice papers states two apparently flagrantly opposing implications, so maybe I am confusing about what they are writing!

 

Btw, I listened to Jerry Shay's presentation time ago and fully agree with you. I found fascinating the preliminary results on « high performing centenarians » featuring longer telomeres when compared to older adults looking similar to “low performing centenarians”, validated also by genetic information and inflammatory biomarkers. But, as to your suggestion, I do not have a take, yet.

[QuestforLife]

I see what you mean. Even though I do think there IS an upper limit (based on telomeres), I don't see how the first paper you mention comes to that conclusion. How does a plateau in mortality imply an upper limit? Surely the opposite conclusion makes more sense.

Maybe they mean mortality stops ratching up at a certain point because everyone is expected (by whatever underlying process is killing them) to be dead.

[Fernando G]

If person practice CRON since birth could go up to 150 or more

[sensei]

At super advanced ages, there is almost nothing left to kill them except ENTROPY.

Care facilities prevent or drastically lessen deaths from falls and accidents.

On staff medical care catches infections early that might otherwise kill.

Cancer, Alzheimer's, etc. were left behind at the age of 95-100.

All that's left is to WEAR OUT.