This talk was presented Dec 4th, 2023, at Longevity SF's 3rd annual Longevity Summit. longevitygl.or...
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@MrStarchild30016 ай бұрын
The talk focuses on maximum lifespan, which is defined as the maximum age at death observed across billions of individuals of a species. This differs from concepts like life expectancy or biological age, which relate more to an individual's remaining lifespan. Some key insights: - Biological processes relating to an individual's time to death often differ from those related to a species' maximum lifespan. For example, smoking shortens individual lifespan but does not affect the maximum lifespan of humans as a species. Eating well may increase an individual's lifespan, but not impact the species maximum. - Short-lived species like mice may not be the most effective models for studying longevity interventions aimed at extending maximum lifespan in humans. Long-lived species like bats and whales may hold more clues. However, it has proven fairly easy to extend lifespan in mice through interventions like calorie restriction or growth hormone manipulation. The key question is whether these mouse interventions can translate to increasing maximum lifespan in humans. - An epigenetic biomarker based on DNA methylation patterns was developed that can accurately predict the maximum lifespan of a species just using a tissue sample, without knowing what species it came from. However, this biomarker shows little association with chronological age or individual mortality risk factors like smoking, obesity, etc. It relates more to developmental genes involved in embryonic development and organ morphogenesis. Still, it may serve as a future benchmark for testing longevity interventions in animal models. - Analyses of methylation change over time found rates of change relate inversely to maximum lifespan, but only in specific regulatory regions of DNA. These dynamic methylation changes relate to cell differentiation and development. Extending maximum lifespan may require interfering with developmental processes and conception itself. - Comparing long-lived to short-lived species, long-lived species tend to have more extreme methylation landscapes with steeper hills and deeper valleys, while short-lived species like mice have flatter, more uniform methylation levels across the genome. - Methylation patterns relating to chronological age differ from those relating to maximum lifespan, with minimal overlap between the two. Age-related methylation relates to genes regulated by the Polycomb Repressive Complex 2, which regulates cell differentiation. - Upstream factors linked to maximum lifespan include some of the Yamanaka factors used to induce pluripotency and cellular reprogramming. This aligns with the involvement of developmental genes in controlling maximum lifespan. In conclusion, maximum lifespan is controlled by evolutionary processes related to developmental genes, cell differentiation pathways and embryonic development. These differ substantially from the biological factors contributing to individual aging and mortality risk. Interventions aimed at maximum lifespan extension may need to act very early in the developmental process or even at the point of conception to change the characteristics of the species. Most longevity research currently focuses more on individual healthspan and lifespan extension, through mechanisms like inflammatory processes, metabolic regulation, senescent cell clearance, etc. But further study of maximum lifespan and its genomic underpinnings could lead to important discoveries that help prioritize what research avenues are most promising for significantly moving maximum human lifespan beyond the current limits. Integrating insights from comparative biology across species with emerging knowledge of the human epigenome will be an important frontier in this endeavor.
@ChessMasterNate22 күн бұрын
I think there are multiple issues with human maximum lifespan. The sample size is much larger. We are tracking down the one in 2-3 billion level. We don't have 2-3 billion elephants or bowheads, and it can't be easily be determined how old they are at death. Their births are not recorded. So we are collecting the extreme outliers in humans, but we are very unlikely to be doing the same for the other mammals. Lab mice, maybe. A third issue is that 122 years. It was likely a case of fraud with a reverse mortgage (daughter pretending to be her mother). And, I suspect it is more useful to go to the level where there are multiple representatives. The real observed limit is likely 119.3 years for women and 115.5 for men. If there were trillions of people, there would probably be more extreme outliers, but that does not really inform us more about the species. Modified to have most of the best longevity alleles present in the human genetic pool, a human could live perhaps much longer than is observed. Fruit fly experiments have shown this, where they were selected for longevity. We know of 130 genes that are significantly more common in centenarians. There could be a lot more, though, because mostly those reaching 100 in the US are from a limited number of locations. East, and South Africa are not well represented, nor aboriginal Australians, New Guineans, Russian Step, and people from many other places. And even though we have a sizable population from India, most of those immigrants are more recently arrived and less likely to be approaching 100 years. That is true of the Middle East to some extent as well. Interesting that there are armadillos on both sides of methylation prediction. How do these predictions compare with similar body temp and SOD activity graphs? Better than just SOD might be all the typical endogenous antioxidants: some being albumen (cysteine-34), bilirubin, glutathione, catalase, uric acid, melatonin, coenzyme Q10, alpha-lipoic acid, vitamin C (most mammals make vitamin C), and peroxiredoxins.