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Metabolomic Signatures of Extreme Old Age


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Posted Today, 10:23 AM


It remains an open question as to whether studying the biochemistry of extremely old people can provide a basis for interventions that will help everyone live meaningfully longer. If genetics has little influence on longevity for the vast majority of people, as seems to be the case, then differences observed in extremely old people emerge from (a) lifestyle choices that we can control and (b) exposures that we presently have less control over, such as infectious disease burden and composition of the gut microbiome. However, any of the biochemical differences observed in extremely old individuals could be the outcome of mechanisms that provide only small improvements in the odds of survival. Is it worth pursuing a mechanism that results in, say, a 2% chance of reaching age 100 in the environment of the past 100 years of medical technology, versus an average 1% chance? That doesn't seem all that great. Better approaches are needed.

The New England Centenarian Study (NECS) provides a unique resource for the study of extreme human longevity (EL). To gain insight into biological pathways related to EL, chronological age and survival, we used an untargeted serum metabolomic approach (more than 1,400 metabolites) in 213 NECS participants, followed by integration of our findings with metabolomic data from four additional studies.

Compared to their offspring and matched controls, EL individuals exhibited a distinct metabolic profile characterized by higher levels of primary and secondary bile acids - most notably chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) - higher levels of biliverdin and bilirubin, and stable levels of selected steroids. Notably, elevated levels of both bile acids and steroids were associated with lower mortality. Several metabolites associated with age and survival were inversely associated with metabolite ratios related to NAD+ production and/or levels (tryptophan/kynurenine, cortisone/cortisol), gut bacterial metabolism (ergothioneine/trimethylamine N-oxide, aspartate/quinolinate), and oxidative stress (methionine/methionine sulfoxide), implicating these pathways in aging and/or longevity.

We further developed a metabolomic clock predictive of biological age, with age deviations significantly associated with mortality risk. Key metabolites predictive of biological aging, such as taurine and citrate, were not captured by traditional age analyses, pointing to their potential role as biomarkers for healthy aging. These results highlight metabolic pathways that may be targeted to promote metabolic resilience and healthy aging.

Link: https://doi.org/10.1101/2025.09.10.675341


View the full article at FightAging




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