Gero is one of a number of longevity industry biotech companies that put a strong focus on computational analysis of data to steer small molecule drug development and repurposing efforts. One of the interesting themes in their papers and presentations is the decomposition of signatures of aging into different distinct components, both in mice and in humans. When one can identify different overlapping trends in age-related changes in omics data, there is something to be said in that about the way in which aging progresses. The usual challenges apply, however, in that it is difficult to take this sort of analysis and link it back to fundamental mechanisms of aging. The research community as a whole struggles to identify concrete links between specific forms of molecular damage and consequential dysfunction on the one hand versus specific changes in biomarkers on the other. There is an enormous body of data, and data has become cheap to manufacture, but obtaining a deeper understanding of the meaning of that data remains a slow and expensive process.
Aging across most species, including mice and humans, is characterized by an exponential acceleration of mortality rates. In search for the molecular basis of this phenomenon, we analyzed DNA methylation (DNAm) changes in aging mice. Utilizing principal component analysis (PCA) on DNAm profiles, we identified a primary aging signature with an exponential age dependency, closely reflecting the Gompertz law's description of mortality acceleration.
This signature is the manifestation of the dynamic instability in the organism's state that drives the aging process in mice. It aligns closely with regression-based aging clocks and responds to interventions such as caloric restriction and parabiosis. Additionally, we identified a linear DNAm signature, indicative of a global demethylation level. Through single-cell DNAm (scDNAm) data from aging animals, we demonstrate that this signature captures the exponential expansion of the state space volume spanned by individual cells within an aging organism, and thus quantifying linearly increasing configuration entropy, likely an irreversible process. Consistent with this interpretation, we found that neither caloric restriction (CR) nor parabiosis significantly impacts the entropic feature, reinforcing its link to irreversible damage.
Link: https://doi.org/10.1...24.02.25.581928
View the full article at FightAging
