Lifespan Uber Correlation

This 2022 study developed new epigenetic clocks:

“Maximum lifespan is deemed to be a stable trait in species. The rate of biological function decline (i.e., aging) would be expected to correlate inversely with maximum species lifespan. Although aging and maximum lifespan are intimately intertwined, they nevertheless appear in some investigations to be distinct processes.

Some cytosines conserved across mammals exhibit age-related methylation changes so consistent that they were used to successfully develop cross-species age predictors. In a similar vein, methylation levels of some conserved cytosines correlate highly with species lifespan, leading to the development of highly accurate lifespan predictors. Surprisingly, little to no commonality is found between these two sets of cytosines.

We correlated the intra-species age correlation with maximum lifespan across mammalian species. We refer to this correlation of correlations as Lifespan Uber Correlation (LUC).

We overlapped genes from the LUC signature with genes found in human genome-wide association studies (GWAS) of various pathologies and conditions. With all due caution, we report that some genes from the LUC signature were those highlighted by GWAS to be associated with type II diabetes, stroke, chronic kidney disease, and breast cancer.

Human aging genes vs mammalian LUC

We used the subset of CpGs found to be significant in our LUC to build age estimators (epigenetic clocks). We demonstrated that these clocks are able to capture effects of interventions that are known to alter age as well as lifespan, such as caloric restriction, growth hormone receptor knockout, and high-fat diet.

We found that Bcl11b heterozygous knockout mice exhibited an increased epigenetic age in the striatum. BCL11B is a zinc finger protein with a wide range of functions, including development of the brain, immune system, and cardiac system.

This gene is also implicated in several human diseases including, but not limited to, Huntington disease, Alzheimer’s diseases, HIV, and T-cell malignancies. BCL11B plays an important role in adult neurogenesis, but is less studied in the context of lifespan disparities in mammals.

Bcl11b knockout affected both DNA methylation and mRNA expression of LUC genes. Our current study does not inform us about the potential role of Bcl11b in aging processes during adulthood since observed patterns could be attributed to developmental defects.

We are characterizing other genetic and non-genetic interventions that perturb the LUC clocks. These we will feature in a separate report that will uncover biological processes regulated by LUC cytosines and their associated genes.” “Divergent age-related methylation patterns in long and short-lived mammals”


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