Abstract
Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression.
Competing Interest Statement
SH is a founder of the non-profit Epigenetic Clock Development Foundation which plans to license several patents from his employer UC Regents. These patents list SH as inventor. The other authors declare no conflicts of interest.
Footnotes
↵† These authors jointly supervised this work: G.S. Wilkinson, S. Horvath
This version now contains a separate Abstract, Introduction, Results and Discussion sections. Additional data were added for one species, an error in the genome annotation pipeline was corrected, and all results were recomputed, which resulted in small changes to all figures. Author order was changed to reflect relative contributions. Additional information on data and code availability are provided.