The rate and timing of onset of aging are diverse among species, but the mechanisms are remained unclear: Greenland sharks age slowly over nearly 500 years, while Ayu (Plecoglossus altivelis) age rapidly as they reproduce. While the DNA damage repair activity of SIRT6 plays a crucial role in rodent lifespan, the regulation of histone modifications and DNA methylation through Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc) improves aging-associated phenotypes in aged mice and Hutchinson-Gilford Progeria Syndrome (HGPS) mice model. These data indicate that epigenetics of aging regulate aging.

To elucidate the threshold of the onset of aging and the epigenetics-mediated regulation of the aging speed, we have developed a mouse model, “ICE” mouse (for inducible changes in the epigenome), in which DNA damage is transiently induced in a tamoxifen-dependent manner (Kato et al., 2021 Dev. Cell; Yang and Hayano et al., Cell, in press). In ICE mice, “loss of identity” is observed, in which cell-specific gene expression and histone modifications are altered with age after DNA damage induction. In addition, induction of the aging phenotype in ICE mice requires a certain period of DNA damage, and the expression of histone/DNA modifiers and senescence genes is changed when the threshold is exceeded. In this seminar, we would like to discuss the molecular mechanisms that determine the “biological clock” and its diversity among species.