Dissecting the impact of differentiation stage, replicative history, and cell type composition on epigenetic clocks

Rebecca Gorelov; Aaron Weiner; Aaron Huebner; Masaki Yagi; Amin Haghani; Robert Brooke; Steve Horvath; Konrad Hochedlinger

doi:10.1016/j.stemcr.2024.07.009

Dissecting the impact of differentiation stage, replicative history, and cell type composition on epigenetic clocks

Stem Cell Reports. 2024 Sep 10;19(9):1242-1254. doi: 10.1016/j.stemcr.2024.07.009. Epub 2024 Aug 22.

Authors

Rebecca Gorelov¹, Aaron Weiner¹, Aaron Huebner¹, Masaki Yagi¹, Amin Haghani², Robert Brooke³, Steve Horvath⁴, Konrad Hochedlinger⁵

Affiliations

¹ Massachusetts General Hospital Department of Molecular Biology, Boston, MA 02114, USA; Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02139, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
² Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Altos Labs, San Diego, CA 92121, USA.
³ Epigenetic Clock Development Foundation, Torrance, CA 90502, USA.
⁴ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Altos Labs, San Diego, CA 92121, USA; Epigenetic Clock Development Foundation, Torrance, CA 90502, USA; Department of Biostatistics, School of Public Health, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Massachusetts General Hospital Department of Molecular Biology, Boston, MA 02114, USA; Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02139, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: khochedlinger@helix.mgh.harvard.edu.

Abstract

Epigenetic clocks, built on DNA methylation patterns of bulk tissues, are powerful age predictors, but their biological basis remains incompletely understood. Here, we conducted a comparative analysis of epigenetic age in murine muscle, epithelial, and blood cell types across lifespan. Strikingly, our results show that cellular subpopulations within these tissues, including adult stem and progenitor cells as well as their differentiated progeny, exhibit different epigenetic ages. Accordingly, we experimentally demonstrate that clocks can be skewed by age-associated changes in tissue composition. Mechanistically, we provide evidence that the observed variation in epigenetic age among adult stem cells correlates with their proliferative state, and, fittingly, forced proliferation of stem cells leads to increases in epigenetic age. Collectively, our analyses elucidate the impact of cell type composition, differentiation state, and replicative potential on epigenetic age, which has implications for the interpretation of existing clocks and should inform the development of more sensitive clocks.

Keywords: DNA methylation; adult Stem; aging; cell Proliferation; differentiation; epigenetic clocks.

MeSH terms

Adult Stem Cells / cytology
Adult Stem Cells / metabolism
Aging / genetics
Animals
Biological Clocks / genetics
Cell Differentiation* / genetics
Cell Proliferation
DNA Methylation*
Epigenesis, Genetic*
Mice
Mice, Inbred C57BL