Profiling epigenetic aging with in vitro cell models may allow for a deeper understanding of the difficult-to-decipher in vivo process, but only if one truly reflects the other; this leaves us wondering: “Is this the real-life? Is this just fantasy?”
In their epigenetic rock opera, bohemians from the lab of Morgan Levine (Yale School of Medicine, USA) report that CultureAGE – a DNA methylation-based epigenetic clock that tracks in vitro cellular aging – functions faithfully when analyzing various in vitro and in vivo models of aging. In detail, CultureAge derives from an in vitro analysis of serially passaged mouse embryonic fibroblasts (MEFs) and can accurately predict passage number from DNA methylation status.
Let’s hear how Minteer and colleagues used a DNA methylation-based epigenetic clock to tell real life from fantasy when it comes to aging:
- CultureAGE increases with age in mouse liver, lung, kidney, blood, and adipose tissues, providing robust evidence that culture models of aging capture physiologically relevant information
- CultureAGE provides similar signals to a more traditional ex-vivo trained epigenetic clock measure (BloodAGE)
- As this epigenetic clock does not correspond with cellular senescence markers directly, CultureAGE likely captures the cellular changes conferring an increased susceptibility to later senescence/tumorigenesis
- CultureAge reflects the:
- 1) Slowing of epigenetic aging in mice under caloric restriction (which enhances longevity)
- 2) Acceleration of epigenetic aging after MEF immortalization (which promotes cell replication),
- 3) Reversal of epigenetic aging during the reprogramming of lung/kidney fibroblasts into induced pluripotent stem cells (which “rejuvenates” cells on multiple levels)
- The study highlights Polycomb factors (e.g., PRC1 and PRC2) as regulators mediating in vitro epigenetic aging
- PRC1 and PRC2-mediated silencing of gene expression (associated with the H3K27me3 modification) generally correlates with DNA methylation levels
- The suggested functional relationship between Polycomb group factors (such as EED) and DNA methylation may represent an in vivo target for anti-aging therapeutics
Overall, the rhapsodical results from this head-bangingly awesome DNA methylation-based epigenetic clock study now demonstrate that in vitro epigenetic aging is real-life and not just fantasy; therefore, the easier-to-control in vitro analyses using this platform can genuinely help to uncover mechanistic insights into epigenetic aging. Furthermore, the authors have begun to translate these findings into human culture models, which will confirm the importance of specific mechanisms and facilitate in vivo aging discoveries.
“Open your eyes, look up to the skies and see” this remarkable new study in Aging Cell, February 2022.