Certain concepts – the speed of light, the electron’s charge, or the need to change cell media at the weekend – represent common constants in life. Many add the constant decay associated with the aging process to this list; however, analysis of DNA methylation in the mouse intestine now reveals that the aging process may not be as “linear” as once thought and that we may age in stages!
Regularly remarkable researchers led by Christoph Kaleta, Christiane Frahm, and Steve Hoffmann (Leibniz Institute on Aging) appreciated studies at proteomic, transcriptomic, and tissue levels reporting “non-linear” functions that argued against aging as a constant process of decay. Their new epigenetic study assessed for non-linear aging-associated DNA methylation alterations in mouse colon cells at distinct time points given that DNA methylation-based epigenetic clock construction employs linear regression models that detect continuous changes, intestinal functions undergo age-related alterations that impact other organs, studies have suggested intestinal barrier disruption as a critical evolutionary conserved aging event, and we understand little of the dynamics of this epigenomic biomarker over a lifespan.
Let’s hear from Olecka, van Bömmel, and colleagues on how DNA methylation analysis suggests that we age in stages:
- DNA methylation profiling via reduced representation bisulfite sequencing to characterize trajectories in aging male mouse colon tissues identifies sudden DNA hypermethylation events at sets of CpGs at specific stages of life
- Epigenomic switches during the early-to-midlife transition (affecting the gut barrier via immune regulation) and the mid-to-late-life (affecting intestinal stem/progenitor cells) transition separate life into three stagesAnalysis of rat peripheral blood DNA had previously identified DNA methylation switches at similar time points
- These data agree with a digital aging hypothesis describing aging as discrete steps resulting from biological mechanisms that vary in activity during a lifespan
- Non-linear DNA methylation dynamics affect CpGs at genes associated with developmental processes and the nervous system, with both possessing bivalent chromatin domains at regulatory regions
- Groups of non-linearly methylated CpGs that accurately predict murine epigenetic stage support the construction of a robust clock-like classifier of mouse epigenetic stage of life called STageR (STage of aging estimatoR)
- Analysis of an independent mouse cohort/publicly available datasets demonstrates the universality of STageR
- A classifier that divides aging into stages may be more practical than those that predict chronological age
- Current epigenetic clocks convey little information on underlying molecular processes; however, the set of CpGs employed in STageR displays enrichment for specific features (such as those mentioned above)
Identifying non-linear epigenetic transitions that split aging into specific stages suggests against the assumed linear nature of this all-important process; furthermore, these findings also suggest that we have barely begun to understand the regulation/consequences of these changes – what other non-linear epigenetic mechanisms in aging await discovery?
For more on how non-linear DNA methylation suggests we age in stages, see Nature Communications, April 2024.