The presence of senescent cells is commonly viewed as a hallmark of aging, as is an increase in cellular DNA methylation age (DNAmAGE). In a recent study, researchers looked at an experimental drug that removes senescent cells (senolytics) and observed the epigenetic and transcriptomic responses in mice.
A team of academic researchers (at the University of Arkansas and others) in collaboration with industrial partners, the Clock Foundation and VUGENE team, examined the effects of this senolytic drug (BI01) on mouse muscle injury (by injection of BaCl2) and regeneration. Previously, this compound was shown to specifically target p53-MDM2 and reduce the abundance of senescent mononuclear cells and improve muscle regeneration (Nolt et al., 2024). Importantly, as biological age is usually a confounding variable, the researchers analyzed the multi-omic effects in both young and old mice.
In this study, following injury, the muscle regeneration significantly decelerated the DNAmAGE clock of aged mice (by 41%-68%, depending on different clocks) relative to baseline measurements. Senolytic treatment on its own didn’t have an effect and even in combination with regeneration, it had a very mild effect, not significant for two clocks, and just only slight significance in one (p-value 0.4). This can be extrapolated to muscle-level regeneration is more important than this particular senolytic agent in slowing down the methylation clock and decreasing the age of the mice.
When looking deeper, while the senolytic treatment on its own did not affect the muscle clock, it had small positive effects on post-injury regeneration due to methylation changes in collagen production-associated regulatory genes. Even 35 days post-regeneration, the DNA methylome in the mouse muscle was widely affected (~26% of all CpGs), mostly impacting collagen production and tissue development.
The observed effects were only significant in aged but not young mice, indicating that biological age matters for response and regeneration. Meanwhile, numerous changes in metabolism, muscle cell proliferation, and mitochondrial genes were observed solely in young mice, possibly explaining impaired skeletal muscle regeneration in older mice.
Finally, combining the transcriptome and epigenome – multi-omic integration uncovered changes in extracellular matrix, MAPK signaling and muscle development regulatory pathways during the regeneration process. While intuitively we might think that hypomethylated genes are less expressed – this is not strictly the case and there are many studies showcasing this, frequently referring to it as paradoxical gene activation (reviewed by Smith et al., 2020). Thus it is important to understand each level separately and in combination to have a fully completed biological puzzle.
Why Does This Matter?
It is extremely important to take the next step and go deeper when aiming to understand novel drugs, especially those intended for improving general health rather than treating the disease. This study showed the importance of biological age for drug effect and how muscle regeneration after injury decelerated the methylation clock only in older mice. Meanwhile, different transcriptomic changes were still observed in both old and young mice. Thus while aiming to change DNA methylation status, we inevitably need to check for changes at other molecular levels, such as transcription and beyond: to proteomics or metabolomics.
Chambers TL, Wells J, Koopmans PJ, Morena F, Malik ZB, Greene NP, Filareto A, Franti M, Sini P, Weinstabl H, Brooke RT, Milčiūtė M, Gordevičius J, Horvath S, Wen Y, Dungan CM, Murach KA. At the Nexus Between Epigenetics and Senescence: The Effects of Senolytic (BI01) Administration on DNA Methylation Clock Age and the Methylome in Aged and Regenerated Skeletal Muscle. Aging Cell, 2025 Jul, 24(7).
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Written by: Ingrida Olendraitė, Austėja Jankevičiūtė
Cover image credits: neurobite / Adobe Stock