It is one thing to point to a mechanism, show it declines with age, and suggest it might contribute to aging. It is quite another to develop an understanding of where this mechanism stands in terms of its relative importance in degenerative aging, and how it relates to other mechanisms. Here, researchers consider a form of histone modification, one type of epigenetic alteration that changes the structure of packaged DNA in the cell nucleus, and thus changes which genes can be accessed in order to manufacture proteins. This in turn changes cell behavior. But what causes the histone modification in the first place? Cells contain feedback loops piled upon feedback loops, creating dynamic links between environment, control of protein manufacture, activity of the manufactured proteins, and so forth. It is very challenging to identify specific chains of cause and consequence and then weigh their significance against all other relevant chains of cause and consequence, not all of which are well mapped.
Epigenetic alterations are among the prominent drivers of cellular senescence and/or aging, intricately orchestrating gene expression programs during these processes. This study shows that histone lactylation, plays a pivotal role in counteracting senescence and mitigating dysfunctions of skeletal muscle in aged mice. Mechanistically, histone lactylation and lactyl-CoA levels markedly decrease during cellular senescence but are restored under hypoxic conditions primarily due to elevated glycolytic activity. The enrichment of histone lactylation at promoters is essential for sustaining the expression of genes involved in the cell cycle and DNA repair pathways. Furthermore, the modulation of enzymes crucial for histone lactylation, leads to reduced histone lactylation and accelerated cellular senescence.
Consistently, the suppression of glycolysis and the depletion of histone lactylation are also observed during skeletal muscle aging. Modulating the enzymes can also lead to the loss of histone lactylation in skeletal muscle, downregulating DNA repair and proteostasis pathways, and accelerating muscle aging. Running exercise increases histone lactylation, which in turn upregulate key genes in the DNA repair and proteostasis pathways. This study highlights the significant roles of histone lactylation in modulating cellular senescence as well as muscle aging, providing a promising avenue for antiaging intervention via metabolic manipulation.
Link: https://doi.org/10.1002/advs.202412747
View the full article at FightAging
