Histone lactylation antagonizes senescence and skeletal muscle aging via facilitating gene expression reprogramming

Abstract One of the prominent drivers of cellular senescence and/or aging is epigenetic alteration, through which orchestrated regulation of gene expression is achieved during the processes. Accumulating endeavors have been devoted to identifying histone modifications-related mechanisms underlying senescence and aging. Here, we show that histone lactylation, a recently identified histone modification bridging metabolism, epigenetic regulation of gene expression and cellular activities in response to internal and external cues, plays a crucial role in counteracting senescence as well as mitigating dysfunctions of skeletal muscle in aged mice. Mechanistically, the abundance of histone lactylation is markedly decreased during senescence and aging but restored following manipulation of the metabolic environment. Genome-wide distribution profiling and gene expression network analysis uncover that the maintenance of histone lactylation level is critical for suppressing senescence and aging programs via targeting of proliferation- and homeostasis-related pathways. We also confirmed that the level of histone lactylation is not only controlled by glycolysis but also regulated by NAD + content in vivo . More intriguingly, running exercise enhances the level of histone lactylation and reconstructs the cell landscape and communications of mouse skeletal muscle, leading to rejuvenation and functional improvement. Our study highlights the role of histone lactylation in regulating senescence as well as aging-related tissue function, implying that this modification could be used as a novel marker of senescence, and provides a potential target for aging intervention via metabolic manipulation.