Sarcopenia, a leading cause for global disability and mortality, is an age-related muscular disorder, characterized by accelerated muscle mass loss and functional decline. It is known that caloric restriction (CR), ketogenic diet or endurance exercise lessen sarcopenia and elevate circulating beta-hydroxybutyrate (beta-HB) levels. Whether the elevated beta-HB is essential to the reversal of sarcopenia, however, remains unclear. Here we show in both Caenorhabditis elegans and mouse models that an increase of beta-HB reverse myofiber atrophy and improves motor functions at advanced ages. beta-HB-induced histone lysine beta-hydroxybutyrylation (Kbhb) is indispensable for the reversal of sarcopenia. Histone Kbhb enhances transcription of genes associated with mitochondrial pathways, including oxidative phosphorylation, ATP metabolic process and aerobic respiration. This ultimately leads to improve mitochondrial integrity and enhance mitochondrial respiration. The histone Kbhb are validated in mouse model with CR. Thus, we demonstrate that beta-HB induces histone Kbhb, increases mitochondrial function, and reverses sarcopenia.

Sarcopenia is an age-related muscle disorder characterized by accelerated loss of muscle mass and functional decline, leading to increased disability and mortality globally. This study demonstrates that beta-hydroxybutyrate (beta-HB) effectively reverses myofiber atrophy and improves motor function in Caenorhabditis elegans and mouse models at advanced ages. beta-HB induces histone lysine beta-hydroxybutyrylation (Kbhb), which is crucial for reversing sarcopenia by enhancing mitochondrial pathways, including oxidative phosphorylation, ATP metabolism, and aerobic respiration.image