Ketone Body β-Hydroxybutyrate Mimics Exercise to Shield the Aging Liver

**Why This Matters** Liver aging accelerates susceptibility to MASLD, alcoholic liver disease, and hepatocellular carcinoma. Worse, the senescent liver secretes pro-aging signals (like TGF-β) that induce systemic aging in other organs. Identifying molecules that slow this process has major implications for healthy aging strategies.

**What Was Studied** Using naturally aged male C57BL/6J mice (15 months old) and an in vitro D-galactose (Dgal)-induced cellular senescence model in AML12 hepatocytes and Raw264.7 macrophages, researchers investigated how aerobic exercise and β-HB modify the aging liver microenvironment. Four mouse groups were compared: young controls, old sedentary controls, old exercised (16 weeks, 5 days/week treadmill running at 15 m/min), and old mice receiving exogenous β-HB injections (200 mg/kg, IP, 5 days/week for 16 weeks).

**Key Mechanistic Findings** In the aging liver, mitochondrial homeostasis is disrupted, leading to cytosolic release of mitochondrial DNA (mtDNA). This acts as a damage-associated molecular pattern that activates the cGAS-STING signaling pathway specifically in liver macrophages (Kupffer cells and infiltrating macrophages), polarizing them toward the pro-inflammatory M1 phenotype. Conditioned medium experiments showed that M1 macrophages indirectly drive lipid metabolic dysregulation and PANoptosis—a newly characterized form of inflammatory programmed cell death integrating pyroptosis, apoptosis, and necroptosis—in hepatocytes. Aerobic exercise elevated circulating β-HB levels, which protected mitochondrial function in macrophages, suppressed mtDNA cytosolic release, blocked cGAS-STING activation, and facilitated macrophage polarization toward the anti-inflammatory M2 phenotype. This macrophage reprogramming subsequently reduced hepatocyte lipid deposition and PANoptosis. STING agonist (DMXAA) reversed β-HB's benefits, while STING antagonist (c-176) replicated them, confirming STING as the central target.

**Translational Validation** Exogenous β-HB administration in aged mice successfully mimicked exercise-induced ketogenesis, restoring mitochondrial homeostasis, reducing inflammatory markers, improving serum liver enzymes (ALT, AST) and lipid profiles (TG, TC, LDL-C), and decreasing PANoptosis in liver tissue. This positions β-HB as an actionable exercise mimetic—especially relevant for aging populations unable to perform regular aerobic exercise.

**Implications and Caveats** This study is the first to map a complete cascade from exercise → β-HB → macrophage mtDNA/cGAS-STING → macrophage polarization → hepatocyte lipid metabolism and cell death in liver aging. It provides mechanistic justification for β-HB supplementation as a nutritional strategy. However, findings are primarily in mice and cell lines, and translation to human clinical settings requires further validation.