Circulating and intrahepatic Hepassocin (HPS) levels decline with age in both mice and elderly humans, and this drop directly impairs hepatic regeneration. In aged HPS-knockout mice, the liver exhibited steatosis, accelerated cellular senescence, compromised autophagy, and sharply reduced regenerative capacity after two-thirds partial hepatectomy — including elevated mortality. Mechanistically, HPS activates AMPK in hepatocytes through a precise four-node cascade: Annexin A2 → ERK2 → p90RSK → LKB1 → AMPK, suppressing mTOR hyperactivation that drives senescence. Critically, AICAR (an AMPK agonist) rescued the aged knockout phenotype, and exogenous HPS administration improved regenerative outcomes in aged wild-type mice.
This finding is genuinely significant within liver aging biology. AMPK's role as a longevity-associated energy sensor is well established, but a hepatocyte-specific upstream activator that declines physiologically with age — and can be pharmacologically restored — is a meaningful mechanistic advance. The ANXA2-ERK-LKB1 cascade provides a druggable pathway distinct from metformin's indirect AMPK activation, potentially offering liver-targeted precision. The exogenous HPS experiment is the most translatable result: it suggests a protein therapeutic strategy rather than small-molecule intervention. Limitations are real — this is entirely preclinical, with human data limited to correlative HPS decline. The jump from mouse hepatectomy models to clinical liver disease or aging therapy is substantial. Still, as hepatokine-based aging research goes, this is more mechanistically complete than most, and warrants accelerated investigation in primate models.
