Loss of the liver protein hepassocin accelerates hepatic aging in old mice and sharply raises post-hepatectomy mortality: both the protein itself and a direct AMPK activator reversed the effect

Loss of the liver protein hepassocin accelerates hepatic aging in old mice and sharply raises post-hepatectomy mortality: both the protein itself and a direct AMPK activator reversed the effect

In mice, hepassocin levels in the liver and blood decline with age, mirroring the pattern seen in older humans. Mice lacking the hepassocin gene died at higher rates after two-thirds hepatectomy than normal old or young animals, and their livers regenerated less effectively. The authors traced hepassocin's signaling to a receptor on the hepatocyte surface and a kinase cascade that activates AMPK: administering the protein itself, or a drug that activates AMPK directly, restored the aged liver's ability to regenerate.

The liver tolerates surgery less well with age: after partial resection, mortality in patients over 70 is higher than in younger patients because the organ fails to regrow the lost mass in time. Cellular senescence underlies this decline. Hepatocytes stop dividing and secrete inflammatory signals that accelerate senescence in neighboring cells. On September 15, a paper was published identifying a molecular regulator of this process, the liver protein hepassocin, also known as FGL1.

The protein has been known since 2000 as a marker of liver regeneration and has been linked to hepatic lipid metabolism and the AMPK/mTOR pathway. Its levels in blood and liver tissue decline with age in both mice and humans: circulating hepassocin is lower in people over 70, and hepatic levels are lower in people over 50, compared with younger individuals.

Old mice lacking the hepassocin gene showed more markers of cellular senescence, worse lipid metabolism, and impaired autophagy (the system that recycles damaged cellular components) even before surgery. After two-thirds hepatectomy the difference became a matter of survival: by day seven, 87% of normal old mice were alive compared with only 40% of hepassocin-knockout mice, and the knockout livers regained only half of the lost mass versus 64% in normal old mice. In young animals the loss of hepassocin had little effect because other pathways that sustain AMPK activity compensated for it; only with age does this reserve become exhausted.

Hepassocin binds the receptor ANXA2 on the hepatocyte membrane and triggers the cascade ERK → p90RSK → LKB1, which activates AMPK, the cell's central energy sensor. Without hepassocin, AMPK is weakened and its antagonist mTOR becomes hyperactive, blocking both autophagy and cell division.

Injections of AICAR, a compound that activates AMPK directly and bypasses hepassocin, restored both regeneration and post-surgical survival in hepassocin-knockout mice, although blocking autophagy only partially abolished the benefit, indicating that part of the protection operated through a separate route. A week-long course of recombinant hepassocin injections before surgery also helped: with increasing doses, normal old mice showed faster liver recovery, and hepassocin-knockout mice showed improved survival. The protein was rapidly absorbed and nontoxic even at 20 times the effective dose.

Hepassocin has an unexpected second life: since 2019, FGL1 has been recognized in oncology as a ligand of LAG-3, an immune checkpoint receptor targeted in cancer immunotherapy to restore the immune attack on tumors.

The study shows that hepatic aging can be countered from two independent directions: direct AMPK activation or hepassocin supplementation. The same age-related decline in hepassocin has already been confirmed in humans, though the treatments have so far been tested only in mice. Pharmacological AMPK activation has already reached human trials: the compound ATX-304 from Cambrian Bio reduced liver fat over eight weeks, but direct AMPK activators carry a history of side effects. A similar Merck compound caused dangerous cardiac hypertrophy.