hepassocin-liver-senescence-regeneration
Loss of the liver protein hepassocin accelerates hepatic aging in old mice and sharply raises mortality after partial organ removal. Administering the protein itself or a drug that directly activates the enzyme AMPK reversed the effect.
In mice, hepassocin levels in the liver and blood decline with age, mirroring the pattern seen in elderly humans. After removal of two-thirds of the liver, mice lacking this gene died at higher rates than either normal old or young animals, and their livers regenerated poorly. The authors traced hepassocin's signaling path to a receptor on the hepatocyte surface and to the enzymes that activate AMPK: administering the protein itself or a compound that activates AMPK directly restored the aging liver's capacity to regenerate.
With age, the liver tolerates surgery less well: after partial resection, mortality in patients over 70 years is higher than in younger patients because the organ cannot regrow the missing mass quickly enough. 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 in which the authors identified 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: concentrations are lower in people over 70 years old and in the livers of people over 50 compared with younger individuals.
Even before surgery, old mice lacking the hepassocin gene already showed more markers of cellular senescence, worse lipid metabolism, and impaired autophagy (the system that recycles damaged cellular components). After removal of two-thirds of the liver, the difference became a matter of survival: by day seven, 87% of normal old mice survived compared with only 40% of hepassocin-deficient mice, and their livers regained only half of the lost mass versus 64% in normal old mice. In young animals, loss of the protein had almost no effect because other cellular pathways maintained AMPK activity, and this reserve is depleted only with age.
Hepassocin binds to the receptor ANXA2 on the hepatocyte membrane and triggers the cascade ERK → p90RSK → LKB1, which activates AMPK, the cell's master energy sensor. Without hepassocin, AMPK activity is diminished and its antagonist mTOR is hyperactive, which blocks both autophagy and cell division.
Injections of AICAR, a compound that activates AMPK directly, bypassing hepassocin, restored both regeneration and postoperative survival in hepassocin-deficient mice. Blocking autophagy only partially abolished this benefit: part of the protection operated through another pathway. A weeklong course of recombinant hepassocin injections before surgery also helped. With increasing doses, normal old mice showed faster liver recovery, and hepassocin-deficient 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 known in oncology as a ligand for LAG-3, an immune checkpoint targeted in cancer immunotherapy to enable immune attack on tumors.
The study shows that hepatic aging can be addressed from two independent directions: direct AMPK activation or hepassocin replenishment. 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 AMPK activators carry a history of side effects. A similar compound from Merck caused dangerous cardiac hypertrophy.