Liver aging and associated diseases

Liver aging is a key risk factor for chronic liver disease, closely linked to metabolic disorders and environmental exposures. As the central metabolic organ, the liver is highly susceptible to stressors such as lipotoxicity, alcohol, viral infections, and drug-induced toxicity, all of which promote cellular senescence. Macroscopically, aging livers show volume loss; microscopically, they exhibit hepatocyte hypertrophy, mitochondrial depletion, and accumulating DNA damage. These changes lead to reduced blood flow and bile production, impaired metabolic enzymes, heightened inflammation, increased fibrosis, poor regeneration, and greater susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD), fibrosis, and hepatocellular carcinoma (HCC). Thus, understanding the molecular mechanisms of liver aging is crucial for uncovering systemic aging processes and developing interventions to prevent chronic liver diseases. Liver aging involves distinct structural and functional changes. Key features include parenchymal atrophy, reduced hepatic perfusion, lipofuscin deposition, and extracellular matrix remodeling. Functionally, aging impairs metabolism, synthesis, detoxification, and regeneration, reflected in lower cytochrome P450 enzyme activity, disrupted glucose and lipid homeostasis, mildly reduced albumin levels, and a markedly regenerative response after injury. The core molecular mechanisms of liver aging involve a tightly interconnected network of signaling pathways across major hepatic cell types. With age, senescent hepatocytes accumulate, showing increased SA-β-gal activity, elevated p16INK4a, p21, p53, and γ-H2AX expression, and a strong senescence-associated secretory phenotype (SASP). In aged livers, hepatic stellate cells (HSCs) undergo telomere shortening and spontaneous activation, marked by higherα-smooth muscle actin (α-SMA) levels and a profibrogenic phenotype. The aging liver’s immune environment shifts toward chronic low-grade inflammation, characterized by more pro-inflammatory M1-like macrophages, activated T-cell subsets, including exhausted PD-1+CD8+T cells and Kupffer cells with reduced phagocytosis but increased cytokine production, along with declining numbers and function of natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s). Liver aging and chronic liver diseases form a self-reinforcing cycle. Aging drives MASLD progression through disrupted lipid metabolism, increased mitochondrial ROS, and persistent inflammation. Conversely, MASLD accelerates hepatic senescence. In viral hepatitis, virus-induced stress promotes senescence, amplifying inflammatory and fibrotic responses. Aged HSCs sustain fibrosis via paracrine SASP signaling. Regarding HCC, senescence has a dual role: it initially suppresses tumors by halting damaged cells’ proliferation, but long-term accumulation of senescent cells creates an immunosuppressive, pro-tumorigenic environment that promotes cancer development, especially as immune surveillance declines with age. Among healthy elderly individuals, the routine of liver function tests is typically normal, making it difficult to assess true liver aging. To address this, the Aging Biomarker Consortium of China has issued the first consensus on liver aging biomarkers, identifying 16 key indicators across functional, imaging, and humoral domains. These focus on cholesterol metabolism, coagulation factors, hepatic steatosis, blood flow dynamics, and hepatokines, providing a comprehensive framework for assessing liver age and guiding early interventions. Therapeutic strategies targeting liver senescence are increasingly diverse and mechanism-based. Foundational approaches include lifestyle changes-caloric restriction and regular aerobic exercise, shown to slow liver aging. Pharmacologically, senolytic (e.g., dasatinib plus quercetin) eliminates senescent cells, while senomorphics (e.g., rapamycin, NF-κB inhibitors, JAK inhibitors) block harmful SASP effects. Emerging therapies include immunotherapies to boost clearance of senescent cells, gene therapies targeting aging pathways, stem cell-based regeneration using partial reprogramming or engineered mesenchymal stromal cells with anti-senescence properties, and epigenetic modulation via sirtuin activation. In conclusion, liver aging is a multifactorial, dynamic process driven by complex molecular interactions among hepatic cells and deeply linked to the development of chronic liver diseases.