Aging profoundly impacts liver physiology by disrupting autophagy, a lysosome-dependent degradation pathway essential for maintaining cellular homeostasis. Autophagy declines with aging due to reduced expression of core autophagy-related (ATG) genes/proteins, defective autophagosome fusion, and impaired selective processes such as lipophagy, mitophagy, and chaperone-mediated autophagy. These alterations contribute to lipid accumulation, oxidative stress, inflammation, and mitochondrial dysfunction, thereby accelerating age-related liver diseases including metabolic-associated fatty liver disease (MAFLD), fibrosis, and hepatocellular carcinoma (HCC). Their molecular mechanisms involve deregulation of nutrient-sensing pathways (mTOR complex 1, AMP-activated protein kinase and sirtuin 1 and 3) and context-dependent roles of autophagy-related proteins (ATG5, ATG7, LC3, Beclin-1, LAMP2A). Importantly, the regulatory role of autophagy differs across disease stages related to liver aging. During early phases, it maintains metabolic balance, mitochondrial quality control, and genomic stability in some diseases such as MAFLD and liver fibrosis. Conversely, in advanced disease, particularly in HCC, persistent autophagy supports tumor cell survival, stemness, and immune evasion. Emerging therapies seek to restore autophagic flux through caloric restriction, physical exercise, caloric restriction mimetics (rapalogs, spermidine, metformin), and pharmacological modulators such as Tat-BECLIN-1 peptides or RUBICON-targeted approaches. However, translating these therapies into clinical practice remains challenging due to systemic effects, stage-specific responses, and lack of reliable non-invasive biomarkers for monitoring autophagy in humans. Advances in nanoparticle-based delivery, biomarker-guided stratification, and combination therapies with tyrosine kinase inhibitors or immune checkpoint inhibitors may offer promising strategies. Overall, precision modulation of autophagy could serve as a potent geroprotective approach to preserve liver function, delay age-related metabolic deterioration, and prevent progression to fibrosis and cancer. Achieving this goal requires considering disease stage, systemic interactions, and autophagy’s context-dependent duality in aging when implementing these strategies.

Aging profoundly impacts liver physiology by disrupting autophagy, a lysosome-dependent degradation pathway essential for maintaining cellular homeostasis. Autophagy declines with aging due to reduced expression of core autophagy-related (ATG) genes/proteins, defective autophagosome fusion, and impaired selective processes such as lipophagy, mitophagy, and chaperone-mediated autophagy. These alterations contribute to lipid accumulation, oxidative stress, inflammation, and mitochondrial dysfunction, thereby accelerating age-related liver diseases including metabolic-associated fatty liver disease (MAFLD), fibrosis, and hepatocellular carcinoma (HCC). Their molecular mechanisms involve deregulation of nutrient-sensing pathways (mTOR complex 1, AMP-activated protein kinase and sirtuin 1 and 3) and context-dependent roles of autophagy-related proteins (ATG5, ATG7, LC3, Beclin-1, LAMP2A). Importantly, the regulatory role of autophagy differs across disease stages related to liver aging. During early phases, it maintains metabolic balance, mitochondrial quality control, and genomic stability in some diseases such as MAFLD and liver fibrosis. Conversely, in advanced disease, particularly in HCC, persistent autophagy supports tumor cell survival, stemness, and immune evasion. Emerging therapies seek to restore autophagic flux through caloric restriction, physical exercise, caloric restriction mimetics (rapalogs, spermidine, metformin), and pharmacological modulators such as Tat-BECLIN-1 peptides or RUBICON-targeted approaches. However, translating these therapies into clinical practice remains challenging due to systemic effects, stage-specific responses, and lack of reliable non-invasive biomarkers for monitoring autophagy in humans. Advances in nanoparticle-based delivery, biomarker-guided stratification, and combination therapies with tyrosine kinase inhibitors or immune checkpoint inhibitors may offer promising strategies. Overall, precision modulation of autophagy could serve as a potent geroprotective approach to preserve liver function, delay age-related metabolic deterioration, and prevent progression to fibrosis and cancer. Achieving this goal requires considering disease stage, systemic interactions, and autophagy’s context-dependent duality in aging when implementing these strategies.