Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD) and aging are locked in a vicious circle: senescence of liver cells accelerates fat accumulation, inflammation and fibrosis, while chronic steatosis in turn hastens hepatic decline. Up to 38 % of adults worldwide have MASLD, and prevalence, severity and mortality all rise with age. Ageing livers shrink by ~30%, clear lipids and glucose less efficiently, and regenerate more slowly after injury. Lipid deposition is driven by falling β-oxidation, leptin resistance and the GPCPD1–glycerophosphocholine pathway; glucose intolerance emerges from insulin resistance linked to visceral obesity and telomere-p53 signalling. Senescent hepatocytes, endothelial cells, stellate cells and Kupffer macrophages each contribute distinct pathologies, but their shared secretion of the senescence-associated secretory phenotype (SASP) propagates damage throughout the organ.
Hepatocytes are the first responders. In aged or obese mice, 60–80 % of hepatocytes display p16, p21 or β-gal positivity; enlarged nuclei, reduced smooth endoplasmic reticulum and fewer mitochondria accompany metabolic reprogramming that favours lipogenesis. SASP cytokines such as IL-6, IL-8 and TNF-α recruit macrophages, perpetuate inflammation and can either restrain or promote hepatocellular carcinoma depending on context. Selective insulin resistance within senescent hepatocytes diverts incoming fatty acids to triglyceride droplets, fuelling steatosis.
Liver sinusoidal endothelial cells (LSECs) undergo “pseudocapillarization” with age: thickness increases, fenestrae decrease and basement membranes form. Loss of fenestrae impedes insulin uptake and lipoprotein exchange, aggravating systemic dyslipidaemia and hepatic fat overload. Senescent LSECs secrete CXCR4 ligands that polarise macrophages toward an M1 phenotype, amplifying fibro-inflammatory signalling. Conversely, restoring C-kit-positive LSECs or activating SIRT1 via Notch inhibition reverses these changes and improves steatohepatitis.
Hepatic stellate cells (HSCs) paradoxically assume a less fibrotic yet senescent state. They lose lipid droplets, produce fewer extracellular-matrix proteins but secrete matrix metalloproteinases that degrade existing scar tissue. p53-dependent IGF-1 signalling and IL-22–STAT3 activation drive this anti-fibrotic senescence, rendering senescent HSCs targets for NK-cell elimination. However, transient persistence of senescent HSCs after partial hepatectomy releases IL-6 and CXCR2 ligands that stimulate compensatory hepatocyte proliferation, illustrating the dual roles of cellular senescence.
Kupffer macrophages accumulate with age and shift toward an M1 pro-inflammatory profile. Autophagy declines, ROS rise and IRF5-mediated transcription of TNF-α and IL-1β intensifies. These macrophages amplify steatohepatitis by recruiting monocytes via CCR2-CCL2 and CXCR3-CXCL10 axes. Depletion of Kupffer cells in mouse models blunts progression from MASLD to MASH, confirming their pathogenic centrality.
Given the intertwining of ageing and steatosis, interventions that target senescence are emerging. Senolytic cocktails—dasatinib plus quercetin, Bcl-2 inhibitors navitoclax or ABT-737, and senolytic vaccination against glycoprotein GPNMB—selectively eliminate p16-high cells, reduce hepatic triglycerides and restore insulin sensitivity in mice. Small-molecule vorapaxar blocks thrombomodulin-PAR1 signalling in senescent hepatocytes, diminishing inflammation and fibrosis. Genetic modulation of BMP4-Gremlin1 or PLA2R1 likewise mitigates steatosis and cellular senescence.
Lifestyle measures complement pharmacology. Exercise and calorie restriction restore AMPK-mediated autophagy, lower hepatic fat and improve glucose tolerance in rodents and humans. The key challenge is to distinguish beneficial, transient senescent cells—needed for wound healing and tumour suppression—from chronic, pathogenic ones. Future trials must therefore refine cell-type-specific senolytic strategies, validate biomarkers and balance efficacy against the physiological roles of senescence in liver homeostasis.
DOI: 10.1007/s11684-025-1133-7