Liver and Aging

On average, adult humans experience liver damage many times throughout their lifetime, especially under physiological conditions. The liver is a unique organ with a remarkable capacity for repair and regeneration, processes associated with survival and recovery after various forms of damage. Previous studies revealed that liver repair depends not only on the regeneration of isolated hepatocytes but also on various cellular interactions.1 This collaborative effort is crucial for the effective restoration of liver function and structure. Furthermore, the underlying molecular mechanisms that orchestrate these complex cellular interactions have been identified. These mechanisms involve key signaling pathways that determine not only cellular behavior but also the ability of the liver to rebuild.

A Dual Role of the Senescence Marker P16Ink4a in Liver Endothelial Cell Function

Attenuating hepatic p16 expression may be a therapeutic approach for improving NAFLD/NASH phenotypes.

P16Ink4a

Autophagy in aging liver

Autophagy is a process of self-degradation of cellular components in which double-membrane autophagosomes sequester organelles or portions of cytosol and fuse with lysosomes or vacuoles for breakdown by resident hydrolases. Defective autophagy plays a significant role in human pathologies, including cancer, neurodegeneration, and infectious diseases (He and Klionsky 2009). The participation of autophagy in different physiological functions is attributable, in almost all cases, to one of its two main functions: as an energy source or as a mechanism for the removal of unwanted cellular structures (Mizushima and Klionsky 2007).
Autophagy is a major protein turnover pathway by which cellular components are delivered into the lysosomes for degradation and recycling. This intracellular process is able to maintain cellular homeostasis under stress conditions, and its dysregulation could lead to the development of physiological alterations.
All cells rely on surveillance mechanisms, chaperones, and proteolytic systems to control the quality of their proteins and organelles and to guarantee that any malfunctioning or damaged intracellular components are repaired or eliminated (Morimoto 2008; Goldberg 2003). Aging is an inevitable physiological process characterized by a progressive accumulation of damaged aberrant macromolecules and organelles in somatic cells during the post-developmental period, leading to the decreased ability of the organism to survive (Guarente and Kenyon 2000; Hekimi and Guarente 2003; Kirkwood and Austad 2000; Bishop and Guarente 2007).
Genetic defects of autophagy genes lead to a host of developmental, metabolic, and pathological aberrations. Similarly, the age‐induced decline in autophagy leads to the loss of cellular homeostatic control. Paradoxically, such a valuable mechanism is hijacked by diseases, during tumor progression and by senescence, presumably due to high levels of metabolic demand.

Macroautophagy and microautophagy

In macroautophagy, random dysfunctional organelles and damaged molecules are engulfed by the elongating phagophore. Phagophore is ultimately sealed, forming a double‐membrane‐bound autophagosome that, by virtue of tethers, binds, and then fuses with lysosome. This creates the autolysosome, where the transferred cargo, is degraded by autosomal hydrolases. In microautophagy, cargoes are directly sequestered by the invagination of the vacuolar membrane. This is then followed by scission, subsequent lysis of membrane, exposing cargo to vacuolar hydrolases for degradation (Schütter et al. 2020 and Aman et al., 2021, Yim and Mizushima 2020).

The link between autophagy and apoptosis: transcription factor FOXO3a

The Forkhead box O (FoxO) family has recently been highlighted as an important transcriptional regulator of crucial proteins associated with the many diverse functions of cells. So far, FoxO1, FoxO3a, FoxO4 and FoxO6 proteins have been identified in humans. Although each FoxO family member has its own role, unlike the other FoxO families, FoxO3a has been extensively studied because of its rather unique and pivotal regulation of cell proliferation, apoptosis, metabolism, stress management and longevity. FoxO3a alteration is closely linked to the progression of several types of cancers, fibrosis and other types of diseases.

Oxidative stress has been identified as a key mechanism in liver damage. The transcription factor FOXO3a has emerged as a critical regulator of redox imbalance. Multiple post-translational changes and epigenetic processes closely regulate the activity of FOXO3a, resulting in synergistic or competing impacts on its subcellular localization, stability, protein–protein interactions, DNA binding affinity, and transcriptional programs. Depending on the chemical nature and subcellular context, the oxidative-stress-mediated activation of FOXO3a can induce multiple transcriptional programs that play crucial roles in oxidative injury to the liver.

Alcoholic liver disease encompasses a wide spectrum of pathogenesis including steatosis, fibrosis, cirrhosis, and alcoholic steatohepatitis. Excessive alcohol consumption and abuse may result in alcoholic liver disease (ALD), a major contributor of liver diseases and deaths [1,2]. Pathogenesis of ALD initiates with simple steatosis in a majority of drinkers and progresses to more severe pathologies including fibrosis, alcoholic hepatitis, and cirrhosis in a fraction of patients. In exceptional cases, ALD may progress to hepatocellular carcinoma [2]. Binge drinking is a form of alcohol abuse defined by consuming more than 5 drinks (males) or 4 drinks (females) in 2 h setting [3]. Around one out of three adults display high risk drinking pattern including binge drinking, but less attention has been given to liver injury induced by acute alcohol exposure despite the fact binge drinking is more common than chronic alcohol abuse [1]. At the physiological level, binge drinking induces glycogen depletion, acidosis, and hypoglycemia [4]. At the cellular level, binge drinking results in mitochondria damage, ablated insulin signaling, steatosis, and free radical generation [5–9]. Paradoxically, binge drinking induces autophagy as a cellular protective mechanism to selectively degrade damaged mitochondria (mitophagy) and lipid droplets (lipophagy), whereas suppression of autophagy by pharmacological inhibitors or small interfering RNAs exacerbates alcohol-induced hepatotoxicity and steatosis [10,11].

Macroautophagy applies for the bulk and non‐selective removal of macromolecules or subcellular organelles within cytosolic double‐membrane‐bound autophagosomes fused with lysosomes....