Senescent Cells as a Cause of Age-Related Fatty Liver Disease

Fatty liver disease, or hepatic steatosis, is both age-related and self-inflicted in the sense that in most sufferers the primary cause appears to be the metabolic dysfunction that accompanies obesity, but the risk also rises with age, and even an exemplary life can sometimes eventually result in the appearance of this condition. Chronic inflammation may play an important role in the development of fatty liver disease without obesity, and whenever that it is the case it is sensible to immediately turn to the age-related accumulation of senescent cells as a potential contributing mechanism, as these cells are a potent source of inflammatory signals. The researchers here do just that, and in the course of their work demonstrate that senescent cells are in fact an important cause of the problem, just as they are for many other age-related conditions. This is good news for patients with fatty liver disease, and those destined to be patients absent an effective treatment, given the present pace of progress towards senolytic therapies capable of safely and selectively destroying these unwanted and harmful cells.

Non-alcoholic fatty liver disease (NAFLD) is characterized by excess hepatic fat (steatosis) in individuals who drink little or no alcohol. NAFLD is more prevalent in older populations. The mechanisms underlying this condition are not understood nor is why its prevalence increases with ageing. It has been speculated that ageing processes may promote NAFLD via different mechanisms, including adipose tissue dysfunction, impaired autophagy, and oxidative stress.

Cellular senescence is a state of irreversible cell-cycle arrest, which can be induced by a variety of stressors, including telomere dysfunction and genotoxic and oxidative stress. Senescent cells frequently have increased secretion of a broad repertoire of proinflammatory factors, collectively known as the senescence-associated secretory phenotype, which can induce tissue dysfunction in a paracrine manner. Senescent cells have mitochondrial dysfunction, with decreased oxidative phosphorylation and concomitantly increased generation of reactive oxygen species (ROS), caused at least partly by failing mitophagy.

A significant fraction of hepatocytes develop a senescent phenotype during the life course of mice and with age-related liver disease in humans. However, the relationship between cellular senescence and liver fat accumulation remains unclear. Here we hypothesized that cellular senescence results in impaired fat metabolism and that removal of senescent cells may diminish liver steatosis.

We found a close relationship between senescence markers and fat accumulation in hepatocytes of mice fed ad libitum (AL), dietary restricted (DR) or following dietary crossover and in a small cohort of NAFLD patients. Furthermore, clearance of senescent cells by suicide gene-meditated ablation of p16Ink4a-expressing senescent cells in INK-ATTAC mice and a senolytic cocktail of dasatinib plus quercetin reduced overall hepatic steatosis in ageing, obese, and diabetic mice. In contrast, hepatocyte-specific induction of senescence by a local DNA repair defect resulted in liver steatosis. Finally, we found that induction of senescence in mouse fibroblasts and hepatocytes resulted in decreased ability to metabolize fat. Our findings suggest that interventions targeting senescent cells may be developed into therapies to reduce steatosis during NAFLD.



Holy crap at this rate senescent cells are going to turn out to be the second most toxic substance in the universe after Plutonium. Is there any bad age related effect that they don't cause/accelerate?

Posted by: Jim at June 19th, 2017 6:35 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.