Senescent cells are play a role in the onset and progression of near every age-related condition. Cells become senescent constantly throughout the body and throughout life, most because they have reached the Hayflick limit to replication. In youth, senescent cells are efficiently removed, either through programmed cell death or by the immune system. With age, the immune system declines in effectiveness. Senescent cells begin to linger and grow in number. These errant cells secrete a mix of pro-growth, pro-inflammation signals that, when present over the long term, disrupt cell and tissue function.
Today's open access review takes a look at senescent cells in the aging liver, and their contribution to liver disease. While human trials have yet to be undertaken for liver conditions, it is plausible that selectively destroying senescent cells using senolytic therapies will prove to be beneficial to patients. This is true of so many different age-related conditions that the research and development community has started in on clinical trials for only a small fraction of them.
Thus there is a role for philanthropy here, to take presently available, low-cost senolytic therapies such as the dasatinib and quercetin combination and run low-cost, rapid trials of efficacy for dozens of age-related conditions. With proof that this can help patients with specific issues, more physicians will be open to prescribing senolytic therapies off-label, and we may see many more aged people benefit sooner than would be the case if the field is left to established institutions.
Cellular senescence is a pathophysiological phenomenon in which proliferative cells enter cell cycle arrest following DNA damage and other stress signals. Natural, permanent DNA damage can occur after repetitive cell division; however, acute stress or other injuries can push cells into premature senescence and eventually a senescence-associated secretory phenotype (SASP). In recent years, there has been increased evidence for the role of premature senescence in disease progression including diabetes, cardiac diseases, and end-stage liver diseases including cholestasis. Liver size and function change with aging, and presumably with increasing cellular senescence, so it is important to understand the mechanisms by which cellular senescence affects the functional nature of the liver in health and disease.
Cholangiocytes, which are morphologically heterogenous, polarized cells lining the biliary epithelium, have high absorptive/secretory functions and play a role in the 1) modification of canalicular bile, 2) paracrine communication with portal cells, and 3) regulation of immune cell infiltration. Cholangiocytes are the target of various liver diseases such as fatty liver diseases: non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), and chronic cholestatic liver diseases including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), biliary atresia, and cholangiocarcinoma. Biliary secretory functions regulate liver inflammation and fibrosis (by both autocrine and paracrine pathways) through secretion of cytokines and other factors which may contribute to liver damage. Cellular senescence increases in cholangiocytes of PSC patients, likely contributing to disease progression.