Aging-Related Molecular Pathways in Chronic Cholestatic Conditions

Abstract

Aging is commonly defined as the time-dependent functional decline of organs and tissues. Average life expectancy has increased considerably over the past century and is estimated to increase even further, consequently also the interest in understanding the aging processes. Although aging is not a disease, it is the major risk factor for the development of many chronic diseases. Pathologies, such as Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC) are cholestatic liver diseases characterized by chronic inflammation, biliary damage and ultimately liver fibrosis, targeting specifically cholangiocytes. To date, the influence of aging in these biliary diseases is not fully understood. Currently, liver transplantation is the only solution because of lacking in efficiently therapies. Although liver cells have a high regenerative capacity, they undergo extensive molecular changes in response to aging. Following time-dependent damage induced by aging, the cells initially activate protective compensatory processes that, if hyperstimulated, can lead to the decline of regenerative ability and the development of pathologies. Recent studies have introduced novel therapeutic tools for cholangiopathies that have showed to have promising potential as novel therapies for PSC and PBC and for the development of new drugs. The recent advancements in understanding of molecular aging have undoubtedly the potential to unveil new pathways for selective drug treatments, but further studies are needed to deepen their knowledge.

Ginsenoside Rg1 ameliorates aging‑induced liver fibrosis by inhibiting the NOX4/NLRP3 inflammasome in SAMP8 mice

“…Increasing evidence has shown that oxidative stress may also be closely associated with the levels of inflammation, which also plays a crucial role in aging-related diseases ( 62 , 63 ). A previous study demonstrated that the accumulation of senescent cells contributed to the development of fibrosis by secreting proinflammatory cytokines and profibrotic mediators ( 64 ).…”

Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases

“…Despite the evidence for a possible protective role of autophagy stimulation in cholestasis, no strategies aimed at its induction have yet been tested in cholangiopathy patients. Current therapeutic strategies directed at replenishing the bile ducts of ductopenic patients are limited to protecting cholangiocytes from death induced by the immunological response [82,83]. The first-line treatments to counteract cholangiocyte death are hydrophilic ursodesoxycholic acid (UDCA) as well as immunosuppressive and anti-inflammatory agents (Table 2).…”

“…The first-line treatments to counteract cholangiocyte death are hydrophilic ursodesoxycholic acid (UDCA) as well as immunosuppressive and anti-inflammatory agents (Table 2). UDCA is the drug of first choice for cholestasis, particularly for PBC but less so for PSC [83][84][85]. Although its actual mechanism of action is not well-known, it appears to act in multiple ways.…”

“…In PSC patients, age at diagnosis increases the risk of developing cholangiocarcinoma (21% for patients older than 60 years) [131]. Elderly liver transplant patients are at greater risk of complications, and survival rates are lower in those older than 60 years [83,132]. Moreover, the increased expression of senescent markers and senescence-associated secretory phenotype (SASP) components described in liver samples from PSC and PBC patients corroborates data obtained in animal models of cholestatic liver injury, stressing the close correlation between ageing and cholangiopathy development [124,133].…”

Comparative Analysis Of Orthologous Mast Cell Chymases Active Sites Using Bioinformatics Tools

“…The role of chymase in the pathogenesis of allergic skin reactions is supported by studies that link the presence of chymase to disease progression (Dell'Italia et al, 2018) Because of the discovery that chymase may transform ANG-I to ANG-II and the potential for this operation in terms of cardiac function, several studies have suggested that chymase can play a role in heart disease (Pichler et al, 2017) Chymases are also involved in the brotic process. In animal models of experimental diabetes (Pinto et al, 2020) and autoimmune liver (Kosanovic et al, 2015) brosis the existence of chymases is associated with brosis; however, chymase inhibitors may minimise brosis (Chen et al, 2017) The exact mechanism by which chymase causes brosis is unknown (de Souza Junior et al, 2015) Although MCs play a role in angiogenesis, their exact function is unknown. Several studies have shown that chymase is involved (Tellechea et al, 2020) Chymase's effect on angiogenesis can result in both pathological and physiological outcomes.…”