The potential role of necroptosis in inflammaging and aging

Abstract

An age-associated increase in chronic, lowgrade sterile inflammation termed "inflammaging" is a characteristic feature of mammalian aging that shows a strong association with occurrence of various ageassociated diseases. However, the mechanism(s) responsible for inflammaging and its causal role in aging and age-related diseases are not well understood. Ageassociated accumulation of damage-associated molecular patterns (DAMPs) is an important trigger in inflammation and has been proposed as a potential driver of inflammaging. DAMPs can initiate an inflammatory response by binding to the cell surface receptors on innate immune cells. Programmed necrosis, termed necroptosis, is one of the pathways that can release DAMPs, and cell death due to necroptosis is known to induce inflammation. Necroptosis-mediated inflammation plays an important role in a variety of age-related diseases such as Alzheimer's disease, Parkinson's disease, and atherosclerosis. Recently, it was reported that markers of necroptosis increase with age in mice and that dietary restriction, which retards aging and increases lifespan, reduces necroptosis and inflammation. Genetic manipulations that increase lifespan (Ames Dwarf mice) and reduce lifespan (Sod1 −/− mice) are associated with reduced and increased necroptosis and inflammation, respectively. While necroptosis evolved to protect cells/tissues from invading pathogens, e.g., viruses, we propose that the age-related increase in oxidative stress, mTOR signaling, and cell senescence results in cells/tissues in old animals being more prone to undergo necroptosis thereby releasing DAMPs, which contribute to the chronic inflammation observed with age. Approach to decrease DAMPs release by reducing/blocking necroptosis is a potentially new approach to reduce inflammaging, retard aging, and improve healthspan.

Role of necroptosis in chronic hepatic inflammation and liver disease in Cu/Zn superoxide dismutase deficient mice

“…All of the current HCC mouse models exhibit HCC in relatively young adult mice. The Sod1KO mice, which show an accelerated aging phenotype (28), develop HCC in the later third of their life, similar to what is seen in humans. Because a variety of factors change with age that can impact cancer, the Sod1KO mice allows one to study HCC in the environment of an aged animal that is relevant to HCC in humans.…”

“…Studies have shown that necroptosis is a major source of inflammation in a variety of tissues, and genetic or pharmacological inhibition of necroptosis can block/reduce inflammation (28). In addition, necroptosis has been reported to be elevated in the livers of patients with CLD (16,17) and also in the livers of mouse models of diet-induced NAFLD (15)(16)(17)(18).…”

“…Previously we reported that necroptosis and expression of proinflammatory cytokines are increased in the adipose tissue of Sod1KO mice (28). Therefore, we hypothesized that increased necroptosis in the liver plays a role in increased inflammation and progression to fibrosis and HCC reported in Sod1KO mice.…”

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

“…Mechanically, upon pathogenic stimuli following TBI, TNF-α-induced receptor-interacting protein 1 activation contributes to the formation of the so-called necrosome, a complex necessary for necroptosis [40,41]. And after necroptosis, inflammatory factors released from damaged cells flow into the extracellular space, boosting the neuroinflammation [41][42][43]. All these primary or secondary pathologic mechanisms contribute to cell death, tissue loss, structural and metabolic abnormalities, and an ultimate neurological dysfunction in the patients [15,44].…”

Expression and clinical significance of SARS-COV-2 receptor ACE2 in colon cancer

“…Immune cells are important constituents of the TME and participate in tumour immune escape and tolerance [54,55]. A large number of studies have shown that there are signi cant differences in the in ltration ratio of immune cells between colon cancer tumour tissues and corresponding adjacent tissues, and is characterised by extensive heterogeneity.…”