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The potential role of necroptosis in inflammaging and aging.

ABSTRACT: An age-associated increase in chronic, low-grade sterile inflammation termed "inflammaging" is a characteristic feature of mammalian aging that shows a strong association with occurrence of various age-associated diseases. However, the mechanism(s) responsible for inflammaging and its causal role in aging and age-related diseases are not well understood. Age-associated 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.

SUBMITTER: Royce GH

PROVIDER: S-EPMC6925091 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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The potential role of necroptosis in inflammaging and aging.

Royce Gordon H GH Brown-Borg Holly M HM Deepa Sathyaseelan S SS

GeroScience 20191113 6

An age-associated increase in chronic, low-grade sterile inflammation termed "inflammaging" is a characteristic feature of mammalian aging that shows a strong association with occurrence of various age-associated diseases. However, the mechanism(s) responsible for inflammaging and its causal role in aging and age-related diseases are not well understood. Age-associated accumulation of damage-associated molecular patterns (DAMPs) is an important trigger in inflammation and has been proposed as a ...[more]

PMID: 31721033

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Project description:BackgroundAging induced chronic systemic inflammatory response is an important risk factor for atherosclerosis (AS) development; however, the detailed mechanism is yet to be elucidated.ObjectiveTo explore the underlying mechanism of how aging aggravates AS advancement.MethodsA young (five-week-old, YM) and aged group (32-week-old, OM) male apoE-/- mice with a high fat diet were used as models, and age-matched male wild-type C57BL/6J (WT) mice were used as controls. AS lesion size, serum lipid profile, cytokines, and gut microbiota-derived LPS were analyzed after 32 weeks of diet intervention. A correlation analysis between the 16S rRNA sequencing of the feces and serum metabolomics profiles was applied to examine the effect of their interactions on AS.ResultsApoE-/- mice developed severe atherosclerosis and inflammation in the aorta compared to the WT groups, and aged apoE-/- mice suffered from a more severe AS lesion than their younger counterparts and had low-grade systemic inflammation. Furthermore, increased levels of serum LPS, decreased levels of SCFAs production, as well as dysfunction of the ileal mucosal barrier were detected in aged mice compared with their younger counterparts. There were significant differences in the intestinal flora composition among the four groups, and harmful bacteria such as Lachnospiraceae_FCS020, Ruminococcaceae_UCG-009, Acetatifactor, Lachnoclostridium and Lactobacillus_gasseri were significantly increased in the aged apoE-/- mice compared with the other groups. Concurrently, metabolomics profiling revealed that components involved in the arachidonic acid (AA) metabolic pathway such as 20-HETE, PGF2α, arachidonic acid, and LTB4 were significantly higher in the aged AS group than in the other groups. This suggested that metabolic abnormalities and disorders of intestinal flora occurred in AS mice.ConclusionsAging not only altered the gut microbiome community but also substantially disturbed metabolic conditions. Our results confirm that AA metabolism is associated with the imbalance of the intestinal flora in the AS lesions of aged mice. These findings may offer new insights regarding the role of gut flora disorders and its consequent metabolite changed in inflammaging during AS development.

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The potential role of necroptosis in inflammaging and aging.

Publications

The potential role of necroptosis in inflammaging and aging.

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