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The potential role of necroptosis in inflammaging and aging

  • Gordon H. Royce
  • Holly M. Brown-Borg
  • Sathyaseelan S. DeepaEmail author
Review
  • 192 Downloads

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.

Keywords

Necroptosis Aging Inflammation Oxidative stress Cell senescence mTOR 

Notes

Funding information

This work was supported by NIH/NIA R01 AG059718, Oklahoma Center for the Advancement of Science and Technology research grant (HR18-053) and Presbyterian Health Foundation (OUHSC) Seed grant to Dr. Sathyaseelan S Deepa. The research was also supported by grants awarded to Dr. Arlan Richardson from the National Institute on Aging (P01AG020591, R01AG045693).

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Copyright information

© American Aging Association 2019

Authors and Affiliations

  1. 1.Stephenson Cancer CenterOklahoma CityUSA
  2. 2.Department of Biomedical Sciences, School of Medicine and Health SciencesUniversity of North DakotaGrand ForksUSA
  3. 3.Department of Biochemistry and Molecular Biology, Reynolds Oklahoma Center on AgingUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA

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