Role of Necroptosis in Aging and Age‐Associated Inflammation

Aging is characterized by low‐level chronic inflammation, termed sterile inflammation or ‘inflammaging’. Inflammaging is an important risk factor for most age‐related diseases as well as both morbidity and mortality in older people. Inflammaging is characterized by high levels of circulating proinflammatory cytokines. Although the exact cause of inflammaging is not known, several pathways have been suggested to cause chronic inflammation with age, e.g., immunosenescence, cell senescence, and increased levels of damage associated molecular patterns (DAMPs), which are a strong inducer of inflammation. Necroptosis is a newly identified non‐apoptotic form of cell death that plays a major role in inflammation through generation of DAMPs. We hypothesized that necroptosis plays a role in aging and age‐associated increase in inflammation. In support of our hypothesis, we found that levels of phosphorylated mixed lineage kinase domain like (P‐MLKL), a marker of necroptosis, is elevated by 2.5‐fold in epididymal white adipose tissue (eWAT) of 25‐month‐old wild‐type (old‐WT) mice, compared to 9‐month‐old WT (young‐WT) mice. Interestingly, only eWAT, not subcutaneous WAT (sWAT), showed an age‐dependent increase in necroptosis. Dietary restriction (DR), an intervention known to reduce inflammation and increase lifespan, reduced necroptosis in eWAT of old‐DR mice to the level found in young‐WT mice. We also measured the level of necroptosis in several tissues of Sod1 −/− ( Sod1 KO) mice. Sod1KO mice show a 20–30% decrease in lifespan and increased inflammation (e.g., circulating levels of pro‐inflammatory cytokines and pathological markers of inflammation). P‐MLKL is increased 3.7‐fold and 0.4‐fold in eWAT and liver of 9‐month‐old Sod1 KO mice. Furthermore, markers of M2 macrophages (anti‐inflammatory) are reduced and M1 macrophages (pro‐inflammatory) are increased in eWAT of Old‐WT and young‐ Sod1 KO mice. Consistent with the shift of M2 to M1 macrophages, we observed that transcript levels of pro‐inflammatory cytokines TNFa, IL‐6 and IL‐1b are elevated in eWAT of old‐WT and young‐ Sod1 KO, compared to young‐WT mice. In summary, we show for the first time that necroptosis increases with age, is elevated in an accelerated aging model and is reduced by DR suggesting a role of necroptosis in age‐associated inflammation and possibly aging. Currently, we are testing the effect of inhibition of necroptosis on inflammaging. Support or Funding Information Supported in part by NIH grants P01‐AG051442 and R01 AG045693 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .