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Inflammatory Necroptosis Increases with Aging and is Slowed by Calorie Restriction

Calorie restriction modestly slows near every measure of aging, so it isn't surprising to see it in action here. Putting that to one side, the interesting part of this paper is the new data on necroptosis, a form of programmed cell death recently enough discovered to receive little attention in comparison to other, similar cell fates. Necroptosis is inflammatory, and rising levels of chronic inflammation occur with aging, driving progression of many of the common age-related diseases. To what degree is this caused by necroptosis versus malfunction in the immune system versus senescent cells versus other causes? Time will tell. Based on research from past years, I'd guess that necroptosis will turn out to be significant as one of the mediating mechanisms linking excess fat tissue with chronic inflammation - there is evidence for cellular debris from dead fat cells to produce that outcome.

Aging is characterized by the progressive increase in chronic, low-grade inflammation termed "inflammaging," which is believed to play an important role in the mechanism underlying aging. Necroptosis is a newly identified form of cell death that initiates an inflammatory process when the dying cells release cell debris and self-molecules, that is, damage-associated molecular patterns, DAMPs or alarmins. DAMPs are a major activator of NLRP3 inflammasome that triggers maturation of interleukin-1β (IL-1β), and NLRP3 inflammasome activation is one of the mechanisms that induces low-grade chronic inflammation with age. Several studies show that blocking necroptosis either genetically or pharmacologically dramatically reduces inflammation in a variety of mouse models. In addition, blocking/reducing necroptosis appears to have an impact on the aging of the male reproductive system and increases the lifespan of ApoE knockout mice and G93A transgenic mouse model of ALS. Necroptosis also appears to play a role in neuron loss in Alzheimer's disease.

To determine whether necroptosis might be a factor in inflammaging, we determined whether necroptosis increases with age and whether it was attenuated by dietary restriction (DR), which retards aging and reduces the increase in chronic inflammation. We measured necroptosis in epididymal white adipose tissue (eWAT), which is a visceral fat depot that is associated with the greatest inflammatory cytokine production, compared to other fat depots, and inguinal WAT (iWAT), which is a subcutaneous fat depot less inflammatory in nature. The level of P-MLKL, a well-accepted marker of necroptosis, was 2.7-fold greater in eWAT of old mice (25-29 months) compared to adult mice (9 months), and DR (started at 4 months of age) reduced P-MLKL to a level similar to adult mice.

We next determined whether the increase in necroptosis in eWAT was associated with increased inflammation. DAMPs produced by necroptosis are reported to increase the release of pro-inflammatory cytokines from innate immune cells through the activation of NF-κB. Therefore, we measured activation of NF-κB in eWAT by the phosphorylation of NF-κB. The level of phospho-NF-κB normalized to NF-κB was 1.4-fold greater in eWAT of old mice compared to adult mice, and DR reduced phospho-NF-κB to a level similar to adult mice.

In summary, our study is the first to demonstrate that biomarkers of necroptosis increase with age. The observation that the changes in necroptosis in eWAT with age and DR are paralleled by changes in the expression of pro-inflammatory cytokines support the possibility that necroptosis may play a role in the age-related increase in chronic inflammation in visceral fat, and possibly inflammaging in the whole animal. Using genetic and pharmacological manipulations which block necroptosis, it will be possible to determine whether the age-related increase in necroptosis causes the increased inflammation observed with age.

Link: https://doi.org/10.1111/acel.12770

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