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. 2018 Aug;17(4):e12770.
doi: 10.1111/acel.12770. Epub 2018 Apr 25.

Necroptosis increases with age and is reduced by dietary restriction

Sathyaseelan S Deepa  1   2 , Archana Unnikrishnan  1   2 , Stephanie Matyi  1   2 , Niran Hadad  3 , Arlan Richardson  1   2   4
Affiliations

Necroptosis increases with age and is reduced by dietary restriction

Sathyaseelan S Deepa et al. Aging Cell. 2018 Aug.

Abstract

Necroptosis is a newly identified programmed cell death pathway that is highly proinflammatory due to the release of cellular components that promote inflammation. To determine whether necroptosis might play a role in inflammaging, we studied the effect of age and dietary restriction (DR) on necroptosis in the epididymal white adipose tissue (eWAT), a major source of proinflammatory cytokines. Phosphorylated MLKL and RIPK3, markers of necroptosis, were increased 2.7- and 1.9-fold, respectively, in eWAT of old mice compared to adult mice, and DR reduced P-MLKL and P-RIPK3 to levels similar to adult mice. An increase in the expression of RIPK1 (1.6-fold) and MLKL (2.7-fold), not RIPK3, was also observed in eWAT of old mice, which was reduced by DR in old mice. The increase in necroptosis was paralleled by an increase in 14 inflammatory cytokines, including the pro-inflammatory cytokines IL-6 (3.9-fold), TNF-α (4.7-fold), and IL-1β (5.1-fold)], and 11 chemokines in old mice. DR attenuated the expression of IL-6, TNF-α, and IL-1β as well as 85% of the other cytokines/chemokines induced with age. In contrast, inguinal WAT (iWAT), which is less inflammatory, did not show any significant increase with age in the levels of P-MLKL and MLKL or inflammatory cytokines/chemokines. Because the changes in biomarkers of necroptosis in eWAT with age and DR paralleled the changes in the expression of pro-inflammatory cytokines, our data support the possibility that necroptosis might play a role in increased chronic inflammation observed with age.

Keywords: adipose tissue; aging; dietary restriction; inflammaging; inflammation; necroptosis.

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Figures

Figure 1
Figure 1
Markers of necroptosis increase with age in eWAT, not iWAT, and DR reduces their expression in eWAT. (a, d) Left panel: immunoblots of eWAT (a) and iWAT (d) extracts from adult (blue bar), old (red bar), and old‐DR (green bar) mice for P‐MLKL, MLKL, P‐RIPK3, RIPK3, RIPK1, and β‐tubulin (n = 5–6/group). Right panel: graphical representation of quantified blots normalized to β‐tubulin. (b, e) Transcript levels of MLKL, RIPK3, and RIPK1 in eWAT (b) and iWAT (e) of adult, old, and old‐DR mice, normalized to β‐microglobulin and represented as fold change. (c, f) Transcript levels of VPS4A, VPS4B, VPS37B, CHMP4B, and CHMP2A in eWAT (c) and iWAT (f) of adult, old, and old‐DR mice, normalized to β‐microglobulin and represented as fold change. Data shown are mean ± SEM. p < .05 is taken as significant for the following: *Adult vs old; ^old vs old‐DR; #adult vs old‐DR
Figure 2
Figure 2
Transcript level of inflammatory markers increases with age in eWAT, not in iWAT, and DR reduces the expression of inflammatory markers in eWAT of old mice. (a) Top panel: immunoblots of eWAT extracts from adult (blue bar), old (red bar), and old‐DR (green bar) mice for phospho‐NF‐κB and NF‐κB (n = 5–6/group). Bottom panel: graphical representation of quantified blots of phospho‐NF‐κB normalized to NF‐κB. (b) Heat maps showing expression of inflammatory cytokines and chemokines, normalized to β‐microglobulin in eWAT (left panel) and iWAT (right panel) of adult, old, and old‐DR mice (n = 4/group). Average value of adult mice was used to normalize values of adult, old, and old‐DR mice. The darker the red indicates the greater the increase in expression, and the darker the blue indicates the greater the decrease in expression. (c) Transcript levels of IL‐6, TNF‐α, and IL‐1β in eWAT and iWAT of adult (blue bar), old (red bar), and old‐DR (green bar) mice. Transcript levels in adult eWAT and iWAT were taken as one, and fold changes relative to adult are represented. Data shown are mean±SEM. The data were analyzed by one‐way ANOVA, and a p < .05 is taken as significant for the following: *adult vs old; ^old vs old‐DR
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