Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

Abstract

The incidence of type 2 diabetes (T2D) increases with age. Low‐grade inflammation in AT is implicated in development of insulin resistance and T2D. We conducted a study to determine if inflammatory responses are upregulated with age in AT. Results show that visceral AT from old mice had significantly higher expression of mRNA levels of IL‐1β, IL‐6, TNF‐α, and COX‐2 than those of young mice (263, 208, 165, and 73%, higher respectively). In determining the relative contribution of different components of AT to these age‐related changes, we found that adipocytes (AD) from old mice produced significantly more (2 to 3 folds) IL‐6 and PGE2 than those from young mice while no significant age difference was observed in their production by stromal vascular cells. There was no significant effect of age on number of Mϕ/g AT and Mϕ of either age group produced significantly more IL‐6 when incubated in conditioned medium from old AD compared to that of young. Blocking NF‐κB activation reduced IL‐6 production while addition of ceramide or sphingomyelinase increased IL‐6 production in young AD to a level comparable to that of old AD. Inhibiting de novo ceramide synthesis reduced IL‐6 production by AD. NF‐κB regulates expression of inflammatory products including COX‐2 and IL‐6. Ceramide was shown to increase COX‐2 expression in aged Mϕ through NF‐κB activation. Thus, these data suggest a potential role for ceramide and NF‐κB in the age‐related increase of AT inflammation. Further research is needed to fully determine the underlying mechanisms of the observed effects and their contribution to T2D in the aged. Supported by USDA #58‐1950‐9‐001 and NIA #R01 AG009140‐10A1.

JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

“…system (53) or altered redox homeostasis (54). Increased numbers of T cells and inflammatory macrophages also are observed in aged adipose tissue (44). Our findings support the possibility that senescent cells contribute to age-related systemic inflammation.…”

“…We observed that 10 wk of treatment with INCB18424 did not alter number of peripheral blood immune cells in aged mice (Table S3). Adipose tissue is a major source of the cytokines in aged animals (44,45). We found that the expression of several inflammatory markers and matrix metalloproteinases in adipose tissue, including IL-6, TNF-α, MMP-3, MMP-12, and EGF-like module-containing mucin-like hormone receptor-like 1 (Emr1 or F4/80), a macrophage marker, was decreased in the INCB18424-treated group, (Fig.…”

“…(iii) p16 Ink4a -positive senescent cells were the main cause of increased IL-6 expression in the stromal vascular fraction of adipose tissue digests from older progeroid mice (21). The stromal vascular fraction is, in turn, the principal site of cytokine release by adipose tissue (44). (iv) Inhibiting the JAK-STAT pathway suppresses the SASP in preadipocytes and endothelial cells as well as SASP-induced adipose tissue inflammation in vitro.…”

“…In this study, we mainly used human primary preadipocytes to study cellular senescence and the SASP because fat tissue is a major source of circulating inflammatory cytokines in aged populations (44,45) and because fat tissue is the largest organ in most humans and preadipocytes thus are perhaps the most abundant progenitor cell type in humans (39). It is likely that senescent cells in other tissues contribute to age-related inflammation as well.…”

Caloric restriction attenuates the age-associated increase of adipose-derived stem cells but further reduces their proliferative capacity

“…Consistent with previous reports in plastic adherent non-adipocytes (Kirkland et al 1994;Wu et al 2007), our data demonstrate an age-associated increase in the density of the lin − SVF (number of cells/g epididymal fat) within white adipose tissue. However, our study extends these results to a specific ASC population.…”