p16INK4a Plays Critical Role in Exacerbating Inflammaging in High Fat Diet Induced Skin

Abstract

Background. Long term high fat diets (HFD) promote skin aging pathogenesis, but detailed mechanisms remain unclear especially for inflammaging, which has recently emerged as a pathway correlating aging and age-related disease with inflammation. p16INK4a (hereafter termed p16) inhibits the cell cycle, with p16 deletion significantly inhibiting inflammaging. We observed that HFD-induced p16 overexpression in the skin. Therefore, we investigated if p16 exacerbated inflammaging in HFD-induced skin and also if p16 deletion exerted protective effects against this process. Methods. Eight-week-old double knockout (KO) ApoE-/-p16-/- mice and ApoE-/- littermates were fed HFD for 12 weeks and their skin phenotypes were analyzed. We measured skin fibrosis, senescence-associated secretory phenotype (SASP) levels, and integrin-inflammasome pathway activation using histopathological, RNA-sequencing (RNA-seq), bioinformatics analysis, and molecular techniques. Results. We found that HFD contributed to inflammaging in the skin by activating the NLRP3 inflammasome pathway, increasing inflammatory infiltration, and promoting apoptosis by balancing expression between proapoptotic and antiapoptotic molecules. p16 knockout, when compared with the ApoE-/- phenotype, inhibited skin fibrosis by ameliorating inflammatory infiltration and proinflammatory factor expression (Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)), and also alleviated inflammaging skin progress induced by HFD in the ApoE-/- mouse model. RNA-seq showed that p16 KO mice inhibited both integrin-inflammasome and NF-κB proinflammatory pathway activation. Conclusions. p16 deletion or p16 positive cell clearance could be a novel strategy preventing long term HFD-induced skin aging.

NLRP3 Contributes to Sarcopenia Associated to Dependency Recapitulating Inflammatory-Associated Muscle Degeneration

“…Additionally, we found high levels of protein expression of cell-cycle inhibitor p16 INK4a indicating an increase in senescence cells in sarcopenic muscle from DP. In turn, p16 activates the NLRP3 inflammasome pathway by increasing integrin alpha L (ITGAL) and integrin alpha M (ITGAM) expression [74] making a feedback loop [75].…”

Exploring the emerging bidirectional association between inflamm‐aging and cellular senescence in organismal aging and disease

“…Further, induction of premature cellular senescence was associated with increased muscle loss in a murine model of chronic kidney disease mediated by pro‐inflammatory aggravation as evidenced by increased TNF‐α, IL‐6, IL‐1β, and IFN gene expression 100 . Conversely, suppression of the p16 Ink4a pathway, involved in senescent cell development, inhibited skin fibrosis by ameliorating immune cell infiltration and expression of pro‐inflammatory cytokines (IL‐1β, IL‐6, and TNF‐α), and also alleviated skin inflamm‐aging in a mouse model, thereby suggesting the underlying role of senescent cells in promoting inflamm‐aging 101 . Interestingly, there is also evidence that the pro‐inflammatory phenotype of immune cells could be a manifestation of the SASP itself as a result of a high nuclear factor kappa B (NF‐κB) activity 102 …”

“…100 Conversely, suppression of the p16 Ink4a pathway, involved in senescent cell development, inhibited skin fibrosis by ameliorating immune cell infiltration and expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and also alleviated skin inflamm-aging in a mouse model, thereby suggesting the underlying role of senescent cells in promoting inflamm-aging. 101 Interestingly, there is also evidence that the pro-inflammatory F I G U R E 3 Schematic representation of the mechanisms involved in cellular senescence mediated augmentation of inflamm-aging.…”

Research Progress in Skin Aging and Immunity

“…These commensal microbes can produce antimicrobial peptides (AMPs) and induce the expression of AMPs by host epithelial cells [29]. Commensal bacteria can also induce keratinocytes and sebaceous gland cells to produce homeostatic cytokines, expand the pool of skin CD4+ and CD8+ T cells, and stimulate skin T cells to produce cytokines [31,32].…”