A High Fat Diet Promotes Cellular Senescence in Skin
Excess visceral fat tissue accelerates the burden of cellular senescence, which is one of several mechanisms by which being overweight generates chronic inflammation to accelerate degenerative aging. Interestingly, the high fat diet (also known as the Western diet) used to generate obesity in mouse models is shown here to also specifically increase the burden of cellular senescence in skin, thus accelerating skin aging. Expression of p16 is involved in cellular senescence and the inflammatory signaling associated with senescence, and disabling it slows the onset of this process. p16 is a tumor suppressor gene, however, and therapies based on disabling it sound like a bad idea. A better approach is to use senolytics to clear the senescent cells that contribute to an environment of chronic inflammation.
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.
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.
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 via 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.
In conclusion, p16 deletion or p16 positive cell clearance could be a novel strategy preventing long term HFD-induced skin aging.