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.

Link: https://doi.org/10.1155/2022/3415528


An interesting assessment, but such diets are not adequately discouraged:
"... In 2006 the typical American diet was about 2,200 calories per day, with 50% of calories from carbohydrates, 15% protein, and 35% fat. These macronutrient intakes fall within the Acceptable Macronutrient Distribution Ranges (AMDR) for adults identified by the Food and Nutrition Board of the United States Institute of Medicine as "associated with reduced risk of chronic diseases while providing adequate intakes of essential nutrients," which are 45-65% carbohydrate, 10-35% protein, and 20-35% fat as a percentage of total energy..."
Though I am not disputing the debilitating effects of such an intake, one wonders whether a reasonably effective exercise program more than overcomes such an assault on one's body.
Which, of course, is not advocating that one may eat whatever crap one wants, as long as you exercise 'it off' in good time. One wonders if bioaccumulation may apply in such a scenario.

Posted by: Jer at December 12th, 2022 7:24 AM

China. 6 Double knockout mice. Paper fails to detail the diet beyond '20% calories from fat'

Posted by: JohnD at December 12th, 2022 7:42 AM

A conflation of high-fat diet and being fat as seen in so many 'studies'. A high-fat diet does not make you fat as most doing keto know, and as most who have studied the metabolic syndrome disaster since Ancel Keys. Starchy carbs and sugar are the criminal. And I have to question the veracity of such studies on creatures whose natural diet is predominantly fat-free being equated with human beings.

Posted by: Neal Asher at December 13th, 2022 3:25 AM

There is no information in the paper describing exactly which foods and ingredients served as fat sources in the diets of the mice. Was the fat mainly from industrially processed "vegetable" oils, such as canola oil, corn oil, and soybean oil? Or was the fat mainly from natural animal sources such as butter and beef tallow? The paper does not specify. In most high-fat-diet mouse experiments, they normally use industrially processed "vegetable" oils, not animal fat, because standard mouse chow used in research studies is almost 100% processed junk food.

Posted by: Andrew Lee at December 18th, 2022 6:44 AM
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