Dietary Selenium Deprivation Oppositely Impacts Longevity and Healthspan in Telomere Dysfunctional Mice

Abstract

Selenium (Se), a trace metalloid essential for life, plays nutritional and physiological roles mainly through selenoproteins. While telomere attrition provokes DNA damage response and, subsequently, replicative senescence, such an aging process is restricted in mice due to their intrinsically long telomeres. To circumvent this limitation and employ a mouse model with humanized telomeres, weanling third generation telomerase RNA component knockout mice carrying short telomeres were fed a Se‐deficient, Torula‐yeast basal diet or the diet supplemented with 0.15 ppm Se as sodium selenate throughout their life. Dietary Se deprivation delayed wound healing and accelerated a wide range of age‐related degeneration including osteoporosis, grey hair, alopecia, cataract, and hyperglycemia. Surprisingly, long‐term dietary Se deprivation paradoxically promoted longevity. Plasma microRNA profiling revealed a circulating signature of Se deprivation and aging, and subsequent ontological analyses predicted dominant changes in metabolism. Dietary Se deprivation accelerated age‐dependent declines in glucose tolerance, glucose‐stimulated insulin production and insulin sensitivity, as well as DNA damage and senescence responses in the pancreas. Selenotranscriptomic and metagenomic analyses identified key selenoproteins and gut bacteria in the response to dietary Se deprivation in the mice at 18 and 24 months of age. Altogether, these results suggest a novel model of aging with conceptual advances, whereby Se at low levels may be considered a hormetic chemical and decouple healthspan and longevity.