Nutritional roles of selenium in cellular and mouse aging

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Oxidative stress and persistent DNA damage response can lead to cellular senescence and aging. The ATM kinase and p53 protein play critical roles in the DNA damage response to reactive oxygen species and other DNA-damaging agents. Although the majority of selenoproteins carry antioxidant activities, little is known about the nutritional role of selenium (Se) in aging. Previous studies indicated that selenoprotein H (SelH) is very sensitive to dietary Se deficiency. Moreover, SelH is a nuclear selenoprotein that is proposed to carry redox domains and to transactivate redox genes including one for glutathione biosynthesis. To determine the role of SelH in genome maintenance, SelH and scrambled shRNA knockdown were stably established in MRC-5 human diploid fibroblast or immortalized cancer cells. SelH shRNA MRC-5 cells showed more pronounced induction of β-galactosidase expression, autofluorescence, growth inhibition, and ATM pathway activation (γH2AX and phospho-ATM Ser-1981) as compared to scrambled shRNA cells. Interestingly, the slow proliferation in SelH shRNA MRC-5 cells was alleviated in the presence of ATM kinase inhibitors KU 55933 and KU 60019, by p53 shRNA knockdown, or by maintaining the cells in 3% O2 incubator (vs. ambient O2). Phospho-ATM Ser-1981 and γH2AX induction by H2O2 treatment (20 M) was temporally exacerbated in SelH shRNA but reversed in the scrambled shRNA MRC-5 cells 1-5 days after recovery. GFP-SelH did not relocalize to sites of oxidative DNA damage. Results from cologenic assays indicated that SelH shRNA HeLa cells were hypersensitive to paraquat and H2O2 but not to other clastogens including hydroxyurea, neocarzinostatin or camptothecin. The H2O2-induced cell death was attenuated in the presence of N-acetyl cysteine (NAC), a glutathione analogue, in SelH but not in scrambled shRNA HeLa cells. In conclusion, SelH protects against cellular senescence specifically to oxidative stress through a genome maintenance pathway involving ATM and p53.

While recent research has demonstrated that mice unable to express selenoproteins in epidermal cells or in osteo-chondroprogenitor cells showed an apparently aging phenotype characterized by alopecia or bone abnormality, respectively. Thus, a role of selenium, particularly at nutritional levels of intake, in aging is largely unknown. What is lacking is an appropriate aging model of dietary Se deprivation displaying many features of normal aging. Telomere attrition provokes DNA damage response and, subsequently, replicative senescence. Because the chromosomes of mice carry longer telomeres than those of humans, the proposed hypothesis is that lengthy telomeres preclude mice deprived of Se to display aging phenotypes and age-related disorders. To test this hypothesis, weanling late generation Terc-/- mice were fed a Se-deficient diet or the diet supplemented with selenate (0.15 ppm) throughout their life. The objectives are to elucidate the role of Se in reducing age-related loss of function and begin to identify the key molecular mediators and selenoproteins during the aging process. As evidenced by changes in metabolic markers (body weight, glucose intolerance, insulin resistance and bone structure) and aging phenotypes (gray hair, alopecia, wound healing and telomere attrition), these data strongly indicate health span deterioration by dietary Se deficiency in the short telomere mice. MicroRNAs (miRNAs) are regulators of messenger RNA stability and translation and have been proposed as biomarkers for a variety of diseases and physiological conditions, including aging. A high-throughput platform, TaqMan low density array, was used to profile more than 800 miRNAs in plasma whose expression were validated by using individual quantitative PCR. The expression of a couple of miRNAs were induced both by dietary Se deprivation and aging. Altogether, a very interesting model of aging is established in this project by deprivation of Se that displays many hallmarks of human aging and can reveal the roles of Se at nutritional levels, in contrast with previous approaches, in which these essential roles in delaying health span deterioration may have been masked by lengthy telomeres.