Open Access1,25‐Dihydroxyvitamin D exerts an antiaging role by activation of Nrf2‐antioxidant signaling and inactivation of p16/p53‐senescence signaling
Author(s) -
Chen Lulu,
Yang Renlei,
Qiao Wanxin,
Zhang Wei,
Chen Jie,
Mao Li,
Goltzman David,
Miao Dengshun
Publication year - 2019
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12951
Subject(s) - senescence , oxidative stress , biology , reactive oxygen species , dna damage , calcitriol receptor , apoptosis , cell growth , downregulation and upregulation , antioxidant , signal transduction , microbiology and biotechnology , endocrinology , medicine , vitamin d and neurology , biochemistry , dna , gene
We tested the hypothesis that 1,25‐dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ] has antiaging effects via upregulating nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2), reducing reactive oxygen species (ROS), decreasing DNA damage, reducing p16/Rb and p53/p21 signaling, increasing cell proliferation, and reducing cellular senescence and the senescence‐associated secretory phenotype (SASP). We demonstrated that 1,25(OH) 2 D 3 ‐deficient [1α(OH)ase −/− ] mice survived on average for only 3 months. Increased tissue oxidative stress and DNA damage, downregulated Bmi1 and upregulated p16, p53 and p21 expression levels, reduced cell proliferation, and induced cell senescence and the senescence‐associated secretory phenotype (SASP) were observed. Supplementation of 1α(OH)ase −/− mice with dietary calcium and phosphate, which normalized serum calcium and phosphorus, prolonged their average lifespan to more than 8 months with reduced oxidative stress and cellular senescence and SASP. However, supplementation with exogenous 1,25(OH) 2 D 3 or with combined calcium/phosphate and the antioxidant N ‐acetyl‐ l ‐cysteine prolonged their average lifespan to more than 16 months and nearly 14 months, respectively, largely rescuing the aging phenotypes. We demonstrated that 1,25(OH) 2 D 3 exerted an antioxidant role by transcriptional regulation of Nrf2 via the vitamin D receptor (VDR). Homozygous ablation of p16 or heterozygous ablation of p53 prolonged the average lifespan of 1α(OH)ase −/− mice on the normal diet from 3 to 6 months by enhancing cell proliferative ability and reducing cell senescence or apoptosis. This study suggests that 1,25(OH) 2 D 3 plays a role in delaying aging by upregulating Nrf2, inhibiting oxidative stress and DNA damageinactivating p53‐p21 and p16‐Rb signaling pathways, and inhibiting cell senescence and SASP.