RETRACTED: 1,25‐Dihydroxyvitamin D exerts an antiaging role by activation of Nrf2‐antioxidant signaling and inactivation of p16/p53‐senescence signaling

Abstract

We tested the hypothesis that 1,25‐dihydroxyvitamin D3[1α,25(OH)2D3] 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)2D3‐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)2D3 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)2D3exerted 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)2D3 plays a role in delaying aging by upregulating Nrf2, inhibiting oxidative stress and DNA damage，inactivating p53‐p21 and p16‐Rb signaling pathways, and inhibiting cell senescence and SASP.

1,25‐Dihydroxyvitamin D protects against age‐related osteoporosis by a novel VDR‐Ezh2‐p16 signal axis

“…We recently reported that p16 deletion can partly postpone aging in 1α(OH)ase −/− mice on a normal diet (Chen et al, ); we now assessed whether p16 deletion could also postpone aging and rescue bone aging phenotypes in 1α(OH)ase −/− mice on the rescue diet. Compound mutant mice with homozygous deletion of both p16 and 1α(OH)ase [1α(OH)ase −/− p16 −/− ] were generated and fed the rescue diet; their lifespan and bone phenotypes were then compared with 1α(OH)ase −/− on a rescue diet and wild‐type littermates.…”

The Polycomb Protein Bmi1 Plays a Crucial Role in the Prevention of 1,25(OH)2D Deficiency-Induced Bone Loss

“…Previous studies have shown that vitamin D is a potent antioxidant . We recently demonstrated that 1,25(OH) 2 D 3 could play an antioxidant role via transcriptionally upregulating Nrf2 mediated through the vitamin D receptor . Bmi1 deletion has been reported to directly induce abnormal ROS elevation and mitochondrial dysfunction, and supplementation with NAC partially corrects the Bmi1 deficiency‐induced premature aging .…”

“…This indicates that providing Bmi1, a downstream target of 1,25(OH) 2 D, can bypass the requirement for 1,25(OH) 2 D/VDR and normalize the 1,25(OH) 2 D 3 deficient phenotype. We previously showed that 1,25(OH) 2 D 3 plays an anti‐aging role by suppressing oxidative stress, DNA damage, p16‐Rb and p53‐p21 pathways, and cell senescence and SASP via upregulating Nrf2 . It has been previously reported that Bmi1 played a vital role in maintaining stem cell self‐renewal in many tissues through transcriptional repression of the p16/Rb and p53/p21 signaling pathways .…”

“…We found that 1,25(OH) 2 D 3 could stimulate, in vitro and ex vivo, the proliferation and osteogenic differentiation of BM‐MSCs derived from WT mice and promote osteoblastic bone formation in WT mice in vivo; these responses were not observed in 1,25(OH) 2 D 3 administered to BM‐MSCs or to mice with Bmi1 deficiency, suggesting that Bmi1 deletion could block 1,25(OH) 2 D‐induced bone anabolic action. We recently reported that 1,25(OH) 2 D 3 plays a vital anti‐aging role, mediated by its function in maintaining both calcium and phosphate homeostasis and redox balance . Calcium and phosphate are essential for normal cellular function, and maintaining calcium/phosphate balance is a primary action of 1,25(OH) 2 D.…”

“…The serum levels of 25(OH)D, parathyroid hormone (PTH) and 1,25(OH) 2 D in 8‐month‐old WT and Cyp27b1 +/− mice were measured following the manufacturer's instructions (Immutopics, Inc., San Clemente, CA, USA) as described …”