The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the “Fountain of Youth” to mediate healthful aging

Abstract

The nuclear vitamin D receptor (VDR) binds 1,25-dihydroxyvitamin D 3 (1,25D), its high affinity renal endocrine ligand, to signal intestinal calcium and phosphate absorption plus bone remodeling, generating a mineralized skeleton free of rickets/osteomalacia with a reduced risk of osteoporotic fractures. 1,25D/VDR signaling regulates the expression of TRPV6, BGP, SPP1, LRP5, RANKL and OPG, while achieving feedback control of mineral ions to prevent age-related ectopic calcification by governing CYP24A1, PTH, FGF23, PHEX, and klotho transcription. Vitamin D also elicits numerous intracrine actions when circulating 25-hydroxyvitamin D 3 , the metabolite reflecting vitamin D status, is converted to 1,25D locally by extrarenal CYP27B1, and binds VDR to promote immunoregulation, antimicrobial defense, xenobiotic detoxification, antiinflammatory/anticancer actions and cardiovascular benefits. VDR also affects Wnt signaling through direct interaction with β-catenin, ligand-dependently blunting β-catenin mediated transcription in colon cancer cells to attenuate growth, while potentiating β-catenin signaling via VDR ligand-independent mechanisms in osteoblasts and keratinocytes to function osteogenically and as a pro-hair cycling receptor, respectively. Finally, VDR also drives the mammalian hair cycle in conjunction with the hairless corepressor by repressing SOSTDC1, S100A8/S100A9, and PTHrP. Hair provides a shield against UV-induced skin damage and cancer in terrestrial mammals, illuminating another function of VDR that facilitates healthful aging.

Lymphoid Enhancer-binding Factor-1 (LEF1) Interacts with the DNA-binding Domain of the Vitamin D Receptor

“…Previous studies have demonstrated an interaction between the VDR and ␤-catenin that is dependent upon 1,25-dihydroxyvitamin D (18,25,35). Although the liganded VDR attenuates canonical Wnt signaling (35,36), ␤-catenin has been shown to be a ligand-dependent coactivator of the VDR (18).…”

“…Although the liganded VDR attenuates canonical Wnt signaling (35,36), ␤-catenin has been shown to be a ligand-dependent coactivator of the VDR (18). Traditional nuclear receptor coactivators are recruited to the VDR in response to a conformational change that occurs upon ligand binding, rendering the AF2 domain accessible for interactions with these cofactors (37).…”

The role of vitamin D supplementation on erectile function

“…[29] The VDR is a member of the thyroid hormone and retinoic acid receptor subfamily of nuclear hormone receptors that heterodimerizes with retinoid X receptor isoforms to regulate the expression of genes encoding factors which, in a variety of cell types, control functions such as proliferation, differentiation, metabolism, ion transport, and apoptosis, etc. [46] Vitamin D and immune system Erectile dysfunction is associated with an incremental inflammatory activation and inflammation plays an important pathophysiological role in both ED and CV diseases. It has been extensively debated that inflammation can exert a detrimental effect on the CV system via two pathways ie.…”

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

“…However, 1,25(OH) 2 D 3 /VDR signaling is also involved in immunity regulation, detoxification of xenobiotics, antimicrobial defense, anti-inflammatory and anticancer effects, and cardiovascular protection (420). VDR also activates the mammalian hair cycle, exemplifying an additional VDR function that promotes healthy aging (174). In addition to these multiple actions, the protective vitamin D effects involve a suppressive action on RAS (see The KLOTHO-Vitamin D-RAS Connection and Fig.…”