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Vitamin D reduces aging and prevents disease (less oxidative stress) - Dec 2022

Mechanisms of action of vitamin D in delaying aging and preventing disease by inhibiting oxidative stress

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Vitamins and hormones https://doi.org/10.1016/bs.vh.2022.09.004


Although several recent studies have shown that vitamin D supplementation beneficially decreases oxidative stress parameters, there is no consensus on this subject in humans. Thus the role of vitamin D supplementation has recently become a controversial topic because large intervention studies in humans have not shown significant benefits. These studies have indicated that supplementation with precursor forms of active vitamin D has no effect on all-cause mortality, cannot reduce the fracture risk of the elderly, cannot reduce the incidence of cancer or cardiovascular disease in the elderly, and cannot significantly reduce the incidence risk of diabetes in the elderly. However, a link between several age-related diseases and enhanced oxidative stress has been found in mice with insufficient or deficient 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of vitamin D, which indicates that reduced active vitamin D accelerates aging and age-related diseases by increasing oxidative stress. Furthermore, supplementation of exogenous 1,25(OH)2D3, or antioxidants, could dramatically postpone aging, prevent osteoporosis and spontaneous tumor development induced by 1,25(OH)2D insufficiency or deficiency, by inhibiting oxidative stress. Mechanistically, the antioxidative effects of 1,25(OH)2D3 are carried out via the vitamin D receptor (VDR) by activation of the Nrf2 oxidative stress response pathway though transcriptional or posttranscriptional activation of Nrf2 or transcriptional upregulation of Sirt1 and Bmi1 expression. Whether discrepancies between studies in humans and in mice reflect the different forms of vitamin D examined remains to be determined.


After ultraviolet B (UVB) irradiation of skin by sunlight, vitamin D3 (cholecalciferol) can be produced by photolysis of its skin precursor, 7-dehydrocholesterol (7DHC). Vitamin D3 synthesized in skin or absorbed in the intestine from the diet or supplements, or vitamin D2 (ergocalciferol) absorbed in the intestine from food sources or dietary supplements, can the transported in the circulation to the liver bound to vitamin D binding protein. In liver, it is hydroxylated at the C-25 position of the side chain, mainly, but not exclusively, via the cytochrome P450 (CYP)-containing microsomal enzyme, Cyp2r1. This produces 25-hydroxyvitamin D 25(OH)D, the most abundant circulating form of vitamin D. 25(OH)D can then be converted to the active form of vitamin D, 1,25(OH)2D (calcitriol) by the action of the mitochondrial enzyme Cyp27b1, which encodes 25-hydroxyvitamin D 1α-hydroxylase 1α(OH)ase. Renal Cyp27b1 is the major source of circulating 1,25(OH)2D but extra-renal synthesis of 1,25(OH)2D can occur in other tissues. The active form of vitamin D, 1,25(OH)2D, then binds to its nuclear receptor, the vitamin D receptor (VDR) to carry out its functions.
Vitamin D is known to contribute to maintaining normal calcium metabolism, but may also be crucial for an extensive range of “non-classical” actions. Vitamin D deficiency may increase the incidence and severity of several age-related common diseases, including metabolic disorders that are linked to oxidative stress. These include obesity, insulin resistance and type 2 diabetes, hypertension, pregnancy complications, memory disorders, osteoporosis, autoimmune diseases, certain cancers, and systemic inflammatory diseases (Wimalawansa, 2019). The link between vitamin D status and risk of age-related diseases could be due, at least in part, to effects on oxidative stress and antioxidant status. Thus, vitamin D deficiency can impair mitochondrial function, and enhance oxidative stress and systemic inflammation. The antioxidant effect of vitamin D is among the newest suggested roles of this compound.
The antioxidant properties of vitamin D reportedly may protect cultured human endothelial cells and retinal cone cells from oxidative challenge (Tohari, Zhou, & Shu, 2016; Uberti et al., 2014). Vitamin D deficiency in early life has been reported to increase arterial blood pressure, promotes vascular oxidative stress, and induces changes in cardiac gene expression (Argacha et al., 2011). Vitamin D deficiency exacerbates hepatic oxidative stress and inflammation during acetaminophen-induced acute liver injury in mice (Wang et al., 2021), causes insulin resistance by provoking oxidative stress in hepatocytes (Tao et al., 2017) and aggravates hepatic oxidative stress and inflammation during chronic alcohol-induced liver injury in mice (Hu et al., 2020).
In humans, reduced vitamin D status was found to be associated with higher levels of oxidative stress biomarkers in obese children (Codoner-Franch et al., 2012). Depleted antioxidant status predisposes to oxidative stress, and logistic regression analysis of data from a study of forty preeclampsia patients revealed a positive association between 25(OH)D levels and plasma total antioxidant capacity (Pourghassem Gargari, Pourteymour Fard Tabrizi, Sadien, Asghari Jafarabadi, & Farzadi, 2016). Significantly lower plasma total antioxidant capacity was found in 58 vitamin D-deficient chronic hepatitis patients compared with nondeficient patients with the same disease, and a significant inverse correlation was seen between levels of plasma 25(OH)D and lipid hydroperoxides (Almeida et al., 2012). In 65 elderly subjects with type 2 diabetes or impaired fasting glucose, 25(OH)D correlated inversely with two oxidative stress biomarkers in plasma, namely, oxidized LDL and advanced protein peroxidation products (Gradinaru et al., 2012).. . .

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Deficiency of 1,25-dihydroxyvitamin D and lifespan

1α(OH)ase homozygous null mice 1α(OH)ase−/− in which the serum 1,25(OH)2D levels were undetectable and serum 25(OH)D levels were increased, develop hypocalcemia, hypophosphatemia and elevated parathyroid hormone (PTH) levels, when fed a normal diet, and survive on average for only 3 months (Chen et al., 2019). 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 a . . .

1,25(OH)2D/VDR and UCP-2/NF-κB

More than two decades ago, Wiseman reported that vitamin D reduced iron-dependent liposomal lipid peroxidation. Structural similarities between cholesterol, vitamin D3 and vitamin D2 may underlie the membrane antioxidant properties of vitamin D (Wiseman, 1993). Vitamin D may act as an antioxidant by mitochondrial function stabilization. For example, it is known that cyanide causes neurotoxicity and neuronal cell death through mitochondrial dysfunction, which at low doses of cyanide is . . . .

Vitamin D deficiency in humans has been associated with an increased risk of all-cause mortality and a variety of chronic diseases, including a variety of cancers, cardiovascular diseases, diabetes, osteoporosis, autoimmune diseases and infectious diseases (Bouillon et al., 2019; Holick, 2007). Recent studies in humans have reported that vitamin D supplementation beneficially decreases oxidative stress parameters, however, there is no consensus on this subject. A systematic review and . . . .

Despite the evidence above, the role of vitamin D supplementation has become a controversial topic because large intervention studies have not demonstrated significant benefits. Vitamin D3 supplementation has been reported to show no effect on all-cause mortality (Neale et al., 2022), cannot reduce the fracture risk of the elderly (Zhao, Zeng, Wang and Liu, 2017, LeBoff et al., 2022), cannot reduce the incidence of cancer or cardiovascular disease in the elderly (Manson et al., 2019), and . . .

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VitaminDWiki pages with OXIDATIVE STRESS in the title (6 as of Dec 2022)

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Longevity studies in VitaminDWiki

Longevity and healthspan increased by Vitamin D - many studies

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