3. Vitamin D–Oxidative Stress
1,25(OH)
2D is involved in many intracellular genomic activities and biochemical and enzymatic reactions, whereas D
3 and 25(OH)D concentrations are crucial to diffuse these compounds into immune and other target cells. For example, calcitriol subdues the renin-angiotensin-aldosterone hormonal (RAS) axis. It stimulates the immune system to overcome inflammation and oxidative stress, enabling the destruction of pathogenic microbes, minimising cell damage from oxidative stress secondary to day-to-day exposure to toxic agents, and controlling the ageing process
[23][24].
Physiologic circulating 25(OH)D concentration (i.e., between 50 and 80 ng/mL) enhances the expression of the nuclear factor, erythroid-2(Nf-E2)-related factor 2(Nrf2)
[25][26][27] and also enhances Klotho, a phosphate regulating hormone and also an antiaging protein
[28][29]. It also facilitates protein stabilisation
[30]. Klotho also regulates cellular signalling systems, including forming antioxidants
[31]. Consequently, in mice, functional abnormalities of the Klotho gene or removal of it through gene knock-out procedures induce premature ageing syndrome
[32]. In animal studies, inefficient FGF23 and/or Klotho expression have been shown to cause premature ageing.
Figure 1 is a schematic representation of various factors and their interactions that influence ageing and death.
Figure 1. Environmental, microbial, biological, and chemical interactions modify the DNA and mitochondrial functions and epigenetics, which modifies the ageing process. Vitamin D deficiency is one of the factors that enhances this oxidative-stress cycle and accelerates premature cell death [abbreviations used: DNA = deoxyribonucleic acid; iNOS = inducible nitric oxide enzyme].
3.1. Influences of Vitamin D on Oxidative Stress
When vitamin D is adequate, harmful intracellular oxidative stress-related activities are downregulated. Having suboptimal concentrations of serum 25(OH)D enhances oxidative stress and augments intracellular oxidative damage, including DNA and the rate of apoptosis. The intracellular Nrf2 level is inversely correlated with the accumulation of mitochondrial ROS
[23][33] and the consequent escalation of oxidative stress. Thus, Nrf2 plays a key role in protecting cells against oxidative stress, modulated by vitamin D
[34][35].
In addition, vitamin D supports cellular oxidation and reduction (redox) control by maintaining normal mitochondrial functions
[36][37][38]. Loss in the redox control of the cell cycle may lead to aberrant cell proliferation, cell death, the development of neurodegenerative diseases, and accelerated ageing
[38][39][40][41]. Peroxisome proliferator-activated receptor-coactivator 1α (PGC-1α) is bound to mitochondrial deacetylase (SIRT3). PGC-1α directly couples to the oxidative stress cycle
[42] and interacts with Nrf2. This complex regulates the expression of SIRT3; this process is influenced by vitamin D metabolites
[43]. In addition, the activation of the mitochondrial Nrf2/PGC-1α-SIRT3 path is dependent on intracellular calcitriol concentrations.
Calcitriol has overarching beneficial effects in upregulating the expression of antioxidants and anti-inflammatory cytokines
[44], consequently protecting the tissues from toxins, micronutrient deficiency-related abnormalities, and parasitic (helminths) and intracellular microbe-induced harm
[45]. It regulates ROS levels through its anti-inflammatory effects and mitochondrial-based expression of antioxidants through cell-signalling pathways
[40][46].
4. Role of Vitamin D in Neutralization of Toxins and Aging-Related Compounds
4.1. The Concept and the Process of Aging
Ageing generally refers to the biological process of growing older, also known as cellular senescence, which is a complex process. Advancing age, beginning from adulthood, is associated with a gradual decline of homeostatic mechanisms in maintaining health as described above, physiological functions and the capacity for regeneration
[47]. Ageing has also been quantified from mortality curves using mathematical modelling; for example, by using the Gompertz equation m(t) = Ae
Gt, for which m(t) = the mortality rate as a function of time or age (
t); A = extrapolated constant to birth or maturity; G = the exponential (Gompertz) mortality rate coefficient]
[48]. Many life insurance companies have used such to assess health risks.
Moreover, efficiency and the functions of the body decline after sexual maturity, suggesting a connection between the ageing process after fulfilling the procreation needs in vertebrates, including humans. Most age-related functions are irreversible, partly due to the accumulation of oxidative stress-related toxic products, methylation of DNA, and mitochondrial damage, and the inability to repair these wholly and efficiently, leading to reduced viability of cells and consequent accelerated cell death
[49]. There is also a parallel decline in the immune system functions (i.e., immune-senescence) and an increase in systemic inflammation, demonstrable with an age-related increase of circulating pro-inflammatory cytokines
[50][51]. These are likely to contribute to many age-related disorders, such as Alzheimer’s disease, cardiovascular, renal and pulmonary diseases, and susceptibility to autoimmunity and infections, especially the SARS-CoV-2 virus
[50][51].
Many bodily functions slow with ageing, including response and reaction time; access to and the memory capacity; pulmonary, gastrointestinal, and cardiovascular capacities; and even the ability to naturally generate vitamin D in the skin. While age is perhaps the most potent risk factor for death, age-related disorders are the number one cause of death among older adults. The presence of vitamin D deficiency significantly aggravates this scenario.
Chronic hypovitaminosis D is associated with cardiovascular and metabolic dysfunctions and premature deaths
[52], even among children
[53]. In children, severe hypovitaminosis D increase Kawasaki-like syndrome and multi-system inflammatory disease following severe infections like COVID-19. Overall data suggest that vitamin D deficiency could be considered important comorbidity and a risk factor not only for infections but also for premature death (all-cause mortality)
[52][53][54][55]. Strong inverse relationships have been reported with vitamin D status with all-cause mortality
[56][57][58], and cancer
[58][59][60][61], etc.
4.2. Effects of Vitamin D on Apoptosis and Aging
The generalised chronic inflammatory and oxidative processes are known to cause cellular and DNA damage and increase apoptosis
[62], as in the case of interstitial tubular cell damage in chronic kidney disease, and thus contribute to the ageing process
[24][27][63]. In addition, hypovitaminosis D and dysfunctional mitochondrial activity significantly increase inflammation
[46][64][65]. As mentioned above, hypovitaminosis D increases the expression of inflammatory cytokines
[63][66]. Hypovitaminosis D increases the expression of inflammatory cytokines
[44][67], including tumour necrosis factor-
α (TNF-
α) and many other cytokines, increasing the expression of the InsP3Rs and resulting in increased intracellular Ca
2+, causing accelerated cellular damage, apoptosis and ageing
[39][68].
In addition, many of the genes in the Klotho–Nrf2 regulatory system has multiple functions that are regulated by calcitriol
[29][35][38]. These include increasing intracellular antioxidant concentration, and maintaining the redox homeostasis and a normal intracellular-reduced environment by removing excess ROS, thereby down-regulating the oxidative stress
[69]. In addition, the vitamin D-dependent expression of
γ-glutamyl transpeptidase, glutamate-cysteine ligase, and glutathione reductase contributes to the synthesis of the key redox agent glutathione (an essential antioxidant of low–molecular-weight thiol)
[67][70]. In contrast, severe adverse outcomes occur in hypovitaminosis D.
Vitamin D also upregulates the expression of glutathione peroxidase that converts the ROS molecule H
2O
2 to water
[70]. Vitamin D affects the formation of glutathione through activation of the enzyme glucose-6-phosphate dehydrogenase
[70]—which downregulates nitrogen oxide (NOx), a potent precursor for generating ROS that converts O
2− to H
2O
2 and upregulating superoxide dismutase (SOD). These vitamin D-related actions collectively reduce the burden of intracellular ROS.
Telomeres are repetitive DNA sequences that cap the ends of linear chromosomes protecting DNA molecules
[71]. Ageing is associated with the shortening of telomeres, including in stem cells. The amount of telomerase present is gradually become too short to maintain its protective effects on DNA during cell division, and thus cell apoptosis. While vitamin D deficiency increases inflammation and intracellular oxidative stress, it also enhances the rate of telomere shortening during cell proliferation, resulting in genomic instability
[18].
4.3. Hypovitaminosis D Leads to Deranged Mitochondrial Respiration
Intracellularly generated calcitriol in peripheral target cells is essential for maintaining physiological respiratory chain activity in mitochondria, facilitating energy generation
[72][73]. In addition, 25(OH)D regulates the expression of the uncoupling protein attached to the mitochondria’s inner membrane that regulates thermogenesis
[74][75][76]. Chronic vitamin D deficiency reduces the capacity of mitochondrial respiration through modulating nuclear mRNA
[77][78][79]. The latter also downregulates the expression of complex I of the electron transport chain and thus reduces the formation of adenosine triphosphate (ATP)
[40][68], another mechanism that increases cancer risks. Consequently, a low level of electron transport chain increases ROS formation and oxidative stress, a common phenomenon following acute and chronic exposure to toxins and many chronic diseases and seen in ageing
[39][80][81].
The accumulation of intracellular toxins and/or age-related products disrupts signalling pathways, including the G protein-coupled systems, caspases, mitochondria, and the death receptor-linked mechanisms, triggering cell apoptosis and premature cell death: a known phenomenon in ageing
[82][83]. The process is aggravated by stimulating G proteins leading to activation of downstream pathways, including protein kinase A and C (PKA and PKC), phosphatidylinositol-3-kinase (PI3-kinase), Ca
2+ and MAP kinase-dependent systems, tyrosine phosphorylation
[68][83], and work additively, aiding cancer genesis
[61] and accelerating the aging process.
4.4. Calcitriol Protects Mitochondrial Functions
Toxins, chronic metabolic abnormalities, and ageing processes are also known to cause mitochondrial dysfunction
[39][75][76][77][84]. Abnormal mitochondria produce suboptimal amounts of ATP while generating excess ROS, creating a vicious cycle of enhanced and persisting effects from excessive oxidative stress
[75][76][85]. These events cause DNA damage (and impairment of DNA repair enzymes), premature cell death, and accelerated ageing
[35][39]. Cumulating data suggest that mitochondrial dysfunction is likely fueled by sustained intracellular inflammation, as in the case of vitamin D deficiency
[48][63][65][86].
Dysfunctional mitochondria also have reduced intracellular Ca
2+ buffering capacity, resulting in increased (and fluctuating) intracellular Ca
2+ levels, which are “cytotoxic” and contribute to the impairment of cell regeneration and the sustenance of several chronic diseases
[77][84]. Sub-physiological concentrations of calcitriol enhance and maintain oxidative stress, autophagy, inflammation, mitochondrial dysfunction (low ATP generation), adverse epigenetic changes, DNA damage, intracellular Ca
2+, and generation and signalling of ROS. Therefore, sustained, adequate serum 25(OH)D concentrations (i.e., above 50 ng/mL) allow target tissues to remain healthy and overcome toxic effects and destructive processes
[41][44][46]. Multiple benefits of controlling excessive oxidative stress are illustrated in
Figure 2.
Figure 2. Oxidative stress is harmful to cells. Controlling oxidative stresses through vitamin D adequacy leads to cellular and organ protection and reduces ageing effects [abbreviations: CNS = central nervous system; DNA = deoxyribonucleic acid; MI = myocardial infarction; PVD = peripheral vascular diseases].