Vitamin D and aging

https://doi.org/10.1016/j.jsbmb.2008.12.020Get rights and content

Abstract

Recent studies using genetically modified mice, such as FGF23−/− and Klotho−/− mice that exhibit altered mineral homeostasis due to a high vitamin D activity showed features of premature aging that include retarded growth, osteoporosis, atherosclerosis, ectopic calcification, immunological deficiency, skin and general organ atrophy, hypogonadism and short lifespan. The phenotype reversed by normalizing vitamin D and/or mineral homeostasis. Thus, hypervitaminosis D due to an increased 1α-hydroxylase activity seems to be a cause of the premature aging.

In several studies, we have described that a complete or partial lack of vitamin D action (VDR−/− mice and CYP27B1−/−) show almost similar phenotype as FGF23−/− or Klotho−/− mice. VDR mutant mice have growth retardation, osteoporosis, kyphosis, skin thickening and wrinkling, alopecia, ectopic calcification, progressive loss of hearing and balance as well as short lifespan. CYP27B1−/− mice do not show alopecia nor balance deficit, which might be apoVDR-dependent or calcidiol-dependent. The features are typical to premature aging. The phenotype is resistant to a normalization of the mineral homeostasis by a rescue diet containing high calcium and phosphate. Taken together, aging shows a U-shaped dependency on hormonal forms of vitamin D suggesting that there is an optimal concentration of vitamin D in delaying aging phenomena.

Our recent study shows that calcidiol is an active hormone. Since serum calcidiol but not calcitriol is fluctuating in physiological situations, calcidiol might determine the biological output of vitamin D action. Due to its high serum concentration and better uptake of calcidiol-DBP by the target cells through the cubilin–megalin system, calcidiol seems to be an important circulating hormone. Therefore, serum calcidiol might be associated with an increased risk of aging-related chronic diseases more directly than calcitriol.

Aging and cancer seem to be tightly associated phenomena. Accumulation of damage on DNA and telomeres cause both aging and cancer, moreover the signalling pathways seem to converge on tumour suppressor protein, p53, which seems to be regulated by vitamin D. Also, the insulin-like growth factor signalling pathway (IGF-1, IGFBPs, IGFR) and fibroblast growth factor-23 (FGF-23) regulate growth, aging and cancer. Vitamin D can regulate these signalling pathways, too. Also NF-κB and telomerase reverse transcriptase (TERT) might be molecular mechanisms mediating vitamin D action in aging and cancer.

Calcidiol serum concentrations show a U-shaped risk of prostate cancer suggesting an optimal serum concentration of 40–60 nmol/L for the lowest cancer risk. Therefore, it is necessary to study several common aging-associated diseases such as osteoporosis, hypertension and diabetes known to be vitamin D-dependent before any recommendations of an optimal serum concentration of calcidiol are given.

Introduction

Aging is a complex biological process at molecular, cellular and organismal level. It is generally characterized by the declining ability to respond to stress, increasing homeostatic imbalance and an increased risk of aging-associated diseases. Although the cellular and DNA damages accumulating with time might be the cause of aging and cancer, the weakening cellular repair mechanisms play an important role [1]. On the other hand, hormonal decline has also thought to be important for aging [2], [3], [4]. Sex steroids (androgens and estrogens) are known to decrease gradually with aging and might be involved in the aging. Aging of the skin is dependent on the serum level of sex steroids [5]. Hormonal forms of vitamin D also decline with advancing age due to decreased synthesis and increased degradation [6]. Other hormones such as insulin-like growth factor-1 (IGF-1) and fibroblast growth factor-23 (FGF-23) are involved in aging processes, too [1], [7]. IGF-1 and serum calcidiol seem to be clinically clearly associated and involved in the development of the metabolic syndrome, which can be regarded as an aging-related disease [8], [9]. During the past 10 years, there has been accumulating evidence that a high vitamin D3 activity is the key mediator of premature aging [6], [7], [10], [11], [12], [13], [14], [15]. It seems that an excess production of calcitriol plays a crucial role in the aging caused by the FGF-23 mutation [14]. All the aging characteristics can be completely reversed by normalizing the serum calcitriol concentration and almost completely by normalizing the mineral homeostasis.

Rickets, osteomalasia, osteoporosis and bone fractures are the well-known outcomes of vitamin D3 insufficiency or deficiency [16], [17], [18]. Furthermore, vitamin D3/calcidiol insufficiency appears to be associated with several aging-related, chronic diseases [19] (summarized in Fig. 1). This is a review of literature and of our own studies related to high or low vitamin D3 action and development of premature aging or aging-related diseases.

Section snippets

Both calcidiol and calcitriol are active hormones

It seems that calcidiol reflects better the clinical situations than calcitriol, but calcidiol according to present paradigm is an inactive prohormone, whereas calcitriol is an active hormone. The discrepancy was not understandable before our recent study [20] suggesting that both are active hormones and act together. The present paradigm, that circulating calcitriol is the active hormone and 25-hydroxyvitamin D3 needs to be activated within the cell through the action of 1α-hydroxylase

Aging and cancer are closely associated

The aging process is influenced by the environment and by the genetic factors. Peto stated in1985 that there is no such thing as aging, and cancer is not related to it [27]. Recent findings support his view that cancer and aging are closely linked (reviewed by Irminger-Finger [1]). On the cellular level, aging and carcinogenesis is thought to be due to an accumulation of damages especially on DNA. Reactive oxygen species are involved in carcinogenesis, aging and DNA and protein damages [28],

Hypervitaminosis D3 and aging

During the past 10 years, Klotho [10], [11], [12] and fibroblast growth factor 23 (FGF-23) [14] have become key mediators of early aging and their effects appear to be mediated by an excess of calcitriol [14], [15]. The early aging phenotype includes thin skin, intestinal atrophy, spleen atrophy, muscle atrophy, weight loss, short life span, osteoporosis and ectopic calcification in blood vessels (atherosclerosis). Because of the tight control of hormonal forms of vitamin D3 by 24-hydroxylase,

Hypovitaminosis D and aging

It has been demonstrated that vitamin D3 insufficiency can increase the risk of such aging-related diseases as osteoporosis [16], [17], [18], cancers [51], muscle weakness [52], [53], respiratory infections [54], autoimmune diseases [55], diabetes [56], hypertension [57], [58], [59], cardiovascular diseases, [60], [61] and congestive hearth failure [62] (Fig. 1). Hypovitaminosis D3 is independently associated with all-cause mortality [63]. Metabolites of vitamin D3 are also known as

Vitamin D and cancer

Numerous in vitro and in vivo studies have shown that vitamin D potently inhibits cell proliferation in a wide range of normal cell types and carcinomas such as cancer of the mammary gland, prostate, colon, skin and brain, myeloid leukaemia cells and many others [77]. Epidemiological studies suggest that nearly 20 types of cancer are inversely correlated with solar ultraviolet-B levels or with the availability of vitamin D [78]. Several studies in vitro suggest that hormonal forms of vitamin D3

Conclusions

In conclusion, an aging hypothesis based on hypo- or hypervitaminosis D is proposed (Fig. 3). The risk of aging related diseases, especially that of cancer is dependent on general aging processes and therefore they appear earlier during a vitamin D imbalance. Because of the high serum concentration, calcidiol instead of calcitriol appears to be the main circulating hormone, which only can enter the target cells through megalin–cubilin system and which can be converted in all cells to

Acknowledgements

The study was supported by the grants from Tampere University Hospital and from the Finnish Cancer Foundation.

References (89)

  • E. Kallay et al.

    Vitamin D receptor activity and prevention of colonic hyperproliferation and oxidative stress

    Food Chem. Toxicol.

    (2002)
  • A. Tomas-Loba et al.

    Telomerase reverse transcriptase delays aging in cancer-resistant mice

    Cell

    (2008)
  • R. Kommagani et al.

    Differential regulation of vitamin D receptor (VDR) by the p53 Family: p73-dependent induction of VDR upon DNA damage

    J. Biol. Chem.

    (2007)
  • K.A. Tuohy et al.

    Hypercalcemia due to excess 1 25-dihydroxyvitamin D in Crohn's disease

    Am. J. Kidney Dis.

    (2005)
  • M. Montero-Odasso et al.

    Vitamin D in the aging musculoskeletal system: an authentic strength preserving hormone

    Mol. Aspects Med.

    (2005)
  • I. Laaksi et al.

    An association of serum vitamin D concentrations <40 nmol/L with acute respiratory tract infection in young Finnish men

    Am. J. Clin. Nutr.

    (2007)
  • E. Hypponen et al.

    Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study

    Lancet

    (2001)
  • R. Scragg et al.

    Plasma 25-hydroxyvitamin D3 and its relation to physical activity and other heart disease risk factors in the general population

    Ann. Epidemiol.

    (1992)
  • A.V. Kalueff et al.

    Behavioural anomalies in mice evoked by “Tokyo” disruption of the Vitamin D receptor gene

    Neurosci. Res.

    (2006)
  • A. Mackay-Sim et al.

    Schizophrenia, vitamin D, and brain development

    Int. Rev. Neurobiol.

    (2004)
  • J. McGrath et al.

    Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study

    Schizophr. Res.

    (2004)
  • L.D. Brewer et al.

    Chronic 1alpha 25-(OH)2 vitamin D3 treatment reduces Ca2+-mediated hippocampal biomarkers of aging

    Cell Calcium

    (2006)
  • W.B. Grant

    A meta-analysis of second cancers after a diagnosis of nonmelanoma skin cancer: additional evidence that solar ultraviolet-B irradiance reduces the risk of internal cancers

    J. Steroid Biochem. Mol. Biol.

    (2007)
  • T. Ylikomi et al.

    Antiproliferative action of vitamin D

    Vitam. Horm.

    (2002)
  • P. Tuohimaa et al.

    Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: vitamin D as a possible explanation

    Eur. J. Cancer

    (2007)
  • C.J. Luscombe et al.

    Exposure to ultraviolet radiation: association with susceptibility and age at presentation with prostate cancer

    Lancet

    (2001)
  • I. Irminger-Finger

    Science of cancer and aging

    J. Clin. Oncol.

    (2007)
  • S.J. Russell et al.

    Endocrine regulation of ageing

    Nat. Rev. Mol. Cell Biol.

    (2007)
  • N.H. Baum et al.

    Testosterone replacement in elderly men

    Geriatrics

    (2007)
  • S. Bayne et al.

    Potential roles for estrogen regulation of telomerase activity in aging

    Ann. N.Y. Acad. Sci.

    (2007)
  • E. Makrantonaki et al.

    Molecular mechanisms of skin aging: state of the art

    Ann. N.Y. Acad. Sci.

    (2007)
  • O.M. Kuro

    Endocrine FGFs and Klothos: emerging concepts

    Trends Endocrinol. Metab.

    (2008)
  • N.G. Forouhi et al.

    Baseline serum 25-hydroxy vitamin D is predictive of future glycaemic status and insulin resistance: the MRC Ely prospective study 1990–2000

    Diabetes

    (2008)
  • E. Hypponen et al.

    Power C. 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British Birth Cohort

    Diabetes

    (2008)
  • M. Kuro-o et al.

    Mutation of the mouse klotho gene leads to a syndrome resembling ageing

    Nature

    (1997)
  • D.E. Arking et al.

    Association of human aging with a functional variant of klotho

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
  • H. Kurosu et al.

    Suppression of aging in mice by the hormone Klotho

    Science

    (2005)
  • M.S. Razzaque et al.

    Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process

    FASEB J.

    (2006)
  • H. Tsujikawa et al.

    Klothoa gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system

    Mol. Endocrinol.

    (2003)
  • J.P. Ruohola et al.

    Association between serum 25(OH)D concentrations and bone stress fractures in Finnish young men

    J. Bone Miner. Res.

    (2006)
  • P. Tuohimaa et al.

    Aging and cancer

    Nutr. Rev.

    (2008)
  • Y.R. Lou et al.

    25-hydroxyvitamin D3 is an active hormone in human primary prostatic stromal cells

    FASEB J.

    (2004)
  • D.G. Albertson et al.

    Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene

    Nat. Genet.

    (2000)
  • R. Peto et al.

    There is no such thing as ageing, and cancer is not related to it

    IARC Publ.

    (1985)
  • Cited by (103)

    • Protective effect of vitamin D on oxidative stress in elderly people

      2020, Aging: Oxidative Stress and Dietary Antioxidants
    • Slow aging in mammals—Lessons from African mole-rats and bats

      2017, Seminars in Cell and Developmental Biology
      Citation Excerpt :

      Vitamin D signaling is involved in the regulation of cell proliferation and differentiation, mineral (including calcium) metabolism, immune responses, and brain function [84]. The pathway is highly conserved across the animal kingdom, and both deficiency and excess of vitamin D are associated with either premature aging or age-associated diseases such as osteoporosis and osteomalacia, Alzheimer’s disease, and autoimmune diseases such as diabetes in vertebrates, including humans (summarized, e.g., by Tuohimaa [85]). Although both mole-rats and bats possess the full molecular repertoire of a functional vitamin D endocrine system, they can be regarded as naturally vitamin D–deficient animals because the endogenous production of vitamin D depends on exposure to sunlight, and both mole-rats (subterranean habitat) and bats (nocturnal activity) occupy light-deprived ecological niches.

    View all citing articles on Scopus

    Lecture presented at the ‘18th International Symposium of the Journal of Steroid Biochemistry and Molecular Biology’, 18–21 September 2008, Seefeld, Tyrol, Austria.

    View full text