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