We found that the offspring of nonagenarians who had at least 1 nonagenarian sibling had lower levels of vitamin D than controls, independent of possible confounding factors and SNPs associated with vitamin D levels. We also found that the offspring had a lower frequency of common genetic variants in the CYP2R1 gene; a common genetic variant of this gene predisposes people to high vitamin D levels. These findings support an association between low vitamin D levels and familial longevity.
Previous research has shown that vitamin D has various functions, including bone mineralization, differentiation of immune cells, and inhibition of proliferation and angiogenesis in cancer.2
Cross-sectional and longitudinal studies have linked low serum levels of vitamin D to a higher risk of death, cardiovascular disease and cognitive decline. Because of limitations in the design of these studies, it was not possible to infer a causal relation between vitamin D and outcome. In the case of mortality, low serum vitamin D levels might be a marker of frailty, because ill patients are expected to spend less time outdoors and may have inadequate nutrition. A similar phenomenon might be involved in the proposed relation between low vitamin D and the onset of cardiovascular disease, in which, for example, BMI and low physical activity (which influences vitamin D levels, via lower exposure to sun light) might be residual confounding factors.4,14
A doubtful causal association between vitamin D and health outcomes is supported by clinical trials showing a lack of reduction in cardiovascular disease and mortality after vitamin D supplementation.8
In our study population, 25(OH) vitamin D levels were not associated with disease history. We found that the offspring of nonagenarian siblings, who had a lower prevalence of cardiovascular diseases and a lower mortality rate compared to controls,9,10
had lower levels of vitamin D. The difference in vitamin D levels between offspring and their partners was not explained by any of the potential confounding factors that we investigated. Our results might indicate that low levels of vitamin D are associated with an increased propensity to reach a very old age.
Vitamin D is produced in the skin in response to ultraviolet B rays and can also be obtained from food and supplements. In the liver, vitamin D is converted to 25(OH) vitamin D, which is later converted in the kidneys to the active hormone that regulates calcium metabolism (1,25 dihydroxyvitamin D [1,25(OH)2
vitamin D]). Vitamin D status is routinely assessed by the measurement of the serum concentration of 25(OH) vitamin D, which is the most stable and abundant metabolite of vitamin D in circulation; this metabolite reflects both vitamin D intake and endogenous production. Because levels of the active hormone 1,25(OH)2
vitamin D do not correlate well with overall vitamin D status, levels of this metabolite are not considered clinically useful.1
The synthesis of 1,25(OH)2 vitamin D is tightly regulated and is stimulated by serum parathyroid hormone and by low levels of calcium and phosphorus. We do not know whether the lower levels of 25(OH) vitamin D observed in the offspring will also result in lower levels of the active hormone 1,25(OH)2 vitamin D. We found that serum parathyroid hormone levels were lower in offspring in the analyses restricted to only couples, but not in the other analyses.
Genetically determined differences may exist in vitamin D metabolism. Indeed, the CYP2R1 gene plays a role in the conversion of vitamin D to 25(OH) vitamin D. However, although the allele frequency of a common genetic variant in this gene was underrepresented in the offspring, the difference in serum vitamin D levels between offspring and controls persisted when we controlled for this genetic variant.
Literature on other potential mechanisms explaining our findings is scarce. We speculate that offspring might have a higher expression of the klotho protein, which is hypothesized to be an “aging suppressor” protein. Lifespan was significantly longer in mice overexpressing this protein.15
In contrast, mice lacking the klotho
gene aged faster and had higher levels of vitamin D than control mice. Elimination of vitamin D from food slowed the aging process, suggesting that vitamin D is directly linked to aging.16,17
A study involving humans reported that high levels of serum klotho protein were associated with a lower rate of mortality,18
lower risk of cardiovascular disease,19
and stronger grip strength in older adults.20
Further research should elucidate whether the expression level of klotho explains the findings presented in this study.
A limitation of this study is that data on tanning bed use and sun exposure were available only for a small subpopulation of participants. However, the subpopulation was random, and vitamin D levels were similar to those in the whole study population. A second limitation is that many participants (36%) were excluded from our analyses because information about possible confounding factors was missing; multiple imputations analysis was not possible for this group. However, the difference in vitamin D levels was also present among the excluded participants, suggesting that the participants included in our study are representative of the total study group.
We found that familial longevity was associated with lower levels of vitamin D and a lower frequency of allelic variation in the CYP2R1
gene, which was associated with higher levels of vitamin D. Future research should focus on elucidating the mechanisms that explain the lower 25(OH) vitamin D levels in familial longevity and other genetic variants associated with vitamin D metabolism, such as the vitamin D receptor.18–23