Levels of 25-hydroxyvitamin D in Familial Longevity: The Leiden Longevity Study

Raymond Noordam MSc, Anton J.M. de Craen PhD, Pardis Pedram MD MSc, Andrea B. Maier MD PhD, Simon P. Mooijaart MD PhD, Johannes van Pelt PhD, Edith J. Feskens PhD, Martinette T. Streppel PhD, P. Eline Slagboom PhD, Rudi G.J. Westendorp MD PhD, Marian Beekman PhD, Diana van Heemst PhD

Competing interests: None declared.

Background: Low levels of 25(OH) vitamin D are associated with various age-related diseases and mortality, but causality has not been determined. We investigated vitamin D levels in the offspring of nonagenarians who had at least one nonagenarian sibling; these offspring have a lower prevalence of age-related diseases and a higher propensity to reach old age compared with their partners.

Results: The offspring had significantly lower levels of vitamin D (64.3 nmol/L) compared with controls (68.4 nmol/L; p = 0.002), independent of possible confounding factors. There was no difference in the levels of parathyroid hormone between groups. Compared with controls, the offspring had a lower frequency of a genetic variant in the CYP2R1 gene (rs2060793) (p = 0.04). The difference in vitamin D levels between offspring and controls persisted over the 2 most prevalent genotypes of this SNP.

This article has been peer-reviewed.

Methods: We assessed anthropometric characteristics, 25(OH) vitamin D levels, parathyroid hormone levels, dietary vitamin D intake and nucleotide polymorphisms (SNPs) associated with vitamin D levels. We included offspring (n = 1038) of nonagenarians who had at least one nonagenarian sibling, and the offspring's partners (n = 461; controls) from the Leiden Longevity Study. We included age, sex, body mass index, during which blood sampling was dietary and supplemental vitamin D intake, creatinine levels as possible confounding factors.

Interpretation: Compared with controls, the offspring of nonagenarians who had at least one nonagenarian sibling had a reduced frequency of a common variant in the CYP2R1 gene, which predisposes people to high vitamin D levels. They also had lower levels of vitamin D that persisted over the 2 most prevalent genotypes. These results cast doubt on the causal nature of previously reported associations between low levels of vitamin D and age-related diseases and mortality.

Association between serum levels of 25(OH) vitamin D and familial longevity. We assessed vitamin D levels in the offspring of nonagenarian siblings whom we have previously shown to have a lower prevalence of cardiovascular diseases and lower mortality compared to age- and environmental-matched controls. We also assessed whether genetic variation in 3 genes was associated with 25(OH) vitamin D levels among the offspring of nonagenarians who had at least 1 nonagenarian sibling, and their partners.

Inhibition of proliferation and angiogenesis in cancer is linked to vitamin D. Low serum levels of 25-hydroxyvitamin D3 (25[OH] vitamin D) are associated with increased mortality, cardiovascular disease, diabetes mellitus, cancer, multiple sclerosis, allergy, asthma, infection, depression, mental illness and musculoskeletal pain. However, because of design limitations, previous studies have not been able to infer causality. A meta-analysis that included 51 studies and more than 30,000 individuals in each treatment group showed no reduction in all-cause or cardiovascular mortality with vitamin D supplementation suggesting that low serum levels of vitamin D are a consequence rather than a cause of disease.

Methods Study design: The Leiden Longevity Study was designed to identify genetic and phenotypic markers related to familial longevity. A total of 421 families were recruited, consisting of long-lived white siblings, offspring, and the offspring's partners. Families were only included if at least 2 long-lived siblings were still alive and met the age criteria (≥89 years for men; ≥91 years for women). There was no selection based on health conditions or demographic characteristics. Nonagenarian siblings had a 41% lower mortality risk compared with sporadic nonagenarians. Because it is difficult to include proper controls for this age group, the nonagenarians' offspring were asked to participate and serve as cases because they have an increased propensity to reach old age. The offspring's partners were asked to participate in the study as environment-matched controls of similar age because they tended to be similar for many of the environmental factors that might influence vitamin D levels.

Vitamin D status is routinely assessed by measurement of serum concentration of the prohormone 25(OH) vitamin D, which ishealth effects of vitamin D is conflicting, and causal relationships have not been established. Low vitamin D levels may be a marker of frailty in some cases and may be influenced by factors such as inadequate nutrition and low physical activity. Clinical trials have also failed to show a reduction in cardiovascular disease and mortality with vitamin D supplementation.