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Zmuda JM, Cauley JA, Ferrell RE. Molecular epidemiology of vitamin D receptor gene variants. Epidemiol Rev

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klotho protein, which is hypothesized to be an “aging suppressor” protein. Lifespan was signifi- cantly longer in mice overexpressing this protein.15 In contrast, mice lacking the klotho gene aged faster and had higher levels of vitamin D than con- trol 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 mortal- ity,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.

Limitations

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 par- ticipants (36%) were excluded from our analyses because information about possible confounding factors was missing; multiple imputations analy- sis 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 repre- sentative of the total study group.

Affiliations: From the Department of Gerontology and Geri- atrics (Noordam, de Craen, Pedram, Maier, Mooijaart, West- endorp, van Heemst), Leiden University Medical Center, Lei- den; the Laboratory of Clinical Chemistry, Hematology and Immunology (van Pelt), Medical Center Alkmaar, Alkmaar; the Division of Human Nutrition (Feskens, Streppel), Wageningen University, Wageningen; the Section of Molecu- lar Epidemiology (Slagboom, Beekman), Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden; and the Netherlands Consortium for Healthy Ageing (de Craen, Maier, Mooijaart, Slagboom, Westendorp, Beekman, van Heemst), the Netherlands.

Conclusion

We found that familial longevity was associated with lower levels of vitamin D and a lower fre- quency of allelic variation in the CYP2R1 gene, which was associated with higher levels of vita- min D. Future research should focus on eluci- dating the mechanisms that explain the lower 25(OH) vitamin D levels in familial longevity and other genetic variants associated with vita- min D metabolism, such as the vitamin D receptor.18–23

Contributors: Anton De Craen, Diana van Heemst, Simon Mooijaart, Andrea Maier, Rudi Westendorp, and Eline Slag- boom designed the Leiden Longevity Study and recruited the participants. Raymond Noordam, Anton de Craen, Pardis Pedram and Diana van Heemst performed the data analyses, interpreted the initial analyses and drafted the first version of the manuscript. Marian Beekman, Eline Slagboom, Johannes van Pelt, Martinette Streppel and Edith Feskens acquired the data. All authors critically commented on the initial versions of the manuscript and approved the final version submitted for publication.

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Funding: This study was supported by the Innovation Ori- ented Research Program on Genomics (SenterNovem; IGE1014 and IGE5007), the Centre for Medical Systems Biology and the Netherlands Genomics Initiative/Nether- lands Organisation for Scientific Research (05040202 Netherlands Consortium for Healthy Ageing).

Acknowledgements: The authors thank the general practi- tioners and pharmacists who participated in the Leiden Longevity Study, as well as Meriam H. van der Star and Ellen H. Bemer-Oorschot for their valuable contributions.