Our study suggests that telomere shortening occurs, at least in part, in an age-independent manner, and that SIRT1 and XRCC6 define two pathways impinging on this telomere decline. Obviously operation of multiple genetic pathways for telomere maintenance adds flexibility and complexity to the age-dependent default rate of telomere attrition. One can imagine that these pathways may act as modulators of environmental factors or conditions that bear the potential to afflict telomere integrity leading to genomic instability.

Acknowledgments Supported by grants from the National Institute on Aging of the National Institutes of Health (P01AG022064 and P01AG017553) and by the Louisiana Board of Regents through the Millennium Trust Health Excellence Fund [HEF(2001-06)-02]. We thank the people of Louisiana and Georgia for participation in our study. We acknowledge the valuable recruitment, data acquisition, data management, and fiscal management efforts of M. Cervantes, D. Rouzan, T. Beard, M. Burgess, K. Grier, E. Jackson, E. McCarthy, K. Shaw, L. Strong, S. Reynolds, S. Anderson, E. Cassidy, M. Janke, T. Savla, and M. Poon. Additional authors include for The Louisiana Healthy Aging Study: M. Allen, I.E. Antikainen, A.M. Arce, J. Arceneaux, Mark A. Batzer, E.O. Boudreaux, L. Byerley, P.A. Callinan, C.M. Champagne, H. Cheng, Y.-W. Chiu, L. Cosenza, M.E. Cress, J.P. DeLany, J. Denver, A. Deutsch, M.J. deVeer, D.A. Dobrosielski, R. Ellis, A. Ermolao, M. Erwin, M. Erwin, J. Fabre, E. Fontham, M. Frisard, P. Geiselman, L. Goodwin, V. Greco, S. Hadie, T. Hall, M. Hamilton, S.W. Herke, K. Hawley, J. Hayden, K. Hebert, F. Holton, H.-C. Hsu, D. Johannsen, L. Kawasaki, B. Kimball, C. King-Rowley, M. Konkel, R. Kuhn, K. Landry, C. Lavie, D. LaVie, M. Leblanc, C. M. Lefante, L. Li, H.-Y. Lin, K. Lopez, B. McEvoy-Hein, J.D. Mountz, E. Olinde, J. Owens, K. Pedersen, A. Pellett, E. Ravussin, P. Remedios, Y. Robertson, J. Rood, H.Rothschild, R.A. Russell, E. Sandifer, B. Schmidt, R. Schwartz, D.K. Scott, J. Silva, F.N. Standberry, L.J. Su, J. Thomson, A. Tiwari, V. Toups, C. Traylor, C. Velasco- Gonzalez, J. Volaufova, C. Waguespack, J.A. Walker. X.-Y. Wang, R.H. Wood, Q. Yu, S. Zehr, and P. Zhang; for The Georgia Centenarian Study: R.C. Green, M. Gearing, W.R. Markesbery, J.L. Woodard, M.A. Johnson, J.S. Tenover, I.C. Siegler, P. Martin, M. MacDonald, C. Rott, W.L. Rodgers, D.B.

Telomere length and longevity

The yeast gene SIR2 and its orthologs are well characterized as lifespan determinants in model organisms (Guarente and Kenyon 2000), but the role of SIRT1 in human longevity hasn’t been established yet. Here, we presented statistical evidence for the involvement of SIRT1 in human longevity. Interest- ingly the same allele was found to be associated with longer telomeres, which tempts us to connect longer telomeres with longevity. However, we didn’t see any correlation of the XRCC6 SNP with longevity, even though it was associated with telomere length. One explanation is that the NHEJ in which Ku70 partic- ipates has deleterious side effects. It is also possible that there is no obligatory link between telomere attrition and lifespan and the association of SIRT1 with longevity depends on other factors. These other factors might act alone or in concert with telomere length. The elucidation of these factors, genetic and environmen- tal, will be aided by studies in additional populations. We are aware of one such study (Flachsbart et al. 2006) in which no association of SIRT1 with longevity was detected. In this regard, it is noteworthy that the size of the SIRT1 effect in the Georgia population is substantially smaller than in the Louisiana population.

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