Telomere maintenance genes SIRT1 and XRCC6 impact age-related decline in telomere length but only SIRT1 is associated with human longevity

Sangkyu Kim • Xiuhua Bi • Malwina Czarny-Ratajczak • Jianliang Dai • David A. Welsh • Leann Myers • Michael A. Welsch • Katie E. Cherry • Jonathan Arnold • Leonard W. Poon • S. Michal Jazwinski

Received: 27 July 2011/Accepted: 20 September 2011/Published online: 5 October 2011  Springer Science+Business Media B.V. 2011

Abstract Leukocyte telomere length is widely con- sidered a biomarker of human age and in many studies indicative of health or disease. We have obtained quantitative estimates of telomere length from blood leukocytes in a population sample, confirming results of previous studies that telomere length significantly decreases with age. Telomere length was also posi- tively associated with several measures of healthy aging, but this relationship was dependent on age. We screened two genes known to be involved in telomere maintenance for association with the age-related

to identify candidate longevity-associated genes. A single-nucleotide polymorphism located in the SIRT1 gene and another in the 30 flanking region of XRCC6 had significant effects on telomere length. At each bi- allelic locus, the minor variant was associated with longer telomeres, though the mode of inheritance fitting best differed between the two genes. No statistical interaction was detected for telomere length between the SIRT1 and XRCC6 variants or between these polymorphisms and age. The SIRT1 locus was significantly associated with longevity (P \ 0.003). The frequency of the minor allele was higher in long- lived cases than in young controls, which coincides with the protective role of the minor variant for telomere length. In contrast, the XRCC6 variant was not associated with longevity. Furthermore, it did not

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J. Dai   S. M. Jazwinski (&) Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center,

Tulane Ave., SL-

, New Orleans, LA

, USA e-mail: sjazwins@tulane.edu

Department of Kinesiology, Louisiana State University, Baton Rouge, LA 70803, USA

Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA

Genetics Department, University of Georgia, Athens, GA 30602, USA

L. Myers

Department of Biostatistics, School of Public Health Tropical Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA

Institute of Gerontology, University of Georgia, Athens, GA 30602, USA

affect the association of SIRT1 with survival. The association of the same variant of with longevity was near significant (P \ 0.07) in second population. These results suggest a role of SIRT1 in linking telomere length and Given the differences between this gene and they point to the distinct impact that pathways of telomere maintenance may have on and exceptional survival.

2010). Leukocyte telomere length shows a high degree of heterogeneity among individuals at any given age (Iwama et al. 1998), and it has been associated with various physiological and pathological conditions (Aubert and Lansdorp 2008). Telomere length is heritable, with heritability estimates ranging from 44 to 80% (Slagboom et al. 1994; Andrew et al. 2006). Long-lived individuals and their offspring maintain longer telomeres compared with controls (Atzmon et al. 2010). Thus, leukocyte telomere length may serve as an endophenotype useful in developing candidate genes for association with longevity and healthy aging.

nance. They include the telomerase complex in proliferating cells and other capping proteins involved in protection of chromosome termini (Cohen et al. 2007; Palm and de Lange 2008). Telomere structure and function can be compromised by excessive telomere shortening in the absence of normal telome- rase activity or by loss of one or more of the capping proteins. It can also be corrupted by various forms of DNA damage. Dysfunctional telomeres can also trigger damage responses, including pathways of double-strand break (DSB) repair that can lead to genomic instability (Lamarche et al. 2010). Unlike germ cells and stem cells, terminally differentiated somatic cells lack telomerase activity (Hastie et al.

Introduction

Telomere length shortens with each cell division in most somatic cells, due to the ‘‘end-replication problem’’ (Harley 1991). Telomere shortening also occurs with cellular senescence and aging in vivo, but its status as a biomarker of human aging is not settled (Shawi and Autexier 2008; Mather et al. 2011). Shortened telomeres are also found in cancer cells, and they are associated with high cancer incidence and mortality, although this association may be related to the presence of the disease and may not be a good predictor of cancer risk (Pooley et al. 2010; Willeit et al. 2010; von Zglinicki 2002). Indeed, longer telomeres appear to be a risk factor for development of cancer according to some studies (Arbeev et al. 2011). Telomere length has been associated with many other factors or conditions, such as oxidative damage (von Zglinicki 2002), UV irradiation (Rochette and Brash 2010), unhealthy lifestyle (Mirabello et al. 2009), and physical and mental functions (Grodstein et al. 2008; Cherkas et al. 2008; Ludlow et al. 2008). Among several age-related decrements, cognitive decline has been associated with decreased telomere length (Devore et al. 2011).