and are associated with human longevity: – a two-stage case control study using a multilocus genotyping

Fausta Di Cianni & Daniele Campa & Federica Tallaro & Cosmeri Rizzato & Francesco De Rango & Roberto Barale & Giuseppe Passarino & Federico Canzian & Federica Gemignani & Alberto Montesanto & Stefano Landi & Giuseppina Rose

Received: 24 January 2012 /Accepted: 17 April 2012 /Published online: 11 May 2012 # American Aging Association 2012

Abstract The pathways that regulate energy homeo- stasis, the mechanisms of damage repair, and the sig- naling response to internal environmental changes or external signals have been shown to be critical in modulating lifespan of model organisms and humans. In order to investigate whether genetic variation of genes involved in these pathways contribute to lon- – gevity, a two-stage case control study in two indepen- dent sets of long-lived individuals from Calabria (Italy) was performed. In stage 1, 317 SNPs in 104 genes were analyzed in 78 cases (median age 98 years) and 71 controls (median age 67 years). In stage 2, 31 π 0 candidate SNPs identified in stage 1 ( 0.1) markers

were analyzed in an independent sample composed by 288 cases (median age 92 years) and 554 controls (median age 67 years). Two SNPs, rs282070 located in intron 1 of the MAP3K7 gene, and rs2111699 lo- cated in intron 1 of the GSTZ1 gene, were significantly associated (after adjustment for multiple testing) with longevity in stage 2 (p0 1.1×10−3 and p0 1.4×10−3, respectively). Interestingly, both genes are implicated in the cellular response to internal and external envi- ronmental changes, playing a crucial role in the in- flammation processes that accompany aging. Our data confirm that long-lived subjects are endowed with genetic variants that allow them to optimize these cellular responses and to better deal with environmen- tal and internal stresses.

Fausta Di Cianni and Daniele Campa, and Stefano Landi and Giuseppina Rose have equal contribution to the study.

Electronic supplementary material The online version of this article (doi:10.1007/s11357-012-9416-8) contains supplementary material, which is available to authorized users.

Introduction

Over the past decades, developed societies have expe- rienced a gradual increase in life expectancy which sharply increased the percentage of elderly people in the population and, at the same time, increased the number of subjects who are not autonomous and are affected by invalidating pathologies (Vaupel 2010). Since this has important implications, especially from a social point of view, there is at present a considerable

D. Campa C. Rizzato F. Canzian Genomic Epidemiology Group, German Cancer Research Center Heidelberg, Germany

interest in understanding how individuals achieve a long and healthy life.

Most of gene-longevity association studies have so far focused on a single or a few candidate genes. However, given the complexity of the longevity trait, a single-locus approach may not be suitable, as each locus is likely to exert a small, if any, effect on the trait. Thus, approaches have been developed that take into account that complex traits can be caused by an intricate pattern of genetic variants, where the epistatic effects may be not negligible. Recent technological improvements in genotyping technology have made whole genome genotyping (>100,000 SNPs) more accessible. Indeed, genome-wide association studies (GWAS) are at present widely used to find genetic variants contributing to variation in human lifespan (Puca et al. 2001; Lunetta et al. 2007; Newman et al. 2010; Walter et al. 2011; Deelen et al. 2011; Nebel et al. 2011; Malovini et al. 2011). Along with GWAS, studies that consider candidate biochemical pathways consisting of many biologically related genes, and a “ ” minimal number of tagging SNPs that efficiently capture all the common genetic variation in the assayed genomic region, are also being routinely used (Passarino et al. 2006; Nebel et al. 2009; Pawlikowska et al. 2009; Flachsbart et al. 2010).

Family-based studies demonstrated the existence of an important familial and genetic component of lon- gevity. Indeed, parents, siblings, and offspring of long- lived subjects have a significant survival advantage and a higher probability to have been or to became long-lived (Gudmundsson et al. 2000; Kerber et al. 2001; Cournil and Kirkwood 2001; Perls et al. 2000, 2002; Schoenmaker et al. 2006; Willcox et al. 2006; Montesanto et al. 2011). Furthermore, the offspring of centenarians show a lower incidence of age-related diseases and a higher degree of physical functioning and autonomy, when compared to appropriately se- lected controls (Terry et al. 2003, 2004; Atzmon et al. 2006). Twin studies have found that approximately 25 % of the overall variation in human lifespan can be attributed to genetic factors (Herskind et al. 1996; Ljungquist et al. 1998; Skytthe et al. 2003), which becomes more relevant at advanced ages (Hjelmborg et al. 2006).

In the past years, there has been a surge of activity aimed at unraveling the effects of genetic variability on aging and lifespan. Specific mutations in single genes (age-1, daf2, sir2, methuselah, and p66) that extend or decrease lifespan in nematode worms (Caenorhabditis elegans), fruit flies (Drosophila), and mice have revealed evolutionary, often interconnected, conserved pathways for aging which are related to nutritional sens- ing, stress response signaling, and DNA repair/mainte- nance (Kenyon 2010; Fontana et al. 2010). The insulin/ insulin-like growth factor-I (IGF-1) signaling pathway and downstream effectors such as the forkhead box O group (FoxO) family, the sirtuin family, the target of rapamycin (TOR) kinase, are perhaps the best studied pathways involved in aging and longevity.