any other genetic variants associated with human aging using a genome-wide association study approach.

In recent years, there has been a growing body of evidence that genetics plays a crucial role in human aging. Up to 30% of those who live to their mid-80s have their lifespan determined by genetic variation. It is likely that an even greater genetic contribution is required for survival to older ages. As genes implicated in age-related diseases such as cancer and neuronal disease have been shown to play a role in affecting human lifespan, the authors of this study selected the 10 most promising late-onset Alzheimer's disease (LOAD) susceptibility genes identified through several recent large genome-wide association studies (GWAS). These 10 LOAD genes were tested for association with human aging using the most significant single nucleotide polymorphisms (SNPs) found in previous studies. The dataset used comprised 1385 samples with documented age at death (AAD), ranging from 58-108 years, with a mean age at death of 80.2 years.

The study found that apart from the APOE locus (rs2075650), which showed compelling evidence of association with risk on human lifespan (p < 5.27 x 10^-4), none of the other LOAD gene loci demonstrated significant evidence of association. Additionally, no genome-wide significant SNPs were discovered when age at death was used as a quantitative trait. The authors suggest that increasing sample size and statistical power will be imperative to detect genuine aging-associated variants in future studies.

The molecular genetics underlying the human aging process is complex and likely due to numerous genes and environmental factors, each exerting a small effect. Identifying genuine aging genes may uncover master genes that increase our understanding of many age-related diseases. This study highlights issues relating to the analysis of genome-wide association studies data from different centers and the bioinformatic approach required to distinguish spurious genome-wide significant signals from real SNP associations.

In conclusion, this study investigated whether known LOAD genes play a role in human aging and searched for any other genetic variants associated with human aging using a genome-wide association study approach. While the study found compelling evidence of association between the APOE locus and risk on human lifespan, no other significant evidence of association was demonstrated. The authors suggest that increasing sample size and statistical power will be imperative to detect genuine aging-associated variants in future studies.Candidate genetic risk factors associated with human survival and aging may merit further study. There are several biological pathways that have been reported to be important in human aging, including lipid/cholesterol metabolism [GO:0006629; GO:0008203] (APOE, PON1, CETP) (Barzilai et al., 2003; de Chaves and Narayanaswami, 2008; Efrat and Aviram, 2010), immune system processes [GO:0002376] (IL6 and IL10) (Jylhava and Hurme, 2009), drug metabolism [KEGG:hsa00982] (GSTT1) (Glatt et al., 2007; Taioli et al., 2001), energy metabolism in mitochondria (SIRT3) (Polito et al., 2010), and the insulin receptor signaling pathway [GO:0008286] (IGF1R, FOXO3A, KLOTHO) (Arking et al., 2005; Suh et al., 2008; Willcox et al., 2008).

2. Methods

Through collaborative efforts, we were able to draw on combined sample GWAS datasets and analyze subject-level genotype data from 1385 subjects (1047 LOAD cases and 338 controls) with documented age at death (AAD) (Table 1). The AAD histogram follows a normal distribution (Fig. 1), with a mean AAD of 80.2 years of age (SD 8.9 years). All of this data were subject to subsequent quality control (QC) procedures and analysis. The data analysis was performed using the PLINK software package (pngu.mgh.harvard.edu/~pedro/ plink) release 1.06 (Purcell et al., 2007).

Insights into human aging have been gained from studying model organisms. The extension of lifespan can be achieved by manipulating a few genes in laboratory animals, such as flies, worms, and mice (Kenyon, 2010). The insulin/insulin-like growth factor 1 (IGF-1) signaling pathway has a well-established role in influencing lifespan within model organisms.

2.1. Datasets; pooling and QC

We obtained data from nine research centers, three from the USA and six from the UK (GERAD1 Consortium). The GERAD1 sample comprised up to 3941 AD cases and 7848 controls. A subset of this sample has been used in this study, comprising 3333 cases and 1225 elderly screened controls genotyped at the Sanger Institute on the Illumina (San Diego, CA, USA) 610-quad chip. These samples were recruited by the Medical Research Council (MRC) Genetic Resource for AD (Cardiff University; Kings College, London; Cambridge University; Trinity College, Dublin), the Alzheimer's Research Trust (ART) Collaboration (University of Nottingham; University of Manchester; University of Southampton; University of Bristol; Queens University, Belfast; the Oxford Project to Investigate Memory and Ageing [OPTIMA], Oxford University); Washington University, St. Louis, MO, USA; MRC PRION Unit, University College London, London; and the South East Region AD project (LASER-AD), University College London; Competence Network of Dementia (CND) and Department of Psychiatry, University of Bonn, Germany; and the National Institute of Mental Health (NIMH) AD Genetics Initiative.