Studies of correlations between longevity, mortality, and specific single nucleotide polymorphisms (SNPs) in humans are becoming more common, but as this one demonstrates they reinforce just how complicated the genetics of metabolism and longevity are. There are many, many correlations with small effects, the majority of which are different in different human populations: "Here we explore association with human longevity of common genetic variation in three major candidate pathways: GH/IGF-1/insulin signaling, DNA damage signaling and repair and pro/antioxidants by investigating 1273 tagging SNPs in 148 genes composing these pathways. In a case-control study of 1089 oldest-old (age 92-93) and 736 middle-aged Danes we found 1 pro/antioxidant SNP, 5 GH/IGF-1/INS SNPs, and 5 DNA repair SNPs to be associated with longevity after correction for multiple testing. In a longitudinal study with 11years of follow-up on survival in the oldest-old Danes we found 2 pro/antioxidant SNPs, 1 GH/IGF-1/INS SNP and 3 DNA repair SNPs to be associated with mortality in late life after correction for multiple testing. ... No formal replications were observed when investigating the 11 SNPs from the case-control study in 1613 oldest-old (age 95-110) and 1104 middle-aged Germans. ... In conclusion, the present candidate gene based association study, the largest to date applying a pathway approach, not only points to potential new longevity loci, but also underlines the difficulties of replicating association findings in independent study populations and thus the difficulties in identifying universal longevity polymorphisms."