An Example of Failure to Replicate Associations Between Gene Variants and Longevity in Humans

Longevity associated genes are not in fact robustly longevity-associated, as this study demonstrates, the researchers failing to find an association for even the very few gene variants thought to be fairly reliable in other data. The overwhelming majority of associations found between gene variants and human longevity have very small effects and cannot be replicated in different study populations, even in the same region of the world. This means that the impact of any individual gene variant on human longevity is tiny at best and non-existent at worst, and in either case that small effect is very dependent on other factors, either genetic or environmental. This suggests to me that comparative genetics, such as the study of centenarian biochemistry and cellular metabolism, is not a field with the potential to move the needle on human longevity; translating small and dubious effects into therapies capable of reproducing those effects just doesn't make sense when there are other, much better approaches to the treatment of aging.

In this study we explored the association between aging-related phenotypes previously reported to predict survival in old age and variation in 77 genes from the DNA repair pathway, 32 genes from the growth hormone 1 / insulin-like growth factor 1 / insulin (GH/IGF-1/INS) signalling pathway and 16 additional genes repeatedly considered as candidates for human longevity: APOE, APOA4, APOC3, ACE, CETP, HFE, IL6, IL6R, MTHFR, TGFB1, SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14.

Altogether, 1,049 single nucleotide polymorphisms (SNPs) were genotyped in 1,088 oldest-old (age 92-93 years) Danes and analysed with phenotype data on physical functioning (hand grip strength), cognitive functioning (mini mental state examination and a cognitive composite score), activity of daily living and self-rated health.

Five SNPs showed association to one of the phenotypes; however, none of these SNPs were associated with a change in the relevant phenotype over time (7 years of follow-up) and none of the SNPs could be confirmed in a replication sample of 1,281 oldest-old Danes (age 94-100). Hence, our study does not support association between common variation in the investigated longevity candidate genes and aging-related phenotypes consistently shown to predict survival. It is possible that larger sample sizes are needed to robustly reveal associations with small effect sizes.



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