As a general rule, one should be skeptical about any and all single studies that identify longevity-associated genes from human data. Typically the results cannot be replicated in different study populations, and the effect sizes are in any case small. Identified gene variants confer only small changes in the odds of reaching a given age. Only a handful of gene variants show up reliably in multiple studies carried out in different human populations. So, unfortunately, however interesting or novel the data in a new study, such as the association of longevity with maintenance of normal iron levels noted in today’s open access research paper, there is a good chance that it will remain unconfirmed.
Other approaches to determining the genetic contribution to longevity tend to indicate that genetic variants are much less important than lifestyle choices for near every individual. This all suggests that there exist a very large number of tiny, interacting, situational gene variants that influence longevity, but most likely nothing more promising than that. This isn’t the road to greatly extended healthy human life spans; it is a road to better understanding the fine details of aging as it occurs today, very little influenced by medicine.
Ageing phenotypes, such as years lived in good health (healthspan), total years lived (lifespan), and survival until an exceptional old age (longevity), are of interest to us all but require exceptionally large sample sizes to study genetically. Here we combine existing genome-wide association summary statistics for healthspan, parental lifespan, and longevity in a multivariate framework, increasing statistical power, and identify 10 genomic loci which influence all three phenotypes.
The effects of loci of interest on male and female lifespan are largely the same, although their effect on survival may be slightly stronger in middle age (40-60 years) compared to old age (older than 80 years). We find these loci of interest colocalise with the expression of 28 cis-genes and 50 trans-genes, some of which are known to become differentially expressed with increasing age. Lastly, we find these genes are enriched for seven hallmark gene sets (particularly haem metabolism) and 32 largely overlapping biological pathways (including apoptosis and homeostasis), and in line with the highlighted pathways, we find a causal role for iron levels in healthy life.
Haem synthesis declines with age and its deficiency leads to iron accumulation, oxidative stress, and mitochondrial dysfunction. In turn, iron accumulation helps pathogens to sustain an infection, which is in line with the known increase in infection susceptibility with age. In the brain, abnormal iron homeostasis is commonly seen in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease and multiple sclerosis. Plasma ferritin concentration, a proxy for iron accumulation when unadjusted for plasma iron levels, has been associated with premature mortality in observational studies, and has been linked to liver disease, osteoarthritis, and systemic inflammation.