No Great Surprises in a Recent Study of the Causes of Variation in Human Lifespan

A recent study of human life expectancy uses a novel approach but the results offer no real surprises, confirming most of the current consensus associations. As a tour of the high level points, it is worth skimming. There are few genetic relationships that are large enough to be seen, and those that are visible are small in comparison to the impact of lifestyle choices. Excess fat tissue is just about as harmful as smoking for the obese: two months of life expectancy lost for every kilogram of excess weight. This all confirms the long-standing common wisdom when it comes to maintaining health for the long term - but also shows that the scope of the possible in the absence of rejuvenation therapies is very limited. You can move your life expectancy a few years up or a good many years down given the tools and techniques of yesterday. For more than that, we must look to the SENS research programs and similar efforts to repair the cell and tissue damage that causes aging.

Longevity is of interest to us all, and philosophers have long speculated on the extent to which it is pre-determined by fate. Here we focus on a narrower question - the extent and nature of its genetic basis and how this inter-relates with that of health and disease traits. In what follows, we shall use longevity as an umbrella term. We shall also more specifically refer to lifespan (the duration of life) and long-livedness (living to extreme old age, usually defined by a threshold, such as 90 years). Up to 25% of the variability in human lifespan has been estimated to be genetic, but genetic variation at only three loci (near APOE, FOXO3A and CHRNA3/5) have so far been demonstrated to be robustly associated with lifespan.

Prospective genomic studies of lifespan have been hampered by the fact that subject participation is often only recent, allowing insufficient follow-up time for a well-powered analysis of participant survival. On the other hand, case-control studies of long-livedness have had success and some technical appeal (focusing on the truly remarkable), but such studies can be limited and costly in their recruitment. We recently showed that the extension of the kin-cohort method to parental lifespans, beyond age 40, of genotyped subjects could be used to detect genetic associations with lifespan with some power in genomically British participants in UK Biobank (UKB).

Here we extend that approach in a genome-wide association meta-analysis (GWAMA) to discovery across UKB European- and African-ancestry populations and 24 further population studies (LifeGen), mainly from Europe, Australia and North America, to search for further genetic variants influencing longevity. We then use those GWAMA results to measure genetic correlations and carry out Mendelian randomisation (MR) between other traits and lifespan seeking to elucidate the underlying effects of disease and socio-economic traits on longevity, in a framework less hampered by confounding and reverse causality than observational epidemiology.

We replicated previous findings of genome-wide significant associations between longevity and variants at CHRNA3/5 and APOE and discovered two further associations, at LPA and HLA-DQA1/DRB1, with replication of the further associations in a long-livedness study. We found no evidence of association between lifespan and the other 10 loci previously found to suggestively associate with lifespan, despite apparent power to do so. We showed strong negative genetic correlation between coronary artery disease (CAD), smoking, and type 2 diabetes and lifespan, while education and openness to experience were positively genetically correlated. Using MR, we found that moving from the 25th to 75th percentile of cigarettes per day, systolic blood pressure, fasting insulin and body mass index (BMI) causally reduced lifespan by 5.3, 5.2, 4.1 and 3.8 years, respectively, and similarly moving from the 25th to 75th percentile of educational attainment causally extended lifespan by 4.7 years.

Our finding that a reduction in one BMI unit leads to a 7-month extension of life expectancy, appears broadly consistent with those recently published by the Global BMI Mortality Collaboration, where great effort was made to exclude confounding and reverse causalit7. We also found each year longer spent in education translates into approximately a year longer lifespan. When compared using the interquartile distance, risk factors generally exhibited stronger effects on mortality than disease susceptibility. Although both CAD and cigarette smoking show a very similar genetic correlation with lifespan, the measured effect of smoking is twice as large as that of CAD, perhaps because smoking influences mortality through multiple pathways.

Our results show that longevity is partly determined by the predisposition to common diseases and, to an even greater extent, by modifiable risk factors. The genetic architecture of lifespan appears complex and diverse and there appears to be no single genetic elixir of long life.



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