Genetic studies of the past twenty years have quite effectively ruled out the idea that genetic variation has a meaningful impact on life span in the overwhelming majority of people. To a first approximation, there are no longevity genes. Rather there is a mosaic of tens of thousands of tiny, situational, interacting effects, that in aggregate produce an outcome on health that is far smaller than the results of personal choice in health and lifestyle. Near the entirety of the effects that your parents have on your health and life span stems from their influence on the important choices – whether you smoke, whether you get fat, whether you exercise.

But this is not to say that there are no longevity genes. It only constrains our expectations on their rarity, just as human demographics constrains our expectations on how large an effect size is plausible. Big databases and modern data mining can still miss rare variants and mutations. There is the example of the single family of PAI-1 loss of function mutants who might live seven years longer than their peers – possibly as a result of the influence of PAI-1 on the burden of cellular senescence. One might also suspect that the exceptional familial longevity of some Ashkanazi Jews is simply too much for good lifestyle choice to explain, though there no single variant really stands out after many years of assessment.

The commentary here notes recent research into rare variants and life span that, once again, fails to find a sizable contribution to longevity or its inheritance. At some point, we must accept that genetics is most likely not a direct and easy path to enhanced human longevity. It is an important tool in the toolkit, enabling therapies for a range of uses, but the goal of a modest adjustment to a few genes that produces an altered metabolism that yields significant gains in longevity (with minimal side-effects) may be a mirage. Time will tell.

Aging: Searching for the genetic key to a long and healthy life

For centuries scientists have been attempting to understand why some people live longer than others. Individuals who live to an exceptional old age – defined as belonging to the top 10% survivors of their birth cohort – are likely to pass on their longevity to future generations as an inherited genetic trait. However, recent studies suggest that genetics only accounts for a small fraction (~10%) of our lifespan. One way to unravel the genetic component of longevity is to carry out genome-wide association studies (GWAS) which explore the genome for genetic variants that appear more or less frequently in individuals who live to an exceptional old age compared to individuals who live to an average age. However, the relatively small sample sizes of these studies has made it difficult to identify variants that are associated with longevity.

The emergence of the UK Biobank – a cohort that contains a wide range of health and medical information (including genetic information) on about 500,000 individuals – has made it easier to investigate the relationship between genetics and longevity. Although it is not yet possible to study longevity directly with the data in the UK Biobank, several GWAS have used these data to study alternative lifespan-related traits, such as the parental lifespan and healthspan of individuals (defined as the number of years lived in the absence of major chronic diseases). These studies have been reasonably successful in identifying new genetic variants that influence human lifespan, but these variants can only explain ~5% of the heritability of the lifespan-related traits.

The GWAS have only focused on relatively common genetic variants (which have minor allele frequencies (MAFs) of ≥1%), and it is possible that rare variants might be able to explain what is sometimes called the ‘missing heritability’. Now researchers report how they analyzed data from the UK Biobank and the UK Brain Bank Network (which stores and provides brain tissue for researchers) to investigate how rare genetic variants affect lifespan and healthspan.

One type of rare genetic variant, called a protein-truncating variant, can dramatically impact gene expression by disrupting the open reading frame and shortening the genetic sequence coding for a protein. The team calculated how many of these rare protein-truncating variants, also known as PTVs, were present in the genome of each individual, and found ultra-rare PTVs (which have MAFs of less than 0.01%) to be negatively associated with lifespan and healthspan. This suggests that individuals with a small number of ultra-rare PTVs are more likely to have longer, healthier lives. This work is the first to show that rare genetic variants play a role in lifespan-related traits, which is in line with previous studies showing rare PTVs to be linked to a variety of diseases. However, these variants only have a relatively small effect on human lifespan and cannot fully explain how longevity is genetically passed down to future generations.