Seeking the Secrets of the Super Long-Lived

With analytical contributions from 23andMe Scientist David Hinds

For all human history people have been obsessed with their own mortality. Early explorers searched the globe for the mythical “fountain of youth,” and now scientists are turning that exploration inward to look at the genomes of people who’ve lived especially long lives.

Longevity runs in families, which suggests that the reason some people live longer than others has something to do with genetics. Indeed, some studies have identified a few genetic variants that occurred more frequently in people who live to be at least 95 years old, for example this small study in Japanese men. These few variants, however, don’t seem to contribute significantly to whether someone will live to be 100.

Larger studies looking broadly across the genome for common variants contributing to longevity have mostly come up empty. A four-study combined analysis published two years ago found no significant associations between common SNPs and longevity, and an initially more promising study published by Paola Sebastiani and Thomas Perls from Boston University was later retracted due to problems with the analysis.

Explorations of lifestyle factors impacting longevity have also turned up somewhat conflicting results. Most studies indicate that those who live longer have healthier diets, exercise more and experience delayed onset of disease, perhaps due to their healthier lifestyles. Smoking seems to lower one’s chances of living longer. Maintaining a healthy weight may also be associated with better cognitive function and lower risk of dementia. But other studies have found no difference in BMI or diet between long-lived individuals and the average population, suggesting that many other factors are involved.

Despite its elusiveness, the quest to uncover the secrets of longevity continues. As more people live longer, larger studies of the super long-lived will become more feasible. The New England Supercentenarian Study led by Boston University, for example, now consists of more than 60 people over the age of 110. Many of these individuals maintain physical independence and mental acuity well past the age of 100. By analyzing the DNA, lifestyle habits, and environmental surroundings of these extremely long-lived people, the researchers hope to learn about genetic as well as non-genetic factors contributing to longevity.

Unfortunately, their most recent findings — a pair of papers authored by the same group (Sebastiani and Perls) whose paper was retracted last year — contain little that can be generalized and have methodological shortcomings that call into question the conclusions they do make.

In the first study, an analysis of the genomes of two supercentenarians, Sebastiani and Perls suggest that the male supercentenarian’s extreme longevity may be due to an excess of common variants linked to longevity. They base this on the man’s enrichment for a set of previously identified longevity-associated genetic variants but without taking into account the fact that many of the variants in that set are correlated with each other. They also point to his high score on the predictive model described in their second paper, a result that is less surprising considering that the man’s data was used to develop that model in the first place. Several other of their conclusions also appear to be over-interpreted.

A close reading of Sebastiani and Perls’ other paper (the republished version of their previous retraction) reveals that the number of genetic variants that they identified for their model is actually quite close to the number of expected false positives (the authors misreport the number of expected false positives by a factor of 10). This means that many of the genetic variants that they suggest are associated with longevity are likely not to be associated with longevity at all. The model’s predictive accuracy is also very high when applied to the training data, but much lower when applied to individuals that were not included in the training set, suggesting that the model does not generalize well.

Studies like these certainly hint at the potential discoveries we could make from analyzing the genomes of people who live to be 100 or older. Can we identify common genetic variation predictive of longevity? Do rarer variants play a role? What genes and pathways are important? Ultimately, however, the latest foray into the genetics of longevity raises more questions about methodology and interpretation than satisfying answers or hypotheses. It appears the secrets of the super long-lived will remain secret for now.