Longevity Briefs: Is Lifestyle More Important Than Genetics Among The Oldest Old?

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Besides a few rare genetic variants that greatly enhance or reduce lifespan, there has been a longstanding lack of scientific consensus concerning how much genetics contributes to human lifespan as opposed to lifestyle and environmental factors. Most studies identify lifestyle and environmental factors as being more important than genetics when it comes to predicting lifespan, though ‘good genes’ are probably necessary to live to exceptional ages. As an analogy, your physical fitness is far more important than your bicycle in a cycling race, but you still need a good bike to compete in the Tour de France. Twin studies estimate longevity in the general population to be at most 25% ‘heritable’, but this number has been reported to increase to around 40% when considering just the people who live past age 85.

In this study, researchers set out to investigate not only the importance of genetic vs environmental factors for longevity, but also how these risk factors influence each other.

The discovery:

The study population included 1545 participants from the China Hainan Centenarian Cohort Study (CHCCS). This was a study including Chinese participants aged 80 and above, with over half of them being centenarians (aged 100 or above) who were followed for a median of 4 years (meaning half of participants were followed for longer than this). Using various collected health data, researchers constructed a modifiable risk factor score (MRFS). This was a score based on the presence or absence of 11 modifiable risk factors such as smoking status, education, exercise and dietary patterns, each weighted according to their estimated contribution to mortality. Researchers also constructed a polygenic risk score (PRS) based on the presence of genetic variants known to correlate with longevity in previous large-scale studies. Somewhat confusingly, this means that PRS represented risk of longevity in this study (in other words, high PRS is a good thing, whereas high MRFS is bad).

Researchers found that when participants were split into thirds based on their modifiable risk score, those in the middle third had a 22% reduced risk of death when compared to those with the highest risk. Those in the lowest risk group, meanwhile, had a 40% risk reduction compared to the highest risk group. Some modifiable risk factors might have a genetic component – for example, one might have a genetic predisposition to obesity. To account for this, researchers used a statistical model that adjusted for polygenic risk score, and found that the risk reductions were effectively unchanged.

Polygenic risk score, on the other hand, was associated with a 13% reduction in mortality among participants with the highest risk (again confusingly, high ‘risk’ actually means having more pro-longevity genetic variants).

Researchers then looked at how these two scores interacted, and this is where things got more interesting. First, they found that regardless of whether participants had a high or low genetic risk score, having a low modifiable risk score was associated with a substantial mortality reduction (about 35% for low PRS and 45% for high PRS). However, the reverse was not true: among people with a high modifiable risk score, having a high PRS (better genetic variants) did not reduce mortality by a statistically significant amount.

Overall, if an 80 year-old had both a favourable genetic and modifiable risk score, they could expect to live 7 years longer than someone with two unfavourable scores. Meanwhile, an 80 year-old with a favourable genetic score and unfavourable modifiable score could only expect to gain one year of life compared to two unfavourable scores.

The implications:

This study suggests that modifiable risk factors remain more important than genetic factors, even among the oldest old. In other words, centenarians aren’t just genetic flukes – while having good genes may help you live a few years longer if you follow a healthy lifestyle, following an unhealthy lifestyle will largely eliminate the benefits of genetic variants favouring longer life.

We should keep in mind that participants were predominantly Han Chinese, and the relative importance of genetic traits could be different in other ethnicities. Since the study specifically looked at 80+ year-old participants, it excludes people who died before the age of 80, meaning that participants are likely to represent a population with healthier lifestyle and genetic characteristics than average. This was the intent of the study – to examine risk factors specifically among those who had already reached an advanced age – but it’s worth pointing out.

One potential limitation of this study is that it didn’t take how people died into consideration. Of course longevity genes aren’t going to do you much good if you get hit by a car, bitten by a snake, or consume botulinum toxin, but these aren’t the kind of environmental factors we are interested in when trying to determine the environmental contribution to lifespan. Since these kinds of deaths are associated with modifiable factors we do care about (better-educated people are less likely to die in industrial or agricultural accidents for example), they may muddy the water. Some studies have even suggested that when these ‘extrinsic’ causes of death are eliminated, genetics actually accounts for roughly half of all variation in human lifespan.