A massive study from the University of Oxford has evaluated the relative impact of genetic and non-genetic factors on aging, mortality, and disease prevalence.
A deeper dive
The question of how strongly genes affect our longevity has been asked before, and the emerging answer is not very much [1]. Most of the variation in human lifespan seems to come from extrinsic factors, such as smoking and physical activity. However, quantifying the correlation between these myriad factors and longevity is tricky. In this new study coming from the University of Oxford and published in Nature Medicine, the researchers use the trove of data accumulated in the UK Biobank (UKB), a unique repository of various health data on hundreds of thousands of British citizens, to bring us closer to the answer.
The authors sought to quantify the relative contributions of environmental factors (the exposome) versus genetics in determining aging, disease risk, and premature mortality. “A strong argument that nongenetic environmental factors play a key role in aging and premature mortality,” the paper says, “comes from the observation that global human lifespan has increased nearly twofold during the past 200 years, while the human genome is expected to have been stable in such a short period.”
The exposome and mortality
The researchers started with a list of 164 environmental exposures recorded in the UKB. They conducted an exposome-wide analysis to identify environmental exposures (in this term’s broadest sense) associated with all-cause mortality and employed various methods of addressing causality and confounding. For instance, some factors, such as household income and the number of cars owned, are interconnected and had to be disentangled using statistical models. These associations were validated in independent replication and validation cohorts.
Most factors associated with mortality were modifiable (such as physical activity) rather than non-modifiable (such as ethnicity). Smoking predictably ended up on top of the list of detrimental factors, along with the frequency of feeling tired and various measures of deprivation, such as renting a home from the local council versus owning one.
On the opposite side, some of the most beneficial factors included high household income, being employed and educated, physical activity, and living with a partner as opposed to living alone. Each of those factors was associated with a hazard ratio of less than 0.8, meaning a 20% or more reduction in mortality risk.
Cornelia van Duijn, St Cross Professor of Epidemiology at Oxford Population Health and senior author of the paper, said, “Our research demonstrates the profound health impact of exposures that can be changed either by individuals or through policies to improve socioeconomic conditions, reduce smoking, or promote physical activity.”
Interestingly, being of any ethnic background other than White (Asian, Black, mixed, or other ethnicity) was also strongly associated with less mortality risk. This correlation has been confirmed for the UK by previous research [2] and stands in stark contrast with the US, where being Black is associated with a shorter lifespan. The possible reasons for this discrepancy include differences in the two healthcare systems, cultural factors such as diet, and self-selection (“the healthy immigrant effect”), as most non-White people in the UK are immigrants.
Connection to aging and diseases
The researchers were also able to tie these exposures to biological aging via the proteomic aging clock that they developed in an earlier study [3]. The clock has been shown to be associated with mortality, major chronic age-related diseases, multimorbidity, and aging-related phenotypes, including frailty and cognitive function.
Each exposure that was associated with both mortality and proteomic aging (in the same direction) was also linked to concurrent incidence of multiple age-related diseases, “indicating that the exposome is a potential catalyst of disease multimorbidity,” the paper says. Smoking (both current status and pack-years for former smokers) was associated with 21 out of 25 diseases included in the analysis, while household income, Townsend deprivation index, home ownership, and frequency of feeling tired were associated with 19 diseases. In other words, age-related diseases rarely come alone, and many environmental factors drive numerous diseases simultaneously.
“Studies on environmental health have tended to focus on individual exposures based on a specific hypothesis,” van Duijn said. “While this approach has seen many successes, the method has not always yielded reproducible and reliable findings. Instead, we have followed a ‘hypothesis free’ exposome approach and studied all available exposures to find the major drivers of disease and death.”
Genes are less important (exceptions apply)
While some diseases are caused by single-gene variants, most do not have such a clear genetic connection and are instead associated with polygenic risk scores. The researchers analyzed these scores for 22 major diseases to find that, on average, they were much less associated with mortality and aging than the exposome.
Most of the variation in mortality was explained by age and sex (with women having lower mortality risk). Genetics only explained less than 2% of additional variation, whereas the exposome explained an additional 17%.
While this was the case for most outcomes, there were some notable outliers. Polygenic risk explained more variation than the exposome in the incidence of dementias along with breast, prostate, and colorectal cancer. The exposome, on the other hand, was much more predictive of lung, heart, and liver diseases.
“While genes play a key role in brain conditions and some cancers, our findings highlight opportunities to mitigate the risks of chronic diseases of the lung, heart and liver which are leading causes of disability and death globally,” van Duijn said. “The early life exposures are particularly important as they show that environmental factors accelerate ageing early in life but leave ample opportunity to prevent long-lasting diseases and early death.”
Dr. Austin Argentieri, lead author of the study at Oxford Population Health and Research Fellow at Massachusetts General Hospital, said, “Our exposome approach allowed us to quantify the relative contributions of the environment and genetics to ageing, providing the most comprehensive overview to date of the environmental and lifestyle factors driving ageing and premature death. These findings underscore the potential benefits of focusing interventions on our environments, socioeconomic contexts, and behaviors for the prevention of many age-related diseases and premature death.”
Professor Bryan Williams, Chief Scientific and Medical Officer at the British Heart Foundation, added, “Your income, postcode and background shouldn’t determine your chances of living a long and healthy life. But this pioneering study reinforces that this is the reality for far too many people.”
Literature
[1] Ruby, J. G., Wright, K. M., Rand, K. A., Kermany, A., Noto, K., Curtis, D., … & Ball, C. (2018). Estimates of the heritability of human longevity are substantially inflated due to assortative mating. Genetics, 210(3), 1109-1124.
[2] White, C. (2021). Ethnic differences in life expectancy and mortality from selected causes in England and Wales: 2011 to 2014. Office for National Statistics.
[3] Argentieri, M. A., Xiao, S., Bennett, D., Winchester, L., Nevado-Holgado, A. J., Ghose, U., … & van Duijn, C. M. (2024). Proteomic aging clock predicts mortality and risk of common age-related diseases in diverse populations. Nature medicine, 30(9), 2450-2460.
