Exploring the role of metabolism in major noncommunicable diseases and lifespan using Mendelian randomization

Abstract

Despite progress in combatting cardiovascular disease (CVD) and cancer, these major noncommunicable diseases (NCDs) remain leading causes of death worldwide and contribute to substantial years of life lost. Differences in occurrence and mortality of CVD and cancer by sex have been observed, with men generally being more disadvantaged than women. Reducing established risk factors has not eliminated these issues. With aging populations, their impacts are expected to rise persistently. Evolutionary biology suggests trade-offs between growth, reproduction, and longevity, with faster growth and earlier maturation favoring reproductive success but compromising health and longevity. Observationally, faster metabolism is linked to poorer health, accelerated aging, and shorter lifespan. These concepts are being increasingly applied to develop novel prevention and treatment strategies for CVD and cancer. However, current evidence on the role of metabolism in CVD, cancer, and longevity mainly comes from observational studies, which are open to confounding and selection bias. Relevant randomized controlled trials are largely limited to those focusing on short-term effects and non-disease outcomes. Moreover, randomized controlled trials to alter metabolism are often unfeasible or unethical. Mendelian randomization (MR), i.e., instrumental variable analysis with genetic instruments, is a viable alternative to study the long-term effects of metabolism on these important health outcomes. MR has an advantage over conventional observational designs of being less open to confounding. To study the long-term effects of metabolism on major NCDs and lifespan, MR was employed by leveraging publicly available summary statistics from large genome-wide association studies. Specifically, MR studies were conducted to examine the effects of glucagon on ischemic heart disease and its risk factors and sex-specifically the effects of basal metabolic rate (BMR) on cancer, neoplasms, site-specific cancers, and lifespan. An MR study using a phenome-wide investigation approach was also conducted to examine the sex-specific effects of BMR systematically and comprehensively on a wide range of health-related outcomes, aiming to explore the mechanisms underlying these processes. Genetically predicted glucagon was positively associated with ischemic heart disease but not with its risk factors, although a possible inverse association with diastolic blood pressure could not be excluded. Genetically predicted BMR was positively associated with cancer and neoplasms in both men and women, with no sex differences. Positive associations with certain site-specific cancers were also observed. These associations with cancer-related outcomes were independent of insulin-like growth factor 1. Genetically predicted BMR was inversely associated with lifespan in both men and women, with a stronger effect in women than men. Using a phenome-wide investigation approach, genetically predicted BMR was associated with a wide range of health-related outcomes independent of body mass index in both men and women, including diseases, biomarkers, and phenotypes related to growth and reproduction. Overall, metabolism has an important role in major NCDs and lifespan. Faster metabolism might have a detrimental effect on health and longevity. Given BMR is a readily modifiable target from diet, lifestyle, medications, and environment, further investigation through intervening on BMR and its drivers and on the downstream effects of BMR is warranted to inform public health actions.