Genetic Variants Associated with Visceral Fat Accumulation Correlate with Longevity
It is well established that excess visceral fat is harmful. This tissue is metabolically active, and generates increased chronic inflammation through numerous mechanisms: a greater number of senescent cells; signaling by fat cells that appears similar to that produced by infected cells; increased debris from dead and dying fat cells that provokes the immune system. Overweight and obese people have a shorter life expectancy, greater incidence of age-related disease, and higher lifetime medical costs, with these disadvantages increasing with a larger burden of visceral fat tissue. It is not surprising, therefore, to find that genetic variations that correlate with increased visceral fat accumulation in humans also correlate with a shorter life expectancy.
Several studies have shown that obesity is a risk factor for numerous diseases, including diabetes mellitus, hypertension, coronary artery disease, stroke, fatty liver disease, sleep-disordered breathing, mental health, and cancer. Obesity has also been shown to be closely related to all-cause mortality. Several observational studies revealed that obesity could accelerate the aging process. Moreover, a meta-analysis indicated that people with extreme obesity may have a reduced life expectancy by about 14 years. However, there is little evidence on the causal relationship between genetic influence of visceral adipose tissue (VAT) accumulation and longevity.
Mendelian randomization (MR) analysis is a useful approach for estimating the causal relationship between an exposure factor and outcome based on observational data from genome-wide association studies (GWASs). Single-nucleotide polymorphisms (SNPs) typically serve as the instrumental variables for investigating the causal role of an exposure factor on a disease or disease-related outcome. A valid instrumental variable is one that is (1) associated with the exposure, (2) independent of confounders, and (3) independent of the outcome conditional on the exposure and confounders. In this two-sample MR analysis, we employed the genetic variants (SNPs) of VAT accumulation as instrumental variables to explore the causal relationship with longevity.
Our MR analysis used 221 genetic variants as instrumental variables to explore the causal association between VAT accumulation and longevity. VAT accumulation (per 1-kg increase) was found to be significantly associated with lower odds of surviving to the 90th (odds ratio [OR] = 0.69) and 99th (OR = 0.67) percentile ages. This MR analysis identified a causal relationship between genetically determined VAT accumulation and longevity, suggesting that visceral adiposity may have a negative effect on longevity.