Evidence of Causality in the Relationship Between Excess Body Weight and Accelerated Progression of Aging
Excess visceral fat tissue produces a greater burden of senescent cells, so in that sense one might argue that it is literally causing accelerated aging. Generally researchers content themselves with pointing to the epidemiological data, in which being overweight correlates with greater incidence of age-related disease, greater lifetime medical costs, and a shorter life expectancy. Here, however, an effort is made to prove causation in human data: that the excess weight does in fact cause all of these problems.
Limited by the quality of evidence, possible potential reverse causality and residual confounding, observational studies have been almost unable to identify a causal association between being overweight and aging. In this regard, randomized controlled trials (RCTs) can be used to reveal cause and effect. However, RCTs are costly in terms of money, time and manpower. Instead, Mendelian randomization (MR) is a popular and effective method for causal inference in recent years. It takes genetic variation (single nucleotide polymorphism, SNP) as the instrumental variable to deduce the causal association between outcome and exposure, which can effectively avoid the confounding bias of traditional epidemiological studies.
We collected genetic variants associated with overweight, age proxy indicators (telomere length, frailty index, and facial aging, etc.), from genome-wide association studies datasets. Then we performed MR analyses to explore associations between overweight and age proxy indicators. MR analyses were primarily conducted using the inverse variance weighted method, followed by various sensitivity and validation analyses.
MR analyses indicated that there were significant associations of being overweight on telomere length, frailty index, and facial aging. Overweight status also had a significant negative causality with life expectancy. Moreover, the findings tend to favor causal links between body fat mass or body fat percentage on aging proxy indicators, but not body fat-free mass. In conclusion, this study provides evidence of the causality between overweight and accelerated aging (telomere length decreased, frailty index increased, facial aging increased) and lower life expectancy. Accordingly, the potential significance of weight control and treatment of overweight status in combating accelerated aging need to be emphasized.