Fig. 3. Complex interplay of aging and metabolism underneath population-level associations.

The age-metabolite associations observed in population studies may reflect a number of underlying processes. One interpretation is that metabolic changes initiate or exacerbate aging processes or affect survival, leading to observed age-metabolite associations in the population. In the reverse conceptualization, biological changes occurring as part of aging processes lead to changes in metabolite level. In both cases, confounding and interaction effects with high-level demographic and lifestyle characteristics—including exercise, social determinants of health, sex, environment, BMI, health conditions, diet, and race and ethnicity—may be modifying the observed associations. Teasing apart these different effects from observational and often cross-sectional data is challenging, requiring careful study design and interpretation.