Age-related biological dysregulation quantified using metabolomics is composed of distinct subsystems with synergistic associations to health outcomes: An analysis of the Canadian Longitudinal Study on Aging

Resilience is a fundamental component of healthy aging, whereby an organism can efficiently respond to external stressors and return to a resting biological and physiological state, known as homeostasis. This capacity declines with age in a heterogenous manner and is aggravated by biological dysregulation, a detrimental state broadly associated with health risk factors and poor outcomes. However, the underlying structure of dysregulation remains unclear, particularly in the context of older adult health trajectories. Here, we take a novel systems-based approach to the quantification of dysregulation using metabolomic data from n=9,992 older adults enrolled in the Canadian Longitudinal Study on Aging. We show that dysregulation across different biological systems is heritable, and exhibit distinct associations with health risk factors, indicators and outcomes, and DNA methylation patterns. Importantly, the effect of systems-specific dysregulation is cumulative, resulting in a significantly higher risk of disease incidence and death in older adults. Our findings broaden our understanding of biological dysregulation as a health state and demonstrate the value of system-specific dysregulation for effective strategies in personalized medicine and risk stratification.