Aging is a multifactorial biological process that affects virtually all organ systems and is a major risk factor for numerous chronic diseases, including cardiovascular disease, neurodegeneration, diabetes, and frailty. While aging is inevitable, the underlying mechanisms that drive healthy versus pathological aging remain only partially understood. Recent studies suggest that the gut microbiota and host systemic metabolism are critical, yet underexplored, components of this process. More importantly, their dynamic interaction may play a pivotal role in shaping age-related physiological changes and disease susceptibility.
The gut microbiota is a complex and diverse microbial community that contributes to digestion, immune function, and metabolic homeostasis. As humans age, the composition and functionality of the gut microbiota undergo substantial shifts, often characterized by decreased microbial diversity, loss of beneficial taxa, and increased abundance of pro-inflammatory species (O'Toole & Jeffery, 2015). Simultaneously, aging is associated with distinct changes in the plasma metabolome, including alterations in amino acids, lipids, bile acids, and microbial-derived metabolites such as short-chain fatty acids (SCFAs) and indole derivatives—compounds that are known to influence systemic inflammation, gut barrier integrity, and even brain function.
While both gut microbiota and circulating metabolites have been individually linked to aging, there is a critical gap in understanding how their interactions evolve over the lifespan. The gut–metabolite axis is inherently bidirectional: microbes produce metabolites that modulate host physiology, and host factors in turn influence microbial composition. However, it remains unclear how this interplay changes with age and whether it contributes causally to healthy or unhealthy aging trajectories.
Understanding these dynamics is urgent for several reasons. First, identifying age-related microbial–metabolic patterns could reveal novel biomarkers for early detection of functional decline. Second, such insights may point to modifiable factors—such as specific microbes or metabolic pathways—that can be targeted through diet, probiotics, or pharmacological interventions to promote healthy aging. Third, with global populations aging rapidly, there is an increasing public health need to shift from disease treatment to prevention and personalized management of aging.
In this study, we aim to characterize the interaction between gut microbiota and plasma metabolites across the human aging process using publicly available multi-omics datasets. By uncovering how this complex relationship shifts with age, we hope to contribute to a deeper systems-level understanding of aging and to identify potential targets for intervention that support longevity and healthspan.