From Primates to People: Mapping Host-Microbiome-Health Relationships in Aging.

The human microbiome profoundly influences host physiology, metabolism, and immune function. A balanced microbial ecosystem supports immune homeostasis and health, whereas dysbiosis contributes to diverse diseases, including metabolic, autoimmune, neurodegenerative, and infectious disorders. Aging, the greatest risk factor for chronic disease, is characterized by hallmarks such as mitochondrial dysfunction, genomic instability, and "inflammaging," a state of chronic low-grade inflammation. Emerging evidence links age-associated microbial dysbiosis to inflammaging and systemic decline, as microbial shifts promote gut barrier dysfunction, increased permeability, and immune activation through translocated microbial metabolites and endotoxins. While most research has focused on the gut, the microbiomes of other tissues, including pulmonary sites, also undergo age-related changes that may influence systemic and neuroinflammatory pathways. However, causality and mechanisms remain unclear. Human studies are limited by ethical and logistical barriers to longitudinal aging studies, and rodent models are limited by microbiomes and immune profiles dissimilar to humans. Nonhuman primates (NHPs), particularly marmosets and macaques, may provide a translational bridge given their evolutionary, physiological, and microbiome similarities to humans. Comparative studies demonstrate greater overlap of gut microbial taxa and shared age-associated microbial trajectories between humans and NHPs as compared to rodents. Moreover, controlled NHP models allow for precise manipulation of diet, environment, and infection to evaluate microbiome-immune-aging interactions. Despite substantial progress, key knowledge gaps persist, including limited longitudinal data, small cohort sizes, lack of standardized methods, and insufficient integration of multi-omic and host phenotypic data. While some supporting evidence already exists, future NHP research should determine if NHP models better recapitulate human age-associated microbial trajectories, immune and inflammatory phenotypes, microbial metabolites, and prediction of intervention responses compared to rodent models. These efforts will inform microbiome-targeted interventions to promote resilience and extend healthspan in aging populations.