Putative integrative pathway via which the human microbiome may mediate frailty onset and progression. This proposed pathway is based on existing data derived from animal models and human studies to date. In this model, host genetic factors, pro-inflammatory clinical parameters, and environmental, lifestyle and behavioral factors promote an inflammatory-microbiome signature characterized by pro-inflammatory alterations in the microbiome (particularly the gut) and functional metagenome that precipitate decreased epithelial barrier function with consequent increased mucosal permeability, translocation of microbial products, dysregulated innate and adaptive immunity, and a heightened systemic inflammatory state. This inflammatory-microbiome signature may intersect further with microbiome-mediated dysregulation of other key human physiologic systems, including neuroendocrine and energy metabolic pathways to precipitate frailty.