Emerging data suggest that aging is associated with changes in the gut microbiome, including reduction in microbial diversity, variation in specific taxa, and alterations in microbial-derived metabolites. Gut microbial alterations have also been linked to age-related diseases such as dementia, physical disability, cardiovascular disease (CVD), cancer, obesity, and diabetes mellitus, potentially through mechanisms that include modulation of inflammation and intestinal permeability. This background supports our overarching hypothesis that the gut microbiome modulates the association between aging, diet, lifestyle, and geriatric outcomes of dementia, disability, frailty and associated chronic diseases. Although growing data suggest that the gut microbiome develops in infancy, and remains relatively stable through mid-adulthood, age-related changes in older adults are poorly understood. Lifestyle and health during aging may modulate or be modulated by the gut microbiome. Studies in older populations, however, are hampered by small sample sizes; cross-sectional microbiome sampling; limited assessment of diet, lifestyle, and medication; and lack of microbial functional profiling. Thus, there is a high unmet need to conduct a large, prospective study to examine the network of interactions between the gut microbiota, lifestyle factors, and aging-related outcomes among older individuals. We recently reported that low dose aspirin (LDA) over 4.7 years in the ?ASPirin in Reducing Events in the Elderly? (ASPREE) randomized controlled trial (RCT) of 19,114 initially healthy individuals ? 65 years did not extend disability-free life12 and was associated with higher all-cause mortality. Among ~13,000 deeply-phenotyped ASPREE participants continuing annual off-trial, in-person follow-up through a 5-year extension study (ASPREE-XT) we propose to a) collect stool specimens in Year 1 and 3 and b) prospectively assess microbiome characteristics in relation to aging outcomes that will be assessed through Year 5. Specifically, we will examine the association of the gut microbiome with cognition/dementia, disability/frailty, cardiovascular disease (CVD), cancer, and healthy lifespan. Our proposal addresses a major research priority in the field and is directly responsive to PA- 18-738 ?Age-related microbiota changes and their implications in chronic disease prevention, treatment and progression ? as one of the first efforts to prospectively characterize gut microbiota in relation to cognitive decline, frailty and healthspan in a large, well-phenotyped older population. By leveraging prospective, repeatedly updated clinical, dietary and lifestyle data collected from a highly engaged and well-characterized older cohort over years of face-to-face follow-up to associate both long- and short-term diet, medication, and lifestyle exposures with the gut microbiome, our proposal is a highly cost-efficient opportunity to address gaps in our understanding of how our complex intestinal microbial communities influence aging and age-related diseases and whether they can be targeted as interventions to modulate health span.
Aging is associated with changes in the gut microbiome, including reduction in microbial diversity, variation in specific taxa, and alterations in microbial-derived metabolites; the gut microbiome in turn has been linked to age- related diseases such as dementia, physical disability, cardiovascular disease (CVD) and cancer, potentially through mechanisms that include modulation of inflammation and intestinal permeability. Our overarching hypothesis is that the gut microbiome modulates the association between aging, diet, lifestyle, and geriatric outcomes of dementia, disability, frailty and associated chronic diseases. In this proposal, we will prospectively examine the association of the gut microbiome in relation to cognitive decline, frailty and healthspan in a large, well-phenotyped older population to address gaps in our understanding of how our complex intestinal microbial communities influence aging and age-related diseases and whether they can be targeted as interventions to modulate health span.
