Prospective Study of the Gut Microbiome in Aging

PROJECT SUMMARY / ABSTRACT
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.

Grant Number: 4R01AG067744-02
NIH Institute/Center: NIH
Principal Investigator: Andrew Chan