. Aging involves a multi-system physiological deterioration. In addition to affected tissues, and likely as a consequence, aging also affects the gut microbiota, an extensive microbial community which contributes to diverse host functions. Imbalances in microbiota composition, or dysbiosis, are often associated with pathology, and recent reports indicate that aging-dependent dysbiosis exacerbates aging phenotypes. Potentially, microbiotas could be rebalanced to ameliorate aging; however, to achieve this, better understanding is required of the reciprocal interactions between host aging and the altered microbiota, and strategies should be devised to enable rebalancing. C. elegans is a valuable model for aging research thanks to its short lifespan. We have recently established it also as a model for microbiome research, offering advantages unmatched in vertebrate models, including the ability to work with genetically homogenous populations, averaging-out inter-individual variation to better discern shared patterns. Two experimental pipelines are used in the lab to raise worms: natural-like compost microcosms, coupled to 16S rDNA deep sequencing for microbiota characterization, or defined synthetic microbiotas consisting of 30 worm gut isolates, characterizing microbiotas size and composition with calibrated qPCR. Work with these models showed that C. elegans harbors a characteristic and persistent gut microbiota shaped (both structurally and functionally) by host genetics, and is capable of preferential endorsement of beneficial commensals from a diverse environment. We further demonstrated that worms undergo extensive remodeling of their microbiota during aging, including an Enterobacteriaceae bloom, reminiscent of the overgrowth seen in aging humans. We propose to take advantage of the C. elegans model to 1) establish causative relationships between host age-dependent gene expression (representing processes of aging) and microbiota composition, and test gene-microbe dependencies using monocultures of individual bacterial strains, drop-out bacterial mixes, and worm mutants; 2) determine functional significance of age-altered commensals to aging, examining effects on motility, immunity, proteostasis and lifespan, and further test the possibility of aging-dependent decline in host selectivity toward beneficial commensals as an underlying cause of dysbiosis; 3) test different strategies to rebalance the microbiota and ameliorate aging, including synbiotic supplementation, or the use of mutants susceptible to manipulation; the Enterobacteriaceae bloom will serve as the first target for rebalancing, as preliminary results suggest that it may be the outcome of declined control over beneficial commensals turning them into opportunistic pathogens. The proposed work will test the hypothesis that age-dependent dysbiosis exacerbates aging and identify the relevant elements in this dysbiosis. It will further serve as a proof of concept for the possibility and strategies required to use microbiota rebalancing to ameliorate aging.

Public Health Relevance

Aging is associated with imbalanced gut microbiotas (dysbiosis), and recent studies demonstrate causative roles for dysbiosis in aging-related pathology. Using the power of the C. elegans model, we propose proof-of- concept experiments to establish causative relationships between host aging and microbiota dysbiosis, and use this knowledge to rebalance the microbiota to ameliorate aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG061302-01
Application #
9641573
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Macchiarini, Francesca
Project Start
2019-01-15
Project End
2023-11-30
Budget Start
2019-01-15
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Biology
Type
Graduate Schools
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704