Project summary. 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.