Gut microbes and aging

The critical impact microbiota have on health and disease make the interaction between host and microbiome increasingly important as we evaluate therapeutics. Here we highlight growing evidence that beyond disease, microbes also affect the most fundamental of host physiological phenotypes, the rate of aging itself.

As you look in the mirror you may only see yourself staring back, but in reality you are not alone; you share your body with trillions of others. Contained on and within our bodies thrives a dynamic population of microbes that form a ‘metaorganism’, comprising 10 bacterial cells for every one of our own. Despite co-evolving in the presence of this ‘microbiome’ for 500 million years (), only recently have advances in sequencing technology allowed us to appreciate the complexities of this relationship, and the manner by which genomes within metaorganisms interact and affect one another. Inter-individual variations in the microbiome impact multiple human pathologies, from metabolic syndrome to cancer (). However, new data in invertebrate systems indicate microbes extend their effects beyond host pathology, to systemic modulation of the rate of aging.

The gut microbiome comprises a complex community of bacterial species that live within intestines of coelomate animals. Historically, the influence of gut microflora on host health has focused on the two extremes of the relationship: pathogenesis and symbiosis. Canonical examples of symbiotic host/microbe relationships include the reliance of some herbivores on gut flora for efficient digestion of cellulose. However, the majority of intestinal microbes are neither pathogenic nor classically symbiotic, but instead ‘commensal’, meaning their effect is non-harmful and neutral. Advances in high-throughput sequencing have facilitated the characterization of these diverse populations of commensal bacteria, defining the metagenome – the ensemble of host and microbiota DNA, and by extension the meta-transcriptome, proteome and metabolome. With endeavors such as the Human Microbiome Project just beginning (), research into the complexity of mammalian microbiome dynamics is in its infancy. Assigning causality to effects of the microbiome in mammalian systems is expensive, technically challenging and requires microbe-free husbandry conditions, and gnotobiotic mice with defined and controlled microbiota ().

Invertebrate model systems such as the fruit fly Drosophila melanogaster and the nematode worm Caenorhabditis elegans also live in the presence of microbiota both in nature and the laboratory (). Due to their genetic tractability and inexpensive husbandry, invertebrate studies allow direct causality to be assigned to the presence or absence of microbiota. Because of their short lifespans, D. melanogaster and C. elegans are also powerful models for studying genetic pathways that modulate the aging process. The ultimate goal of this research is to develop novel therapeutics with beneficial impacts on overall health in old age, complementing disease-centric approaches that focus on proximal determinants of individual pathologies. This work has uncovered conserved genes that modulate healthy aging in invertebrates and mammals, and are linked to extreme longevity in humans (), including the insulin/IGF-1 like signaling (IIS) pathway, the target of rapamycin (TOR) and AMP-activated protein kinase (AMPK). However, little attention has been paid to how the microbial environment and the microbiome itself might affect the ability of these interventions to promote longevity. Here we review examples of microbiota in invertebrates directly and indirectly influencing the host genome to affect longevity, and discuss the impact these emerging data have on the field of aging research.

Direct Interspecies Signaling and Aging

Given the proximity of microbes and host within the metaorganism, diffusible molecules originating in bacteria can directly affect cells in the host (). Recent work suggests this interspecies signaling can impact host aging rate. C. elegans are commonly grown ‘monoxenically’ in co-culture with non-pathogenic strains of E. coli ‘OP50’ bacteria. E. coli act as nutrition for the worm, providing mandatory nutrients and essential components for life that the nematode cannot synthesize de novo. Although not considered pathogenic, E. coli OP50 do proliferate inside older animals, and raising C. elegans on non-dividing bacterial lawns suppresses this infection and increases worm lifespan (). In young worms however, E. coli are mechanically broken down before entering the gut and do not live in the animal as a true microbiome. Despite this, it is becoming apparent that beyond their role as a nutrient source and potential pathogen, E. coli secrete diffusible molecules, including metabolites and small RNAs that can directly impact C. elegans aging.

An example of a direct interspecies signal secreted by microbes that can promote longevity is nitric oxide (NO) (). NO is a small, short-lived free radical that affects the activity of proteins both directly and indirectly via post-translational modifications. As a critical signaling molecule, NO has been implicated in multiple functions including neurotransmission, immunity and cardiovascular function (). C. elegans are rare amongst eukaryotes as the cannot produce their own NO since they lack NO synthase. Gusarov et al. therefore speculated that worms might be utilizing NO produced from the bacteria within their microenvironment. Supporting their hypothesis, culturing C. elegans with NO-deficient Bacillus subtilis shortens their lifespan, while exogenous supplementation of NO increases it. Strikingly, an in vivo fluorescent sensor detected NO in multiple C. elegans tissues, suggesting it acts as a bona fide interspecies longevity signal. RNA-Seq analysis of worms fed NO identified specific transcriptional responses regulated by two transcription factors, DAF-16/FOXO and heat shock factor -1 (HSF-1), both known to mediate lifespan (). Worms lacking DAF-16/FOXO or HSF-1 do not respond to the life prolonging effects of bacterial NO, meaning bacterial NO modulates C. elegans lifespan via effects on host transcription (Fig. 1A).

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Microbe-modulation of invertebrate aging and physiology

A. Bacterial-derived signals NO and ncRNAs regulate C. elegans longevity. B. Metformin increases C. elegans lifespan via effects on bacterial folate metabolism. C. L. plantarum drive Drosophila growth under low nutrient conditions via the longevity modulator TOR. D. Different bacterial species elicit specific transcriptional responses in C. elegans.

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