Author response: Regulation of life span by the gut microbiota in the short-lived African turquoise killifish

Article Figures and data Abstract eLife digest Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract Gut bacteria occupy the interface between the organism and the external environment, contributing to homeostasis and disease. Yet, the causal role of the gut microbiota during host aging is largely unexplored. Here, using the African turquoise killifish (Nothobranchius furzeri), a naturally short-lived vertebrate, we show that the gut microbiota plays a key role in modulating vertebrate life span. Recolonizing the gut of middle-age individuals with bacteria from young donors resulted in life span extension and delayed behavioral decline. This intervention prevented the decrease in microbial diversity associated with host aging and maintained a young-like gut bacterial community, characterized by overrepresentation of the key genera Exiguobacterium, Planococcus, Propionigenium and Psychrobacter. Our findings demonstrate that the natural microbial gut community of young individuals can causally induce long-lasting beneficial systemic effects that lead to life span extension in a vertebrate model. https://doi.org/10.7554/eLife.27014.001 eLife digest Our bodies are home to lots of microorganisms, many of which are found throughout the gut. Gut microbes play important roles in human health, where they cooperate with our own cells to develop the immune system, synthesize essential vitamins, and help to absorb nutrients. When the cooperation between our own cells and the gut microbes fails, the microbial community within the gut can become a source of infection, sometimes leading to life-threatening diseases. Healthy individuals typically have many different types gut microbes, whereas people with poor health, or older individuals, will often have less diverse and a higher percentage of disease-causing microbes. For example, African turquoise killifish only live a few months, during which the composition of their gut microbes undergoes dramatic changes. While young fish harbor highly diverse microbial communities, older fish have less diverse communities and more microbes associated with disease. Until now, it was not known whether manipulating the gut composition could affect the aging process. By using the killifish as a model for their study, Smith et al. revealed that gut microbes affect how the fish survived and aged. When the guts of middle-aged fish were colonized with microbes transferred from younger fish, the older fish lived longer and were more active later in life. These fish also maintained a more diverse microbial community throughout their adulthood and shared key microbes with young fish – possibly associated with the improved health benefits. These results suggest that controlling the composition of the gut microbes can improve health and increase life span. The model system used in this study could provide new ways to manipulate the gut microbial community and gain key insights into how the gut microbes affect aging. Manipulating gut microbes to resemble a community found in young individuals could be a strategy to delay the onset of age-related diseases. https://doi.org/10.7554/eLife.27014.002 Introduction Life expectancy of different species in nature is regulated by a complex combination of genetic and non-genetic factors. Genetic manipulations in model organisms have revealed key conserved molecular pathways, including the insulin-IGF1 and the mTOR(definition) pathways, which regulate aging and life span across several species, spanning from yeast to mammals (Kapahi et al., 2010; Kenyon et al., 1993; Lapierre and Hansen, 2012). Environmental interventions such as temperature and dietary manipulations have also been importantly associated with life span modulation in several species. Among these, lower temperatures (Conti et al., 2006; Miquel et al., 1976; Valenzano et al., 2006a; Van Voorhies and Ward, 1999) and reduced nutrient intake (Fontana et al., 2010; Mair and Dillin, 2008) are key environmental factors that have been associated with prolonged life span. Complex microbial communities covering external surfaces live at the interface between organisms and the external environment – from roots and leaves in plants, to skin, mucosal surfaces and gut in animals. These microbial communities participate in a wide range of key biological processes, including nutrient absorption (Semova et al., 2012), development (Sommer and Bäckhed, 2013), metabolism (Nicholson et al., 2012), immune modulation (Geva-Zatorsky et al., 2017), defense against pathogens (Kamada et al., 2013; Schuijt et al., 2016) and disease (Sampson et al., 2016). Individual gut microbiota (GM) composition changes dramatically in various diseases (Baumgart and Carding, 2007; Garrett, 2015; Sokol et al., 2008) and during aging in flies, mice and humans (Clark et al., 2015; Langille et al., 2014; O'Toole and Jeffery, 2015). Healthy GM is typically characterized by large bacterial taxonomic diversity, whereas frailty is associated with loss of diversity and expansion of more pathogenic bacterial species (Claesson et al., 2012). Following antibiotic treatment, pathogenic bacterial species, such as Clostridium difficile and Enterococcus faecalis, can restructure the human GM and cause severe chronic conditions that pose a major threat for public health (Bäckhed et al., 2012; Cox and Blaser, 2015). Studies across different human age cohorts have shown that large changes in the abundance of subdominant bacterial taxa in the gut are a hallmark of aging; moreover, exceptionally long-lived individuals – including supercentenarians – are characterized by the persistence of bacterial taxa associated with a more healthy status (Biagi et al., 2016). While diversity-associated microbial taxa often decline during age, specific bacterial taxa, such as Clostridiales, are associated with malnutrition and increased frailty (O'Toole and