Raising animals in germ-free environments, including the absence of a gut microbiome, is a difficult and expensive undertaking, but it is known to slow the pace of aging in a variety of species, including mice. Researchers here work with flies, digging deeper into the mechanisms by which the absence of microbial species produces this outcome. At the high level we might take these studies to underscore the importance of the immune system in aging, and the degree to which it is negatively impacted by life-long interaction with various microbial species. That removal of pathogens is beneficial tells us something about the priority that should be placed on the development of means to restore and repair the aged immune system.
Commensal microbes provide a critical contribution to aging. Caenorhabditis elegans grown without a bacterial microbiome (axenic) live twice as long as those grown conventionally. Similarly, most analyses have suggested that Drosophila lifespan is extended by axenic growth, though that relationship depends on both growth conditions and the details of how such studies are performed. For example, lack of a microbiome, particularly early in life, may limit the development of a robust innate immune response and alter the expression of stress-response genes, and therefore sensitize an individual to later microbial challenge. Moreover, the presence of a microbiome can compensate for a diet with low protein content, perhaps because the bacteria themselves act as a food source. Multiple mechanisms, therefore, contribute to the modulation of lifespan in axenic conditions.
Additionally, some studies link the microbiome-dependence of lifespan to specific commensal species, or to the interaction of specific commensals with variants in the host genome or compounds in the environment. For example, in C. elegans, at least some of the linkage between the microbiome and aging seems to be mediated by specific microbially-secreted metabolites. Such specificity, however, is difficult to understand in light of the generality of the phenomenon, given the variety of species and experimental paradigms in which it has been observed.
Here, we perform genome-wide gene expression profiling of Drosophila raised either under conventional growth conditions or under axenic conditions. We find that approximately 70% of the systematic changes in gene expression that we observe with age under conventional conditions fail to happen when we grow the flies axenically. In essence, many of the typical correlates of Drosophila aging become uncoupled from the passage of time for the greater part of adulthood if the flies lack a bacterial microbiome.
Among the genes that do not show expected, time-dependent changes in expression when flies are raised axenically are those associated with two features of aging that are observed widely across animal evolution, a decline in the expression of stress-resistance genes and progressive activation of innate immunity, as well as others. Thus, while these processes are clearly critical regulators of organismal lifespan, our data suggest that they are separable from other aspects of the typical progression of age-associated changes in organismal gene expression. They seem, rather, to reflect a succession of strategies that the organism has evolved for different stages of its lifecycle in order to exist in a microbe-rich environment.
In contrast, genes associated with some age-correlated processes, including rhythmic behavior, maintenance of cuticular structure, olfaction, and a subset of metabolic and redox processes, show changes in level over time in the axenic state that are similar to those observed under conventional conditions, allowing us to use them as biomarkers to quantify the age-correlated physiological state of the germ-free animal. The experiments reported here, therefore, support the view that the organism is subject to a progression of separable processes that individually modulate organismal longevity, while also identifying biomarkers of a time-dependent, internal state of the animal that reflects its effective age.