Arguing for Intestinal Dysfunction as an Important Component in Degenerative Aging

Researchers investigating aging in flies have found that loss of intestinal function is a very strong determinant of degeneration and mortality in that species. Interventions that slow that decline, such as by manipulating intestinal stem cell activity or improving intestinal tissue quality control, also reduce mortality and extend life. There has been some discussion over whether this importance of intestinal function in aging is a characteristic unique to flies, and here the authors of this open access paper argue that it is not, and that there should be more targeted investigation in mammals:

A dramatic increase of intestinal permeability occurs in Drosophila melanogaster during aging in normal condition. The assay presented in this article uses a blue food dye to detect increased intestinal permeability in vivo. A blue coloration throughout the body marked the positive individuals, which were referred to as 'smurfs' from then on. Interestingly, the authors showed that genetic or physiological interventions increasing lifespan in flies significantly decreases the proportion of Smurfs compared to the control population at any given chronological age. This apparent link between the age-related increase of intestinal permeability and lifespan led them to more thoroughly analyze the Smurf phenotype. This phenotype allows the identification of individuals that are about to die of natural death amongst a population of synchronized Drosophila melanogaster individuals and those individuals show numerous other hallmarks of aging. Such a stereotyped way to die is unexpected; this could indicate a physiological phenomenon crucial during normal aging. Here we propose to test the hypothesis that such an important phenomenon should be evolutionarily conserved.

We chose to search for such a 'Smurf transition' in two other Drosophila species, Drosophila mojavensis and Drosophila virilis whose last common ancestor with Drosophila melanogaster existed approximately 50 million years ago, the nematode Caenorhabditis elegans whose divergence time with D. melanogaster is around 750 million years, and finally the vertebrate zebrafish Danio rerio, which diverged from D. melanogaster around 850-950 million years ago. We investigated whether Smurf-like animals could be observed in individuals from populations of these evolutionarily distant organisms. For each tested species, we could identify individuals showing extended dye coloration throughout their bodies. Moreover, we observed heterogeneity in a given population with only a fraction of the individuals exhibiting increased dye level outside the intestine. Thus, at least in old animals, it is possible to identify individuals with increased intestinal permeability.

One of the most striking characteristic of Smurf individuals previously described in Drosophila is the high risk of impending death they exhibit compared to their age-matched counterparts in a given population. So we decided to verify whether Smurf individuals were also committed to die in the other organisms we studied in this article. We showed that the proportion of individuals showing increased intestinal permeability grows linearly - or quasi-linearly - as a function of chronological age in these different organisms as it was previously reported in Drosophila melanogaster. Finally, we validated that, similar to what has been shown in D. melanogaster, the Smurf phenotype is a strong indicator of physiological age since it is a harbinger of natural death occurring during normal aging.

Intestinal dysfunction, as measured by the smurf assay in different species, associated to sharp transitions in gene expression and behavior appears to be a conserved hallmark of impending death. If this phase of aging is as broadly present in living organisms as our present study suggests, highly stereotyped molecularly and physiologically as well as sufficient to explain longevity curves, then we think that identifying the very events responsible for entering into this phase or those characterizing the high risk of impending death associated with that phase could answer fundamental questions about aging and lead to treatments able to significantly improve lifespan/healthspan across a broad range of species.