Starting in on the Identification of Mechanisms by which Gut Bacteria Influence Aging

It is now fairly well established that gut bacteria have a degree of influence on the pace of aging, though just how much of individual variation can be explained in this way is still a question mark. The next step in the process of investigation is to identify the most significant mechanisms involved. This will no doubt proceed in much the same way as investigations of the mechanisms of calorie restriction and exercise, with researchers seeking ways to mimic the presence of favorable gut bacteria populations via pharmaceuticals. Just like those other parts of the field, this probably isn't going to result in therapies that can meaningfully slow aging any time soon, however. It is a challenging area of development, as illustrated by the lack of practical outcomes resulting from the past decade of work on calorie restriction mimetics. Further, the possible effect sizes are too small to care about in comparison to what can be achieved in principle through rejuvenation biotechnologies such as those of the SENS research portfolio.

A class of chemicals made by intestinal bacteria, known as indoles, help worms, flies and mice maintain mobility and resilience for more of their lifespans, scientists have discovered. Healthspan is a term used to describe the length of time a human or animal, while aging, can stay active and resist stress. In this research, the focus is on whether the animals live healthier, but not necessarily longer. "This is a direct avenue to a drug that could make people live better for longer. We need a better understanding of healthspan. With medical advances, people are living longer; but you might not really want to live longer if it means spending those extra years frail and infirm." The burden imposed by diseases of aging on the healthcare system is expected to skyrocket in coming decades.

Interest in the health effects of the microbes that live in our bodies has exploded in recent years. In humans and mice, some studies have shown that the spectra of bacteria in our bodies become narrower with age. Indole, produced by many types of bacteria through breakdown of the amino acid tryptophan, can smell noxious or flowery depending on the concentration. Indole and its chemical relatives can be found in plants, especially vegetables such as broccoli and kale. One such relative is also known as auxin, a growth hormone for plants needed for light-seeking and root development.

The roundworm C. elegans is one of the premier organisms in which to study aging. Studies in C. elegans led to discovery of a set of genes that control how long the worms can live. Several of the genes are components of the insulin signaling pathway, and they influence lifespan in flies and mice as well. Worms normally eat bacteria. So researchers fed them E. coli bacteria that produce indoles, and compared them with worms fed E. coli that cannot produce indoles. As they age, older worms spend less time moving around, can't swallow as well and are more sensitive to stressors. Although indoles didn't change the maximal lifespan, they markedly increased the amount of time worms were mobile after the age of 15 days, and it increased their swallowing strength and resistance to heat stress, even in young animals. In addition, worms usually stop reproduction at the age of 5 days, but dietary indole more than doubled their reproductive span, allowing them to remain fertile up to 12 days.

Indole had similar effects on mobility and resistance to heat in Drosophila fruit flies, and with mice, a comparable pattern was evident. Researchers treated mice with antibiotics to eliminate the existing flora, and then re-colonized them with either normal E. coli, or, as a control, with bacteria that cannot produce indole. In very old mice (28 months), indoles helped animals maintain their weight, mobility and activity levels. In younger mice, indoles extended survival after exposure to lethal radiation. Indoles may be keeping the intestinal barrier intact and/or limiting systemic inflammatory effects. Researchers are now investigating how indoles exert their effects in aging animals, how dysregulation of indoles produced by the microbiota contribute to frailty, and how indoles can be used to reverse these effects.