Previous research has shown the aging process and frailty may be associated with a perturbed gut microbiome in elderly people. Indeed, gut microbes could be a major driver of age-associated inflammation in mice, and specific microbial signatures of healthy aging have been previously reported in long-lived individuals. However, it is still unknown whether targeting gut microbes can be effective in promoting healthy aging.
A new study, led by Prof. Meng Wang from the Huffington Center on Aging and Department of Molecular and Human Genetics at Baylor College of Medicine in Houston (USA), has found that the genetic variations of gut microbes may modulate the production of pro-longevity metabolites in the host Caenorhabditis elegans.
In order to investigate whether the genetic composition of the microbiome could be important for longevity, the researchers used the nematode C. elegans as a simple model for human metabolism due to its evolutionary similarity to humans and its comparable relationship with microbes.
To study the impact of individual bacterial genes on the lifespan of C. elegans, the researchers first designed a screening platform to identify microbial pro-longevity factors from the entire collection of Escherichia coli non-essential gene deletion mutants, each lacking one of 3,983 genes. C. elegans were fed with each individual mutant bacteria and each one’s impact on worm lifespan was noted.
Of the 3,983 bacterial genes tested, 29 genes, when deleted, increased the C. elegans lifespan. Besides this, 12 of the bacterial mutants that increased the length of survival of the worms also significantly delayed the age-related progression of tumour growth and accumulation of amyloid-beta, a characteristic of Alzheimer’s disease in humans.
Using both genetic and biochemical analyses, the scientists found that several bacterial mutants promoted longevity by over-producing the polysaccharide colanic acid (CA), an exopolysaccharide secreted by many enterobacterial species that regulates mitochondrial dynamics and unfolded protein response in the host. On the other hand, other mutants increased longevity by modulating several of the known worm pathways involved in aging. The deficiency of genes involved in chorismate metabolism, a precursor for many aromatic metabolites, also explained the prolonged host lifespan by some E. coli mutants and exerted additive effects together with CA overproduction.
With the aim of directly studying the efficacy of CA in promoting host longevity, purified CA was supplemented to wild-type C. elegans. Purified CA supplementation prolonged the lifespan of C. elegans when supplemented with gram-negative E. coli BW25113 and HT115 and with gram-positive Bacillus subtilis. CA also showed similar effects in wild-type Drosophila melanogaster (fruit flies). Altogether these data support a well-conserved pro-longevity effect of CA across evolutionarily distant hosts. Mechanistically, CA acted on host mitochondria -which have been related to aging processes– to promote longevity, via inducing mitochondrial fission (division of a single organelle into two or more independent structures) in the host gut but with no effect on proteasome activity.
According to Dr. Wang: “These findings are also interesting and have implications from the biological point of view… Mitochondria seem to have evolved from bacteria that millions of years ago entered primitive cells. Our finding suggests that products from bacteria today can still chime in the communication between mitochondria in our cells.” She continues, “Fully understanding microbe-mitochondria communication can help us understand at a deeper level the interactions between microbes and their hosts”.
To sum up, microbial genetic variations are involved in modulating longevity in some host species. Further studies on bacteria-mitochondria interactions could open new targets for healthier aging.
Han B, Sivaramakrishnan P, Lin CJ, et al. Microbial genetic composition tunes host longevity. Cell. 2017; 169(7):1249-62. doi: 10.1016/j.cell.2017.05.036.