Scientists found the elixir of youth in the gut

Gut bacteria produce metabolites capable of directly influencing host lifespan. This was confirmed by Japanese researchers from Kindai University and Kanazawa University. The results were published in the scientific journal mBio.

The gut microbiota influences many aspects of host physiology, including metabolic and immune functions. Many metabolites produced by gut bacteria can cross the intestinal epithelium and enter host tissues. However, determining the specific contribution of individual bacterial metabolites to lifespan has remained challenging until now.

To address this gap, the team used gnotobiotic Drosophila flies colonized with genetically modified strains of Escherichia coli (E. coli). This allowed them to compare insects harboring bacteria capable of producing polyamines with those harboring bacteria in which polyamine production genes had been deleted.

"Polyamines, including putrescine and spermidine, are well-known metabolites of gut microbes associated with improved biological functions and life extension. We wanted to understand whether polyamines produced specifically by gut bacteria could directly influence host lifespan, independent of polyamines obtained from the diet," explained Dr. Shin Kurihara, who led the study.

First, the scientists examined the effect of dietary polyamines on germ-free flies maintained on a chemically defined diet without polyamines, supplemented with either putrescine or spermidine. Both supplemented groups lived significantly longer than flies on the polyamine-free diet. The median lifespan was 20.8 days for those receiving putrescine and 21.1 days for those receiving spermidine, compared to only 18.2 days in the control group.

The team then tested whether polyamines produced specifically by gut bacteria could contribute to life extension. Flies were colonized with one of three genetically distinct E. coli strains: SK929 (wild type, producing putrescine), SK930 (a mutant with three putrescine biosynthesis genes deleted), and SK931 (a complemented strain capable of producing putrescine). All groups were maintained on a modified polyamine-free diet.

Putrescine was detected in whole-fly homogenates of flies colonized with SK929 and SK931 at levels of approximately 1.2 and 1.3 nmol/mg, respectively. In flies with SK930, it was below the detection limit. Spermidine was detected in all three groups, consistent with the flies' ability to synthesize polyamines on their own. Higher putrescine levels in flies with the producing strains indicate uptake of bacterial putrescine by the host and its conversion to spermidine.

Lifespan results showed sex-dependent differences. In males colonized with the putrescine-producing strains SK929 and SK931, the median lifespan was 13.8 and 12.6 days, respectively, compared to 11.0 days in flies with the non-polyamine-producing strain SK930. Both groups with producing strains lived significantly longer.

In females, the effect was less consistent across strains. Females with SK929 lived a median of 14.9 days—significantly longer than the 11.0 days of the control group with strain SK930—however, the complemented strain SK931 yielded a median lifespan of only 10.7 days. The average life-extending effect was 14–35%, depending on the strain and sex of the individual.

The researchers also investigated the molecular mechanisms underlying the lifespan extension. Compared to the polyamine-free control group, the host's interaction with polyamine-producing bacteria correlated with a significant reduction in the expression of TotM and Halo. Since TotM is associated with the immune/stress JAK/STAT signaling pathway, which becomes activated with age, its downregulation may contribute to lifespan extension. However, the exact mechanism remains to be elucidated.