In a recent study, lifelong, repeated microbiota transfer from young mice to old mice improves intestinal permeability, coordinative ability, and metabolic profiles while reducing pro-inflammatory responses [1].
Small in size, but mighty in impact
Previous research has found that the composition and function of gut microbes (microbiota) changes as we age. These changes are linked to health and lifespan [2], suggesting that the microbiota can be targeted for lifespan and healthspan extension.
Initial experiments with microbiota transfer in model organisms gave positive results, suggesting the possibility of lifespan extension [3] or improvements in brain function [4]. However, such studies usually involve only one transfer and use mostly germ-free mice, which exhibit many changes in physiology, from an attenuated immune system to problems with nutrient absorption [3]. Being raised germ-free, without any microbiota in the gut, is also not an approach that can be translated into human therapeutic strategies in the future.
A different approach
The authors of this study took a different approach. They performed recurring (every 8 weeks) fecal microbial transfers and used conventionally raised mice. Before each colonization procedure, they treated them with an antibiotic to wipe the intestinal microbiota and improve the efficiency of microbiota transfer. Using antibiotics comes with some downfalls, such as the possibility of developing antibiotic resistance and the potential impact of antibiotics on aging processes.
To achieve a rejuvenating effect, the microbiota was derived from 8-week-old mice (young microbiota); in the control animals, the researchers transferred the microbiota from animals of the same age.
Optimizing for a longer lifespan
The researchers monitored the animals until the end of the experiment (week 120), when a large proportion of mice in the control group died quickly. This suggested lifespan extension in the group receiving the young microbiota transfer; however, this result is not statistically significant due to a low number of remaining animals.
The researchers suggest that the lack of statistical significance, despite the relatively large number of animals at the beginning of the study (20 per group), could be due to variability in biological response to the treatments. They also note that the death of several animals in both groups of early time points could contribute to the lack of statistical significance. Those deaths were induced by lesions caused by forcibly feeding the animals when transferring the microbiota.
In future studies, they recommend optimizing the treatment regimen for optimal lifespan extension. They believe that such parameters as antibiotic dosing, frequency of transfers, and less invasive fecal transplant methods are essential.
Improvements, but not everywhere
The researchers analyzed a few aging-related phenotypes. They noted no difference between groups regarding glucose homeostasis, as measured by the glucose tolerance test.
Muscle function, assessed by measuring grip strength, also didn’t show differences between groups, but the researchers observed coordination improvements in the mice receiving young microbiota transplants.
Rejuvenated microbiota rejuvenates the host
Since the microbiota has direct contact with the intestinal walls, the researchers analyzed the impact of the microbiota transplants on the intestinal barrier. Young microbiota transfers reduced the amount of bacterial antigen leakage, suggesting improved intestinal barrier function.
Changes were also observed in the composition of microbiota. The group that received the young microbiota transplant had a microbiota composition more similar to that of the 8-week-old animals. The metabolic functions of the microbiome were also rejuvenated. This rejuvenated microbiota “provided beneficial metabolic functions to the host and thereby may contribute to delaying physiological processes associated with aging.”
Among the improved composition of microbiota content in the animals receiving young microbiota transfer, the researchers pointed to the increased abundance of Akkermansia, a bacterium linked to improved health and lifespan in mice [5]. However, some results need further investigation and clarification, including the reduced abundance of Lactobacillus bacteria, which are normally considered beneficial, in animals receiving the young microbiota transfer. The researchers speculate that differences in specific strains might drive the differences, but they require further investigation.
Rejuvenated biological processes
Transplanting young microbiota led to gene expression changes in immune, colon, and small intestine cells. Many of those changes were cell-type specific, and they pointed to effects on some aging-related processes.
First, the researchers assessed mesenchymal scores by measuring the expression of signature mesenchymal genes in epithelial cells. More epithelial cell transition into a mesenchymal-like state is associated with older age. They observed lower mesenchymal scores in several types of intestinal epithelial cells in animals who received young microbiota transfers compared to the control group, suggesting rejuvenation processes.
Next, the researchers used gene expression associated with aging-related inflammation to create an inflammatory score. This score was lower in young mice compared to old mice.
In mice who underwent lifelong microbiota transplants, the inflammatory score was lower in multiple immune cells from mice who received young microbiota transplanta. This observation aligns with the previously observed restored intestinal barrier in those animals, as reduced leakage through the barrier helps reduce inflammation.
Apart from gene expression, the researchers also investigated ligand-receptor interactions, interactions between two proteins that, after recognizing each other, can initiate and regulate many biological processes.
An analysis suggested fewer ligand-receptor interactions in epithelial and immune cells derived from mice receiving young microbiota. However, there were differences between those two cell types, with epithelial cells showing stronger interactions. According to the authors, these results suggest “more focused transcriptional response after microbiome rejuvenation.”
However, in the immune cells, the interaction strength decreased, with macrophages and T cells contributing the most to the decrease in the number and strength of interactions. Further investigation is needed to understand those differences and their connection with rejuvenation.
Optimizing for better health in humans
While this study didn’t report significant differences regarding lifespan extension following continuous young microbiota transfers in mice, it reported substantial healthspan-related improvements such as better coordinative ability, a tightened intestinal barrier, reduced inflammation, and cell type-specific changes in gene expression and rejuvenated metabolic profiles. This study’s results suggest that microbiota transfer can be an interesting treatment for healthspan or lifespan extension, but it needs further optimization and testing in humans.
Literature
[1] Sommer, F., Bernardes, J. P., Best, L., Sommer, N., Hamm, J., Messner, B., López-Agudelo, V. A., Fazio, A., Marinos, G., Kadibalban, A. S., Ito, G., Falk-Paulsen, M., Kaleta, C., & Rosenstiel, P. (2025). Life-long microbiome rejuvenation improves intestinal barrier function and inflammaging in mice. Microbiome, 13(1), 91.
[2] Sommer, F., & Bäckhed, F. (2013). The gut microbiota–masters of host development and physiology. Nature reviews. Microbiology, 11(4), 227–238.
[3] Smith, K., McCoy, K. D., & Macpherson, A. J. (2007). Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Seminars in immunology, 19(2), 59–69.
[4] Parker, A., Romano, S., Ansorge, R., Aboelnour, A., Le Gall, G., Savva, G. M., Pontifex, M. G., Telatin, A., Baker, D., Jones, E., Vauzour, D., Rudder, S., Blackshaw, L. A., Jeffery, G., & Carding, S. R. (2022). Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain. Microbiome, 10(1), 68.
[5] Bárcena, C., Valdés-Mas, R., Mayoral, P., Garabaya, C., Durand, S., Rodríguez, F., Fernández-García, M. T., Salazar, N., Nogacka, A. M., Garatachea, N., Bossut, N., Aprahamian, F., Lucia, A., Kroemer, G., Freije, J. M. P., Quirós, P. M., & López-Otín, C. (2019). Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nature medicine, 25(8), 1234–1242.
