Fecal microbiota transplantation from young mice to older mice improved multiple metabolic parameters and some hallmarks of aging, such as inflammation and telomere shortening [1].
Bringing back the balance
Dysbiosis, an imbalance in the gut microbiome, is a newly recognized hallmark of aging [2]. Dysbiosis elevates the risk of many diseases, including cardiovascular diseases [3]. However, the mechanism behind this association is poorly understood.
The authors of this study discuss that vasculature can be especially susceptible to dysbiosis due to the proximity between the intestine and the blood circulation and reference previous research that, by altering gut microbes, such as through antibiotic treatment, influenced vascular function [4].
In this study, the researchers transplanted fecal microbiota from young to middle-aged and aged mice to test the effects of such intervention on vascular function and metabolism.
Metabolic and vascular improvements
The researchers started their investigation by comparing the microbial composition of young and aged mice. Unsurprisingly, they found age-dependent differences in mouse gut microbes. After confirming that gut microbes in the old and young mice differed, they performed fecal microbiota transplants from young (8 weeks old) mice to middle-aged (40-42 weeks old) and aged (over 75 weeks old) mice.
Humans and rodents normally lose weight in advanced age, but in aged mice, fecal microbiota transplantation slowed down this weight loss slightly. This happened despite no changes in food intake, suggesting that the treated mice were absorbing more nutrients from the food.
Fecal microbiota transplantation also altered glucose and lipid metabolism, impacting insulin resistance and cholesterol levels. In middle-aged mice, HDL, the “good” cholesterol, was significantly increased, but LDL, the ”bad” cholesterol, was decreased.
These results suggested the possibility that endothelial function might also be impacted. Previous research had shown that detrimental metabolic changes can damage the endothelium [5], the layer of cells that lines the blood vessels.
The researchers measured endothelium-dependent relaxations as a proxy for endothelial state. They noted that fecal microbiota transplants improved endothelium-dependent relaxations in the aortae and the mesenteric arteries, which distribute blood from the aorta to the gastrointestinal tract, of middle-aged mice.
Aging is associated not only with metabolic changes but also with changes to molecular signaling. In this paper, the researchers observed aging-related downregulation of endothelial nitric oxide synthase (eNOS), AMP-activated protein kinase (AMPK) phosphorylation, and sirtuin 1 (SIRT1) expression in mouse aortae.
Fecal microbiota transplants helped to alleviate those changes. In middle-aged mice following the procedure, the researchers observed increased levels of eNOS and eNOS upstream regulators, AMPK, and SIRT1, in the aorta. This observation suggested the activation of signaling pathways that can potentially improve endothelial function and reduce vascular aging. They also add that “receiving young microbiota at a younger age might be of higher therapeutic efficacy in vasculature.”
Reversing some hallmarks of aging
Aging is known to be associated with chronic inflammation, which can lead to endothelial dysfunction and vascular damage [6], and age-associated dysbiosis is one of the factors that promote inflammation [7]. A fecal microbiome transplant from young to middle-aged mice helped to alleviate this inflammation, as confirmed by the lower levels of pro-inflammatory cytokines in the serum and aortae of middle-aged mice following the transplant.
Researchers believe that the transplant’s anti-inflammatory effect was achieved by reducing leaky gut. This refers to the aging-associated increase in intestinal permeability, the ability of substances and molecules to get through the protective gut membrane. Following fecal microbiota transplantation, the researchers observed lower levels of fecal and serum endotoxins and intestinal fatty-acid binding protein, a biomarker of increased intestinal permeability, in middle-aged mice.
Fecal microbiome transplants were also successful in helping with telomere attrition. These researchers found that fecal microbiota transplantation in middle-aged mice led to the upregulation of telomerase reverse transcriptase, enhanced telomerase activity, and delayed the shortening of relative telomere length in the aorta.
The researchers note that the positive effect of fecal microbiota transplant on telomeres “was lower in aged mice when compared to middle-aged mice”, suggesting that optimizing the timing of this intervention can enhance its positive effects.
The authors performed similar testing on the intestine, which is in direct contact with the microbiota. They observed that this tissue and the vasculature received similar beneficial effects in middle-aged mice: decreased expression of pro-inflammatory genes, reduced telomere dysfunction, and increased expression of AMPK and SIRT1. Some of the improvements were better in the intestine than in vascular tissues.
Further optimization needed
The researchers believe that further research is needed to investigate the long-term effects, impacts on other organs and tissues, safety, and efficacy of fecal microbiota transplants and whether similar beneficial effects can be observed in humans. The authors believe that a better understanding of the gut-vascular connection can be an avenue for designing therapeutic strategies for age-associated cardiometabolic diseases.
They also point out that the timing of this intervention is essential for optimal results. They believe that since “the pace of aging becomes substantially higher after certain critical timepoints in life [7],” therapeutic effects might be greatly reduced after certain timepoints.
Literature
[1] Cheng, C. K., Gao, J., Kang, L., & Huang, Y. (2024). Fecal Microbiota Transfer from Young Mice Reverts Vascular Aging Hallmarks and Metabolic Impairments in Aged Mice. Aging and disease, 10.14336/AD.2024.0384. Advance online publication.
[2] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243–278.
[3] Hou, K., Wu, Z. X., Chen, X. Y., Wang, J. Q., Zhang, D., Xiao, C., Zhu, D., Koya, J. B., Wei, L., Li, J., & Chen, Z. S. (2022). Microbiota in health and diseases. Signal transduction and targeted therapy, 7(1), 135.
[4] Brunt, V. E., Gioscia-Ryan, R. A., Richey, J. J., Zigler, M. C., Cuevas, L. M., Gonzalez, A., Vázquez-Baeza, Y., Battson, M. L., Smithson, A. T., Gilley, A. D., Ackermann, G., Neilson, A. P., Weir, T., Davy, K. P., Knight, R., & Seals, D. R. (2019). Suppression of the gut microbiome ameliorates age-related arterial dysfunction and oxidative stress in mice. The Journal of physiology, 597(9), 2361–2378.
[5] Bakker, W., Eringa, E. C., Sipkema, P., & van Hinsbergh, V. W. (2009). Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity. Cell and tissue research, 335(1), 165–189.
[6] Donato, A. J., Machin, D. R., & Lesniewski, L. A. (2018). Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease. Circulation research, 123(7), 825–848.
[7] Thevaranjan, N., Puchta, A., Schulz, C., Naidoo, A., Szamosi, J. C., Verschoor, C. P., Loukov, D., Schenck, L. P., Jury, J., Foley, K. P., Schertzer, J. D., Larché, M. J., Davidson, D. J., Verdú, E. F., Surette, M. G., & Bowdish, D. M. E. (2017). Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability, Systemic Inflammation, and Macrophage Dysfunction. Cell host & microbe, 21(4), 455–466.e4.
