Youthful Gut Microbiomes as Drivers of Rejuvenation and Healthy Aging - PROJECT SUMMARY/ABSTRACT The gut microbiome, often described as an “extra organ”, is essential for maintaining systemic homeostasis and human health. Aging profoundly alters the gut microbial ecosystem, leading to dysbiosis that contributes to cognitive decline, metabolic dysfunction, immune senescence, and increased susceptibility to age-related diseases. Targeting the microbiome therefore represents a novel and transformative strategy to slow aging and extend healthspan. Fecal microbiota transplantation (FMT) restores microbial diversity and function and is clinically effective for recurrent Clostridioides difficile infection, with growing promise in conditions such as hepatic encephalopathy and inflammatory bowel disease. However, the anti-aging and rejuvenating potential of youthful microbiomes (YMs) remains largely unexplored. Our preliminary studies demonstrate that autologous FMT (autoFMT) using banked YMs in mice produces striking anti-aging effects. YM-autoFMT preserved cardiac and hepatic function, reduced fibrosis, enhanced mitochondrial activity, lengthened telomeres, decreased DNA damage, and completely prevented spontaneous cancers observed in aged controls. These findings suggest that YMs suppress key molecular hallmarks of aging and protect against tumorigenesis. We hypothesize that YMs mitigate molecular and functional hallmarks of aging, thereby slowing or reversing physiological decline, whereas old microbiomes (OMs) exacerbate aging processes and promote dysfunction. To test this hypothesis, Aim 1 will determine whether YM-autoFMT delays physiological and molecular aging in mature adult mice at their functional peak, integrating organ function assessments, organ-specific transcriptomics, and microbiome profiling. Aim 2 will define the rejuvenating potency of YMs versus the pro-geronic effects of OMs in aged mice through allogeneic FMT (alloFMT). We will establish a composite “rejuvenation index” incorporating cardiac, hepatic, and neurocognitive outcomes, and identify microbial taxa and functional pathways distinguishing YMs from OMs to inform the rational design of YM-based microbial consortia. This project positions the gut microbiome as a modifiable driver of aging and pioneers the concept of YM-based rejuvenation. By integrating system-level physiological outcomes with molecular and microbiome-level insights, we will establish whether YMs can preserve healthspan and reverse age-associated decline. These studies will lay the foundation for future R01-funded toxicity and mechanistic investigations, first-in-human trials of YM-FMT, and the development of YM-based microbial therapeutics. Collectively, this work will advance innovative microbiome-targeted strategies to delay or reverse aging, prevent Alzheimer’s disease, and reduce cancer risk.
