Microbiome Contributions to Age-Associated Cognitive Decline

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PROJECT SUMMARY/ABSTRACT Aging is an inexorable, multifactorial process in which organisms lose fitness and ability to maintain homeostasis. With advances in modern medicine and standards of living across the globe, life expectancy, and thus aging, is set to expand rapidly. Cognitive decline due to Alzheimer’s disease and other age-associated dementias is one of the most debilitating aspects of aging, robbing millions of people of everyday function and independence. Healthier aging and independence are potentially worth trillions of dollars in addition to unquantifiable social and emotional benefits. As we get older, our cells are not the only thing in our body that age. The microbiome is the collection of trillions of microorganisms that inhabit our gastrointestinal tract. Like organ systems, the microbiome also changes with age, losing diversity and gaining deleterious species. It is widely accepted that the microbiome plays an important role in metabolism, digestion, and obesity, but recently it has also been linked to disease processes in the brain, such as autism and depression. The vagus nerve connects the central and enteric nervous systems to mediate gut-to-brain signaling, and its ablation has been shown to induce cognitive deficits in rats. Additionally, it has also been shown that performing fecal microbiome transplants (FMT) from old mice into young germ-free mice induces cognitive deficits. In initial experiments, I have shown that passive transfer of the microbiome by cohousing young and old mice induces cognitive deficits in young mice. This effect is not seen in cohoused germ-free or antibiotics-treated mice and is reproduced upon FMT into young germ-free mice from old stool donors. Ablating or inhibiting afferent vagal neurons also induces a cognitive deficit, while vagal stimulation with low dose capsaicin or hormonal activation reverses deficits associated with the aged microbiome. Thus, I propose that the aged microbiome impairs cognition through inhibition of gut-to-brain signaling. To explore this, I will first use bacterial sequencing to identify bacterial species in the aged microbiome that are sufficient to induce cognitive deficits (Aim 1). Next, I will determine which components of gut-to-brain signaling are required for learning and memory (Aim 2). Finally, I will characterize the effects of the aged microbiome with brain-wide mapping of neuronal activation during memory encoding (Aim 3). These studies will provide insight into understudied mechanisms of aging and potentially identify new targets to combat age-associated cognitive decline. I have collected a significant amount of preliminary data and possess the tools and skills required to pursue these aims. The institutional support and resources of the University of Pennsylvania, along with the expertise and mentorship of my sponsors, Dr. Virginia Lee, internationally renowned for her research in neurodegeneration, and Dr. Christoph Thaiss, a microbiome expert, maximize my chances at success. The training I will receive during this proposal will position me to be a future leader in aging and neurodegeneration as a physician-scientist.