The adage tells us the way to someone’s heart is their stomach; a pair of UConn Health researchers are learning the same can be said for the aging process.
Drs. Yanjiao Zhou and Ming Xu have received a $2.7 million award from the National Institutes of Health to gain a better understanding of how the microbiome affects aging and age-related diseases. Zhou is an assistant professor in the UConn School of Medicine. Xu is an assistant professor of genome sciences in the UConn Center on Aging and the Department of Genetics & Genome Sciences.
From birth, our guts begin building a network of bacteria. These benevolent bacteria help support normal digestive functions, boost the immune system and help filter toxins. Changes to the makeup of the microbiome throughout our lives have important consequences for our health.
Over the last decade, researchers have identified cellular senescence, the process by which cells stop dividing and replacing themselves, and the alteration of gut microbial composition as primary processes that facilitate aging and associated metabolic dysfunction.
While the importance of the microbiome and senescence in aging is increasingly recognized, how they two interact remain largely unknown.
“Cellular senescence and the microbiome are two promising modifiable targets in aging,” Zhou says. “Understanding their underlying interaction will provide potential novel therapeutic avenues for improving health and increasing longevity.”
Previous studies showed a high-fat diet accelerated cellular senescence, increased the number of inflammatory gut bacteria and aggravated metabolic function. By contrast, caloric restriction decreased gene expression associated with senescence. Caloric restriction also increased the abundance of Akkermansia, a bacterium with strong anti-inflammatory and anti-aging properties.
The researchers used a novel mouse model in which cells highly expressing cyclin-dependent kinase inhibitor p21 can be eliminated or modulated. These cells play an important role in diseases related to obesity or aging, making it an important target for this study.
Given this knowledge, the team will test the hypothesis that cellular senescence modulates microbiome composition and function. They will alternatively transplant or clear senescent cells in older mice. They will observe the impact of adding or removing these cells on the gut microbiome and microbial metabolism.
The researchers will also investigate the role of senescence-associated secretory phenotype (SASP) in microbiome changes. This phenotype is associated with senescent cells’ high levels of inflammatory cytokines, immune modulators, growth factors and proteases. Xu and Zhou predict inactivation of NF-κB, a protein important for DNA transcription, would suppress SASP in senescent cells with high p21. This will likely have an adverse effect on microbiome makeup.
Conversely, the team will test the hypothesis that the gut microbiome modulates senescence development. They will transplant microbiota derived from a high-fat diet, intermittent fasting diet and a specific microbe into mice to determine which kinds of microbiota suppresses senescent cells.
The results from this study will paint a clearer picture of the impact of diet-related microbiota on cell senescence. This knowledge can be translated to the development of robust interventions targeting senescence, the microbiome or both. Such interventions can have a substantial, wide-ranging impact on health and longevity.
“This study will likely improve our understanding of the microbiome-senescence interaction and how it influences age-associated diseases, which is currently largely unknown” Xu says. “It will lay the groundwork to develop robust interventions including manipulation of senescence, microbiomes, or both to improve health and increase longevity”
Zhou earned her M.D. at Zhangjiakou Medical College. She holds a Ph.D. from Tianjin Medical University in microbiology. She was one of the lead analysts in the first and second phase of Human Microbiome Project. Her research interests include the development of microbiome-based diagnostics and therapeutics for multiple sclerosis and other diseases.
Xu holds a Ph.D. in rehabilitation science from the University of Kansas Medical Center. He completed a fellowship at the Mayo Clinic. His research focuses on leveraging novel mouse models and primary human cells to examine the role and und underlying mechanisms of senescent cells and finding new drugs to target senescent cells.