Normal’ Aging and the Decline of the Immune System

Developing strategies to boost immunity to slow severe infections 

Dr. Brandt Pence, associate professor in the College of Health Sciences, was awarded an Academic Research Enhancement Award (R15) grant from the National Institute on Aging, a division of the National Institutes of Health.

The 3-year, $414,136 award entitled “Mitochondrial determinants of monocyte dysfunction in aging” is focused on defining how normal aging leads to a decline in the function of the immune system. Pence’s research has previously shown that monocytes, a key immune cell circulating in the blood, have dysfunctional mitochondria when isolated from older adults compared to younger adults. Mitochondria, colloquially known as the “powerhouse of the cell”, are important hubs for metabolism and are central to cellular energy production. Dysfunctional mitochondrial have defects in their ability to maintain cellular energy availability, potentially leading to suboptimal cellular functions. Pence’s previous research, which was funded by the American Heart Association, has also shown that monocytes from older adults do not respond as well to stimuli which activate immune and inflammation responses.

The current NIA grant will focus on linking these observations, to show that impaired mitochondrial function leads to immune system suppression during aging. Pence’s team will examine the function of several mitochondrial proteins to pinpoint how aging causes mitochondrial dysfunction in monocytes, and will test several drugs to bypass dysfunctional metabolic pathways. Co-investigator Dr. Yufeng Zhang, assistant professor in the College of Health Sciences and an expert on mitochondrial biology, will work with Pence’s laboratory staff on this effort. Additionally, co-investigator Dr. Aaryani Tipirneni-Sajja, assistant professor in the Department of Biomedical Engineering, will work with the team to measure levels of intermediate metabolites in several important metabolic pathways. These experiments will generate essential information for future efforts to design therapeutics to counteract the effect of aging.

In collaboration with Dr. Amandeep Bajwa, associate professor in the Department of Surgery at the University of Tennessee Health Science Center, Pence and his team will also transplant healthy mitochondria into monocytes isolated from older adults, as well as to aged mice. They will test whether these mitochondrial transplants can improve immune responses which are typically suppressed during aging. This novel “mitotherapy” is an emerging strategy for treating a variety of inflammatory diseases and has been used successfully in preclinical studies in a variety of animals, as well as in limited human studies in pediatric heart disease patients.

As illustrated by the ongoing COVID-19 pandemic, older adults have reduced immune function which can lead to more severe infections. These changes also are linked to increased risk of many chronic diseases including cancer and heart disease. Pence’s goal is to develop safe, effective, and inexpensive strategies to boost immunity in older adults, a demographic (defined as age 65 or older) which is rapidly expanding in the United States and is expected to reach 80 million by 2040.

For more information, contact Pence at bdpence@mempihs.edu.