UCI study reveals why immunity declines as we age

Researchers identify path to restore T cell effectiveness to fight disease in older adults

April 12, 2022
UCI Health neurologist Michael Demetriou, MD, PhD, and fellow researchers identify mechanism that leads to weak immune systems as we age.
“Through this study, we have gained a new understanding of why older adults are more susceptible to infectious diseases, which will enable us to identify potential new treatments," said Michael Demetriou, MD, PhD, a professor of neurology who leads the Department of Neurology's multiple sclerosis and neuroimmunology group at the UCI School of Medicine. Photo by Steve Zylius / UCI

Irvine, Calif. — UCI researchers have discovered how older adults become significantly more susceptible to infectious diseases as they age, a critical societal issue highlighted by the COVID-19 pandemic.

They also were able to reverse the severity of bacterial infection in preclinical tests. These findings pave the way to develop therapeutic targets that could rejuvenate the immune systems of older people and reduce their risk of infectious disease, according to the UCI study published in Nature Aging.

“Through this study, we have gained a new understanding of why older adults are more susceptible to infectious diseases, which will enable us to identify potential new treatments,” said the study's senior author, Michael Demetriou, MD, PhD, a UCI School of Medicine professor of neurology and chief of the Department of Neurology's division of Multiple Sclerosis and Neuroimmunology.

'Potential fountain of youth'

“We’ve identified a potential fountain of youth for the immune system,” added Haik Mkhikian, MD, PhD, assistant professor of pathology and first author of the research paper, titled "Age-associated impairment of T cell immunity is linked to sex-dimorphic elevation of N-glycan branching."

The study showed that the body's T cell function declines with age, increasing the severity and mortality from infectious disease. T cells are the quarterback of the immune system and they coordinate immune responses to fight off infections. T cell functioning is suppressed by the addition of complex and branched carbohydrate chains called glycans to proteins.

Researchers found that branched glycans increase with age in T cells due to age-associated increases in an important sugar metabolite (N-acetylglucosamine) and signaling by the T cell cytokine interleukin-7. This occurs more in female T cells than in those of males.

“Our research reveals that reversing the elevation in branched glycans rejuvenates human and mouse T cell function and reduces severity of salmonella infection in old female mice,” Demetriou said.

Mkhikian added, “This suggests several potential novel therapeutic targets to revitalize old T cells, such as altering branched glycans or the age-triggered elevation in serum N-acetylglucosamine and IL-7 signaling.”

Targeting immune dysfunction

Aging-associated immune dysfunction, referred to as immunosenescence, contributes to increased morbidity and mortality from both infectious and neoplastic diseases in adults ages 65 and older.

For example, up to 85% of U.S. seasonal flu-related deaths occur in people who are age 65 and older, a group that represents about 16% of the nation’s population. The vulnerability of this population to viral infections has been tragically highlighted by the emergence of the SARS-CoV-2 virus, which has claimed the lives of nearly 1 million Americans, about 74% of them age 65 and older.

Increased morbidity and mortality in older adults also occurs with common bacterial infections, such as those caused by the enteric pathogen salmonella. The efficacy of immunizations also declines with age, further increasing risk of infection in older adults. The rapid aging of populations in developed countries heightens the need for effective interventions to target immunosenescence.

Previous studies of age-associated dysfunction examined transcriptome changes in highly purified aged T cell subsets. In this study, researchers analyzed T cell populations by age and sex, with results suggesting sex-specific differences, which imply that effective methods to reverse immune dysfunction in older adults may require sex-specific strategies.

The study was supported by funding from the National Institute of Allergy and Infectious Disease, the National Center for Complementary and Integrative health, The Burroughs Wellcome Fund and a predoctoral fellowship from the American Heart Association.

About the UCI School of Medicine

Each year, the UCI School of Medicine educates more than 400 medical students and nearly 150 doctoral and master’s degree students. More than 700 residents and fellows are trained at UCI Medical Center and affiliated institutions. The School of Medicine offers an MD; a dual MD/PhD medical scientist training program; and PhDs and master’s degrees in anatomy and neurobiology, biomedical sciences, genetic counseling, epidemiology, environmental health sciences, pathology, pharmacology, physiology and biophysics, and translational sciences. Medical students also may pursue an MD/MBA, an MD/master’s in public health, or an MD/master’s degree through one of three mission-based programs: the Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), the Leadership Education to Advance Diversity-African, Black and Caribbean (LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UCI School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit som.uci.edu.

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