Penn Dental Medicine Study Illuminates Aging-related Inflammatory Condition

As humans age, hematopoietic stem cells—the immature precursor cells that give rise to all blood and immune cells—tend to accumulate mutations. Some of these mutations enhance the ability of these stem cells to self-renew and expand more effectively than their non-mutated counterparts. This condition, known as clonal hematopoiesis of indeterminate potential (CHIP), is relatively poorly understood but is detectable in over 10% of individuals older than 65. CHIP is associated with increased risks of various inflammation-related diseases.

"These mutations alter the nature of the progeny cells, making them more inflammatory," says Dr. George Hajishengallis from Penn Dental Medicine. "When a significant portion of your immune cells derives from these mutant stem cells, it bodes poorly for chronic inflammatory diseases."

Recently, a research team led by Hajishengallis, in collaboration with scientists from the Dresden University of Technology and the University of North Carolina at Chapel Hill (UNC), has made significant strides in understanding the mechanisms behind CHIP. Their study also revealed that rapamycin, an FDA-approved drug used to prevent organ transplant rejection, could potentially block these mutant stem cells and treat CHIP-driven inflammatory bone loss conditions like periodontitis and arthritis. Their findings were published in the journal Cell.

"We discovered a compelling observational link between DNMT3A, a gene most commonly affected in CHIP, and the prevalence and severity of periodontitis in a study group of 4,946 individuals aged 52 to 74," notes Hajishengallis. "Moreover, we confirmed these findings in our mouse model, demonstrating a robust causal relationship between DNMT3A mutations and heightened susceptibility to inflammatory bone loss disorders. Most excitingly, we showed that rapamycin effectively protected mice from CHIP-exacerbated inflammatory bone loss, paving the way for future treatments in humans."

Considering potential therapeutic strategies, Hajishengallis emphasizes the importance of screening for CHIP in the elderly population. Such screening could identify those at increased risk for inflammatory comorbidities.

These individuals might benefit from therapeutic interventions aimed at blocking the abnormal expansion of CHIP-mutant hematopoietic stem cell clones and mitigating their negative impact on chronic inflammatory diseases.