Session Will Highlight Intersection of Cellular Aging, Age-Related Inflammation, and Autoimmune Dysfunction

Chronic, low-grade, aging-related inflammation — inflammaging — is a core mechanistic feature of a broad swath of age-related disorders, including cancers, Alzheimer’s disease, and osteoarthritis. Inflammaging is also linked to immune dysfunction and autoimmunity-mediated rheumatologic disorders.

During Inflammaging: Old Cells Die Hard, which will be held on Monday, Nov. 18, from 10–11:30 a.m. ET in Room 143ABC of the Walter E. Washington Convention Center, experts will delve into inflammaging and immunologic dysfunction/cellular senescence, and their roles in autoimmunity and aging. The session will be available on demand within 48 hours for registered ACR Convergence 2024 participants.

James Kirkland, MD, MSc, PhD, Director of the Center for Advanced Gerotherapeutics, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center and Emeritus Professor of Medicine, Mayo Clinic, will provide an overview of inflammaging and senescent cells, their impact in a range of disease states across the lifespan, and senolytics — drugs or therapies that promote removal of senescent cells.

“Senescence is a cell fate, an alternative to fates such as cell division, necrosis, or differentiation,” Dr. Kirkland said. “Senescent cells can develop at any point during life and in any cell type as a response to damage or stress, including mechanical/shear stress and infections.”

Although senescent cells themselves are resistant to apoptosis, Dr. Kirkland explained, they can promote the death of surrounding cells. Moreover, senescent cells attract, anchor, and activate immune cells, which normally mediate clearance of senescent cells. Senescent cells have important physiological functions, such as in tissue remodeling. However, persistence or accumulation of senescent cells can drive pathologic changes.

Senescent cells can be non-inflammatory or inflammatory, according to Dr. Kirkland, with the potential for rapid interconversion between these subtypes based on exogenous factors. Persistent senescent cells can cause tissue dysfunction and fibrosis, induce immune dysfunction, produce growth factors that accelerate cancer growth, cause spread of senescence locally and distantly, decrease the ability to respond to injury, and contribute to many acute and chronic conditions and diseases, leading to multimorbidity, frailty, loss of independence, and mortality.

Transiently disabling pro-survival pathways in senescent cells, via senolytics, allows those senescent cells that are tissue-damaging to self-kill, Dr. Kirkland explained.

“The field of senescence-targeted therapeutics has moved remarkably quickly — from the first article about senolytics in 2015, to the first published clinical trials in 2019, a bench-to-bedside process that usually takes 12 to 17 years,” he said.

Dr. Kirkland heads the National Institutes of Health (NIH) Translational Geroscience Network, through which 87 clinical studies of aging, including over 20 clinical trials of senolytics for different disorders and diseases, are currently underway. Some of these clinical studies — for osteoporosis, macular degeneration, and Alzheimer’s disease — have generated promising results or met study endpoints, he said. Retrospective analyses also reveal potential senolytic or senomorphic — inhibiting the production of damaging factors by senescent cells — effects of some drugs, such as the bisphosphonate osteoporosis drug zoledronate. Patients with osteoporosis treated with zoledronate have delayed development of multiple diseases, including cancers and vascular diseases. Other senomorphics include agents related to rapamycin, metformin, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) inhibitors.

Dr. Kirkland noted that rheumatologists overall are more aware of the role of senescent cells than practitioners of most other medical specialties, yet there is a need for more research on the role of senescent cells in autoimmune and rheumatologic disorders before the potential of senescence-targeted therapies can be actualized in this setting.

“Senescent cells are essentially part of the immune system and engage with and regulate the immune system via reciprocal interactions and signaling,” Dr. Kirkland said. “There is a tremendous interplay between senescent cells and the immune system at all levels.”

Stella Victorelli, PhD, Assistant Professor of Physiology at the Mayo Clinic in Rochester, will review the role of the mitochondria in regulating senescence.

During senescence, mitochondria become dysfunctional, Dr. Victorelli said, explaining that they have less efficient oxidative phosphorylation, produce more reactive oxygen species (ROS), and generally become hyperfused. There is also some evidence that senescent cells cannot get rid of damaged mitochondria as efficiently as young cells, which might contribute to the accumulation of dysfunctional mitochondria.

“One study from our lab has demonstrated that mitochondria are essential for promoting the pro-inflammatory phenotype of senescent cells, implicating mitochondria as major drivers of inflammation during senescence,” Dr. Victorelli said, adding that leakage of mitochondrial DNA (mtDNA) into the cytosol in senescent and aged cells can lead to activation of pro-inflammatory pathways. “Importantly, we showed that if we inhibit the pathway involved in mtDNA cytosolic leakage, we can reduce age-related inflammation and improve the health span of aged mice.”

Dr. Victorelli noted that they also found that leakage of mitochondrial double-stranded RNA during senescence regulates the pro-inflammatory phenotype of senescent cells, and that pathways involved in the recognition of cytosolic RNA also play a role during aging and disease, such as metabolic dysfunction-associated steatohepatitis (MASH).

The evidence suggests that mitochondria are promising targets for the development of drugs that decrease inflammation and improve health span during aging, she said. She also discussed a new perspective on the role of mitochondria, not just as powerhouses of cells, but as signaling hubs that reflect the overall health of the cells. When homeostasis is disturbed, mitochondrial integrity might become compromised, allowing mitochondrial contents to leak into the cytosol. Given the bacterial origin of mitochondria, these molecules may lead to cell death or inflammation, contributing to chronic inflammation and inflammation-associated pathogenesis.

Bernard Khor, MD, PhD, Affiliate Assistant Professor at the University of Washington and Assistant Member of the Benaroya Research Institute, will focus on how Down syndrome may inform the understanding of inflammaging.

“People with Down syndrome have molecular, cellular, and clinical features of immune dysregulation, and many of those features resemble what you see with inflammaging, such as impaired response to vaccines, increased incidence of autoimmunity, and susceptibility to infections,” Dr. Khor said. “Uncovering mechanisms of immune dysregulation in Down syndrome may help us improve therapies for not only individuals with Down syndrome, but ultimately a broader population with immune dysregulation.” 

To this end, Dr. Khor and colleagues have generated high-performing mathematical models for characterizing the immune architecture.

“We are trying to search for the biology that fits the math, instead of trying to force the math upon the biology,” he said.

Linear models are more readily applied to other cohorts, he explained. Although mathematical modeling of aging has long been explored, a significant challenge is generating robust models, as many features may not change linearly with age. Dr. Khor and colleagues have developed a model development approach that relies on an unbiased feature search. This strategy is complementary to other modeling methods, such as clustering-based approaches, to help curate data and identify conceptual frameworks underlying inflammaging.

Their work shows that the immune system of a person with Down syndrome resembles that of someone without Down syndrome who is up to 18 years older, he said, suggesting that Down syndrome is associated with an advanced immune-aging phenotype. Of the many features of the immune system, their work can identify the subset of aging-related changes that are dysregulated in people with Down syndrome.

“There is a higher incidence of autoimmune and rheumatic disease in people with Down syndrome, who also exhibit an inflammaging phenotype,” Dr. Khor said. “People with Down syndrome, therefore, represent a population predisposed to autoimmune dysfunction, and following aging-related changes in this subset may provide insights on aging-related inflammatory pathways in autoimmune diseases.”