UVA researchers discover key driver of chronic inflammation that accelerates aging

University of Virginia School of Medicine researchers have discovered a key driver of chronic inflammation that accelerates aging. That finding could allow us to slow the clock to live longer, healthier lives, and will allow us to forestall age-related conditions reminiscent of deadly heart disease and devastating brain disorders that rob us of our schools.

So what drives this harmful inflammation? The reply is improper calcium signaling within the mitochondria of certain immune cells. Mitochondria are the ability generators in all cells, and so they rely heavily on calcium signaling.

The UVA Health researchers, led by Bimal N. Desai, PhD, found that mitochondria in immune cells called macrophages lose their ability to take up and use calcium with age. This, the researchers show, results in chronic inflammation answerable for lots of the ailments that afflict our later years.

The researchers consider that increasing calcium uptake by the mitochondrial macrophages could prevent the harmful inflammation and its terrible effects. Because macrophages reside in all organs of our bodies, including the brain, targeting such “tissue-resident macrophages” with appropriate drugs may allow us to slow age-associated neurodegenerative diseases.

I believe we have now made a key conceptual breakthrough in understanding the molecular underpinnings of age-associated inflammation. This discovery illuminates recent therapeutic strategies to interdict the inflammatory cascades that lie at the center of many cardiometabolic and neurodegenerative diseases.”

Bimal N. Desai, PhD, UVA’s Department of Pharmacology and UVA’s Carter Immunology Center

The inflammation of aging – ‘inflammaging’

Macrophages are white blood cells that play critical roles in our immune systems and, in turn, our good health. They swallow up dead or dying cells, allowing our bodies to remove cellular debris, and patrol for pathogens and other foreign invaders. On this latter role, they act as necessary sentries for our immune systems, calling for help from other immune cells as needed.

Scientists have known that macrophages grow to be less effective with age, however it has been unclear why. Desai’s recent discovery suggests answers.

Desai and his team say their research has identified a “keystone” mechanism answerable for age-related changes within the macrophages. These changes, the scientists consider, make the macrophages vulnerable to chronic, low-grade inflammation at the very best of times. And when the immune cells are confronted by an invader or tissue damage, they’ll grow to be hyperactive. This drives what’s often called “inflammaging” – chronic inflammation that drives aging.

Further, the UVA Health scientists suspect that the mechanism they’ve discovered will hold true not only for macrophages but for a lot of other related immune cells generated within the bone marrow. Which means we may find a way to stimulate the correct functioning of those cells as well, potentially giving our immune systems an enormous boost in old age, once we grow to be more at risk of disease.

Next steps

Fixing “inflammaging” won’t be so simple as taking a calcium complement. The issue is not a shortage of calcium a lot because the macrophages’ inability to make use of it properly. But Desai’s recent discovery has pinpointed the precise molecular machinery involved on this process, so we should always find a way to find ways to stimulate this machinery in aging cells.

“This highly interdisciplinary research effort, on the interface of computational biology, immunology, cell biology and biophysics, would not have been possible without the determination of Phil Seegren, the graduate student who spearheaded this ambitious project,” Desai said. “Now, moving forward, we’d like an equally ambitious effort to determine the wiring that controls this mitochondrial process in various kinds of macrophages after which manipulate that wiring in creative ways for biomedical impact.”

Aging findings published

The researchers have published their findings within the scientific journal Nature Aging. The article is open access, meaning it’s free to read.

The research team consisted of Seegren, Logan R. Harper, Taylor K. Downs, Xiao-Yu Zhao, Shivapriya B. Viswanathan, Marta E. Stremska, Rachel J. Olson, Joel Kennedy, Sarah E. Ewald, Pankaj Kumar and Desai. The scientists reported that they haven’t any financial interests within the work.

The research was supported by the National Institutes of Health, grants AI155808, GM108989, GM138381, P30 CA044579 and T32 GM007055-46, and by the Owens Family Foundation.