Mega Doctor News
Newswise — Understanding how aging reshapes the body and why physical function often declines over time has become a central focus of modern biomedical research.
A new Yale School of Medicine (YSM) study, published in Aging Cell, points to progressive stiffening of the pulmonary artery, the main vessel supplying blood to the lungs, as a potential explanation for some of the age-related declines in heart and lung function.
“When you’re caring for older people, about one out of every three patients over 65 will come in saying, ‘I’m short of breath,’” says Edward Manning, MD, PhD, assistant professor of medicine in the Section of Pulmonary, Critical Care, and Sleep Medicine (Yale-PCCSM). “You can often do an extensive medical workup and still not find an explanation. Their heart, lungs, and arteries seem relatively normal, yet their symptoms persist.”
To explore whether changes in the pulmonary circulation might help explain this persistent breathlessness, Manning, first author and YSM MD-PhD student Ruben De Man, and collaborators across Yale-PCCSM and partnering institutions focused on the pulmonary artery. Using preclinical models, the team examined mechanical, structural, and molecular changes that could serve as biomarkers and potential therapeutic targets for age-related declines in heart and lung function.
Manning’s focus on the pulmonary artery stems from a key insight in vascular biology. The aorta carries oxygen-rich blood from the heart to the rest of the body, while the pulmonary artery carries blood from the heart to the lungs for oxygenation.
“We’ve learned that stiffening of the aorta is one of the strongest predictors of end-organ dysfunction – damage to vital organs such as the kidneys, brain, and heart – throughout the body,” says Manning, who is also a physician at the West Haven VA Medical Center and a Yale Pepper Center Pepper Scholar. “But the lungs are supplied by the pulmonary artery, not the aorta, which raised a simple question: Does the pulmonary artery also stiffen with age, and could this impair lung function?”
The researchers found age-related mechanical and structural changes in the proximal pulmonary artery, the section nearest the heart, including progressive stiffening and reduced capacity to store mechanical energy. These changes were associated with measurable declines in lung function, right-heart performance, and exercise capacity.
They also observed shifts in gene expression and cell signaling within the pulmonary artery consistent with cellular aging and remodeling of the surrounding tissue. In particular, transcriptional analyses highlighted a potential role for perivascular macrophages – immune cells that reside along the outer vessel wall.
“These macrophages seem to help regulate communication among the cells that make up the arterial wall,” Manning says. “In older arteries, their signaling increases and they show signs of senescence, which suggests they could represent a therapeutic target to slow age-related changes in this tissue.”
Manning notes an important unanswered question is how pulmonary arterial stiffening develops over time. “We’re still trying to understand the pathogenesis – whether the pulmonary artery stiffens first, or whether damage in the smaller vessels and lung tissue leads to stiffening of the larger artery,” he says. “But our hypothesis is that once the large pulmonary artery becomes stiff, that change is closely linked to declining lung function.”
Increased stiffness can accelerate the pressure waves traveling through the vessel wall, potentially injuring the delicate lining of blood vessels and nearby capillaries, according to Manning, similar to mechanisms implicated in chronic kidney disease and other forms of end-organ damage.
“This work is a superb example of the potential value of the integration of physiology, biomechanics, and single-cell RNA omics in aging research,” says Naftali Kaminski, MD, Boehringer Ingelheim Pharmaceuticals, Inc. Professor of Medicine (Pulmonary) at YSM and chief of Yale-PCCSM.
For Manning, this research – and aging research more broadly – is ultimately about preserving function, not simply extending lifespan.
“It’s more than just trying to live longer,” he says. “From a geroscience perspective, we want the added years of life to remain functional. If slowing stiffening of the proximal pulmonary artery can help preserve breathing and cardiopulmonary function, then people can live better for as long as they are alive.
“Ultimately, the goal is simple,” Manning adds. “Breathe better, longer.”
Pulmonary, Critical Care and Sleep Medicine is one of 10 sections in the Yale Department of Internal Medicine. To learn more about Yale-PCCSM, visit PCCSM’s website, or follow them on Facebook and X/Twitter.
