Scientists at the Medical College of Georgia at Augusta University have published new research examining why bone and muscle health decline with age. Their findings, recently featured in JCI Insight, indicate that drugs blocking the aryl hydrocarbon receptor (AhR) improved bone mass and prevented muscle function loss in older mice.
The research is part of a program developed over nearly 15 years and supported by a Program Project Grant, which enables multidisciplinary collaboration among researchers. The team includes Meghan McGee-Lawrence, PhD; Sadanand Fulzele, PhD; and Mark Hamrick, PhD. They discovered that activating AhR—particularly through kynurenine—can lead to frailty, bone loss, and muscle decline. AhR is a protein found in cells that responds to environmental toxins and certain metabolic byproducts.
“Our hope is that the discoveries we make during the research will provide new ideas on how to counteract or block the harmful effects of aging on our bones and muscle. We lose bone and muscle as we age, resulting in osteoporosis and sarcopenia. Being able to prevent this bone and muscle loss would let us remain healthier for longer,” said Carlos M. Isales, MD, the J. Harold Harrison, MD Distinguished University Chair in Healthy Aging and chief of the Division of Endocrinology.
McGee-Lawrence explained that their work focuses on a pathway changing with age that may drive bone and muscle loss in older adults. In experiments using drugs to inhibit AhR in aging mice, they observed improved cortical bone mass and enhanced muscle function due not to increased size but to better mechanisms controlling contraction. Preservation of neuromuscular junctions was noted as especially beneficial for movement strength among female animals studied.
Isales’s lab first targeted kynurenine—a compound increasing with age—as it may mediate bone loss. His team has been developing animal models where they can partially knock out an enzyme responsible for converting tryptophan into kynurenine.
“Our hope is that the discoveries we make during the research will provide new ideas on how to counteract or block the harmful effects of aging on our bones and muscles,” Isales said. “We lose bone and muscle as we age, resulting in osteoporosis and sarcopenia. Being able to prevent this bone and muscle loss would let us remain healthier for longer.”
McGee-Lawrence’s group also studied AhR’s role as a mediator of age-related decline as well as kynurenine’s impact on bone health. She pointed out that significant losses in bone and muscle after age 65 are common worldwide—including in the United States—and increase risks such as falls or fractures.
Fractures are particularly problematic: many do not heal well in older individuals, leading to impaired mobility or diminished quality of life; one-fifth of those over 65 who suffer hip fractures do not survive them while most others require some form of assisted care afterward.
According to McGee-Lawrence, hospitalizations from age-related fractures now surpass those from strokes, breast cancer or heart attacks combined—highlighting musculoskeletal decline as a major public health concern.
“When we work together, the science that we can do together is more impactful,” McGee-Lawrence said. “One of the great things about being part of this program project grant is that we all interact regularly. We have weekly meetings with our team of musculoskeletal scientists and also all of the other investigators who study mechanisms of aging on campus to talk about science and talk about where our research is leading us. With these types of collaborative studies, while it is a lot of work to coordinate the efforts across different labs, the payoff is tremendous.”
Hamrick emphasized his group’s focus on understanding mechanisms underlying age-related muscle loss—particularly how elevated AhR activation driven by altered tryptophan metabolism accelerates decline with aging—with hopes this knowledge could lead toward strategies preserving function among older adults.
Fulzele added insight into how AhR signaling alters lipid metabolism within muscles—a process tied closely with weakness or frailty—and noted pharmacological inhibition helped preserve function while preventing detrimental metabolic changes associated with aging.
McGee-Lawrence stressed sharing results across scientific communities enhances impact: “We saw these beneficial effects preventing age-related loss and muscle strength and bone mass in mice across several independent studies in each of our labs. We believe that at least for the bone-side of that equation, that benefit is coming from making the stem cells in the bone marrow that go on to become bone-forming cells proliferate faster,” she said.“The results that agree across independent studies give us confidence this should be pursued further from a translational perspective.”
