Aging cells rewire their surroundings and trigger plaque instability
Deep within the walls of blood vessels, aging cells that refuse to die have long been suspected of quietly destabilizing the architecture of human health. Now, researchers at MD Anderson Cancer Center have traced a precise molecular chain — from the loss of regulatory proteins to the awakening of an enzyme called CD38 — that transforms these lingering cells into engines of inflammation, offering a potential explanation for why plaques that seem stable can suddenly rupture and claim a life.
- Senescent cells stripped of their LATS1/2 regulatory proteins don't simply go quiet — they become hyperactive, leaking inflammation into surrounding tissue and destabilizing the very plaques that protect blood vessel walls.
- The enzyme CD38 emerges as the critical trigger, rewiring cellular metabolism to burn excess energy in ways that fuel clotting and vascular damage — a molecular betrayal hidden inside aging tissue.
- The mechanism was confirmed not just in laboratory models but in actual human plaque samples, closing the gap between bench science and clinical reality and raising the stakes for rapid therapeutic translation.
- Cancer patients face a compounding threat: chemotherapy accelerates cellular aging, and this same CD38 pathway may explain why so many survivors face elevated risks of heart attacks and strokes.
- A potential off-switch already exists — CD38 inhibitors approved by the FDA for blood cancers could be repurposed to stabilize plaques, though biomarker validation in human patients remains the next critical step.
Scientists at MD Anderson Cancer Center have mapped a molecular pathway explaining how aging cells inside blood vessels can abruptly turn lethal. The discovery centers on senescent cells — those that have stopped dividing but persist in tissue — and what happens when they lose a pair of regulatory proteins called LATS1/2. Without these proteins, an enzyme named CD38 activates and fundamentally rewires how the cells consume energy, making them hyperactive and inflammatory. The consequence is atherothrombosis: unstable plaques prone to sudden rupture and clotting, the immediate cause of most heart attacks and strokes.
The research team, led by cardiologists Sivareddy Kotla and Jun-ichi Abe, focused on endothelial cells lining blood vessel walls. Removing LATS1/2 from these cells produced a paradox — senescence and abnormal hyperactivity at once. Elevated CD38 alone was sufficient to reprogram cellular metabolism and destabilize plaques, while blocking CD38 reversed the damage in both laboratory and living models. Crucially, the same molecular signatures appeared in human plaque samples taken from actual patients, lending the findings immediate clinical weight.
The implications reach beyond cardiovascular disease. Many chemotherapy regimens accelerate cellular aging as a side effect, and the CD38 pathway may explain the elevated cardiac risk that haunts cancer survivors. If so, blocking this enzyme could serve a dual purpose — treating cancer while shielding the heart. Some CD38 inhibitors are already FDA-approved for blood cancers, making repurposing a realistic near-term possibility, pending the identification of reliable biomarkers and further validation in human trials.
Scientists at the University of Texas MD Anderson Cancer Center have identified a molecular mechanism that explains how aging cells inside blood vessels can suddenly turn dangerous, triggering the kind of plaque ruptures that cause heart attacks and strokes. The discovery, published in Circulation Research, traces a specific chain of events: when certain regulatory proteins called LATS1/2 go missing from senescent cells—cells that have stopped dividing but refuse to die—an enzyme called CD38 springs to life. Once activated, CD38 rewires how these aging cells burn energy, making them hyperactive and inflammatory. The result is unstable plaques prone to clotting, a condition researchers call atherothrombosis.
The team, led by cardiologists Sivareddy Kotla and Jun-ichi Abe, studied endothelial cells, the delicate tissue that lines the interior of blood vessels. When they removed LATS1/2 proteins from these cells in laboratory models, something unexpected happened: the cells became senescent but also abnormally active at the same time. They leaked, inflamed their surroundings, grew abnormally, and created the kind of plaques that could suddenly clot. The key driver turned out to be CD38. When the researchers looked closely, senescent cells missing LATS1/2 showed dramatically elevated CD38 levels. Overexpressing CD38 alone was enough to reprogram the cells' metabolism, forcing them to consume extra energy in ways that fueled inflammation and destabilized plaques. Blocking CD38 reversed the damage both in test tubes and in living models.
What makes this finding particularly significant is that the researchers validated it using actual human plaque samples taken from patients. Those samples showed the same metabolic signatures and molecular pathways the team had observed in their preclinical work. This bridge between laboratory discovery and human tissue suggests the mechanism is real and potentially actionable. Kotla emphasized the clinical stakes: understanding how aging cells rewire their environment and trigger plaque instability is essential for developing treatments that could prevent sudden cardiovascular events.
The implications extend beyond atherosclerosis alone. Many cancer treatments accelerate cellular aging as a side effect, and patients undergoing chemotherapy often face increased risk of heart attacks and strokes. If this CD38 pathway is indeed responsible for that cardiovascular toxicity, then blocking it might protect cancer patients from these serious complications. Abe noted that the findings reveal a previously hidden connection between blood flow patterns, cellular metabolism, and vascular disease—a connection that opens new avenues for prevention.
Perhaps most intriguingly, some CD38 inhibitors are already FDA-approved for treating certain blood cancers. Those drugs could potentially be repurposed to stabilize plaques and reduce thrombosis risk, though the researchers acknowledge that more work is needed to identify biomarkers and validate targets in human patients. The pathway from aging cell to heart attack, it turns out, may have a molecular off-switch that medicine already possesses.
Notable Quotes
Understanding how aging cells rewire their surroundings and trigger plaque instability is essential for developing therapeutic strategies that can reduce the risk of serious cardiovascular events.— Sivareddy Kotla, associate professor of Cardiology, UT MD Anderson
These findings reveal an entirely new connection between blood flow patterns, cellular metabolism and vascular disease, opening new avenues for preventing plaque progression and thrombotic complications.— Jun-ichi Abe, professor of Cardiology, UT MD Anderson
The Hearth Conversation Another angle on the story
Why does it matter that these cells are senescent rather than simply dead?
Because senescent cells don't disappear—they linger and become metabolically active troublemakers. They're like a factory that's shut down but still burning fuel and creating pollution.
So the loss of LATS1/2 proteins is the trigger?
It's the key that unlocks CD38. Without LATS1/2 acting as a brake, CD38 goes into overdrive, forcing the cell to consume energy in ways that fuel inflammation.
And this happens in the plaques themselves?
Yes. The senescent cells are part of the plaque's structure. When they become hyperactive, they destabilize the entire plaque from within, making it prone to rupture and clot.
Why would cancer treatments cause this same problem?
Many chemotherapy drugs deliberately trigger senescence in tumor cells. But they also damage healthy cells the same way, accelerating aging in blood vessel tissue and potentially activating this same CD38 pathway.
If CD38 inhibitors already exist for cancer, why haven't they been used for heart disease?
Because nobody knew CD38 was the problem. This research provides the mechanistic rationale—the proof that blocking CD38 could actually prevent plaque instability. That changes the conversation about repurposing.
What's the next step?
Human trials. They need to confirm the pathway works the same way in living patients, identify who's at highest risk, and test whether CD38 inhibitors actually prevent heart attacks and strokes.