A failing recycling pathway disables senescent cells and the macrophages meant to remove them. Restoring it with an oral compound cut senescent-cell buildup across several organs in aged mice.
Senescent cells are cells that have stopped dividing but refuse to die. They accumulate with age, and they are not merely inert: they secrete inflammatory signals that damage surrounding tissue and are implicated in fibrosis, arthritis, cardiovascular disease and a lengthening list of age-related conditions. The nickname is zombie cells, and much of the geroscience field has spent a decade trying to kill them.
A study in Nature Aging from the Albert Einstein College of Medicine proposes a different approach, based on a different diagnosis of why they build up. The problem is not only that more senescent cells are produced. It is that the immune cells responsible for clearing them stop being able to.
One failing pathway, two failing cell types
The mechanism the team identifies is chaperone-mediated autophagy, or CMA — a cellular recycling process that selectively picks out damaged proteins and delivers them to the lysosome for breakdown. CMA activity declines with age, which has been known; what this work shows is that the decline disables both sides of the senescent-cell problem at once.
On the senescent-cell side, the researchers found that cells from old mice failed to raise their CMA activity when pushed into senescence, unlike cells from young mice, which do. The consequence is that damaged proteins go undigested, and the cells secrete toxic substances that both drive nearby cells into senescence and impair the macrophages trying to clear them.
On the immune side, macrophages from older animals had lower CMA activity than those from younger animals, and the deficit reduced their ability to engulf senescent cells. The cleaners are impaired by the same age-related failure as the mess they are meant to clean.
“In older animals, age-related changes in both senescent cells and the immune cells responsible for removing them allow these zombie cells to accumulate and play a role in disease,” said Dr Ana Maria Cuervo, distinguished professor of developmental and molecular biology and of medicine at Einstein, co-director of its Institute for Geroscience, and the study’s leader.
“Our research connects two major drivers of aging — declining CMA and cellular senescence — and shows for the first time how their interaction allows senescent cells to evade clearance by the immune system in old organisms,” she said.
The wound that would not close
The most direct demonstration came from a wound-healing experiment. Mice whose macrophages specifically lacked CMA accumulated more senescent cells at wound sites and healed more slowly.
That design is the useful one, because it isolates the macrophage contribution. Knocking out CMA only in the immune cells, and still seeing senescent cells pile up, shows that impaired clearance is sufficient to cause accumulation — the senescent cells need not be producing more of themselves for the problem to worsen.
Restoring the pathway
The intervention was an oral CMA activator designated CA77.1, given daily for five months to aged mice. It reduced zombie-cell buildup in several organs and reduced signs of inflammation and fibrosis.
Treating macrophages from aged mice with the compound restored their engulfing ability to levels comparable with young mice — an unusually clean result, in that a single intervention returned an aged cell’s function to a youthful level on that specific measure.
The strategic argument Cuervo draws from this is the paper’s most interesting claim. “We’ve also found that instead of trying to kill zombie cells, we may be able to restore their interaction with the immune system so that the body can clear them naturally,” she said. “By restoring cellular recycling, we may be able to help the body’s own defenses clear these cells more effectively.”
That is a pointed alternative to the dominant approach. Senolytics — drugs that kill senescent cells — have been the field’s main line of attack, and they face a persistent difficulty: senescence is a protective program as well as a damaging one, deployed to stop damaged cells becoming cancerous, and a drug that kills senescent cells broadly may remove cells that were doing a job. Restoring immune clearance would, in principle, let the body apply its own judgement about which cells to remove.
The human thread
The clinical hook is idiopathic pulmonary fibrosis, a progressive scarring of the lungs with a median survival of three to five years after diagnosis and almost nothing in the way of effective treatment. Lung samples from IPF patients showed markedly reduced CMA activity, and in a mouse model of the disease, CA77.1 started early after lung injury reduced the severity of fibrosis along with senescence and inflammation.
The human tissue analysis is what lifts this above a purely murine result: the pathway the team identified in mice is demonstrably disrupted in the human disease. That is correlation in human tissue rather than intervention, but it is the right kind of supporting evidence.
The qualifier “started early after lung injury” deserves weight. IPF patients present with established fibrosis, often years into the process. A compound that prevents fibrosis from developing when given promptly after injury may do much less for scarring already in place.
What the release does not provide
The gaps here are mostly quantitative. The release gives essentially two numbers — five months of treatment, and the three-to-five-year IPF survival figure — and no sample sizes, effect sizes or statistics for any experiment. How much senescent-cell buildup was reduced, in which organs, by how much, with what variability, are all absent.
Five months of daily dosing in a mouse is a substantial fraction of its life, and the release reports nothing about side effects or toxicity. CMA is a general cellular process; a compound that boosts it systemically for months might have consequences beyond the intended ones, and the absence of any safety comment is a gap rather than a reassurance.
There is no formal conflict-of-interest statement. The release does note that Albert Einstein College of Medicine holds intellectual property related to the research and is seeking licensing partners, providing a contact for interested parties — which is a commercial interest disclosed in substance if not in form, and readers should weigh it. Funding came from the NIH National Institute on Aging, the Hevolution Foundation, the Freedom Together Foundation and the Rainwaters Foundation; the work grew out of an Einstein Hevolution Partnership Award that Cuervo led.
Rebecca Sereda is named as first author, having done the work as a graduate student in Cuervo’s laboratory, co-mentored by Dr Susmita Kaushik, with a long list of collaborators at Einstein, Ohio State, the Centre de Recherche des Cordeliers, Gustave Roussy and the University of Pittsburgh.
Cuervo’s own assessment of the distance remaining is the right note to end on. “The next challenge is determining whether this approach can eventually be developed into a safe treatment for age-related diseases in people,” she said.
Notes
- Sereda, R., et al. “Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells.” Nature Aging, 2026. DOI: 10.1038/s43587-026-01240-w.
- Albert Einstein College of Medicine. “Einstein researchers discover why ‘zombie cells’ accumulate with age.” EurekAlert!, 5 October 2026. https://www.eurekalert.org/news-releases/1146420.