A new study links an age-related decline in cellular maintenance to impaired immune clearance. Activating the pathway reduced signs of senescence in aged mice [1].
Senescence and autophagy
Cellular senescence, which occurs when cells stop dividing and start emitting largely pro-inflammatory stress signals, the senescence-associated secretory phenotype (SASP), is a double-edged sword. On the one hand, it plays an important role in processes like development and wound healing as well as in regeneration in some animals. On the other hand, with age, senescent cells accumulate in tissues, driving inflammation, fibrosis, and cancer, which earned cellular senescence a place on the Hallmarks of Aging list.
One of the reasons for the age-related accumulation of senescent cells might be the declining ability of immune cells to clear them away. A new study from the Albert Einstein College of Medicine, published in Nature Aging, investigates a mechanism that might be responsible for that.
The researchers focused on chaperone-mediated autophagy (CMA). Autophagy is the process of degrading and removing intracellular junk, such as misfolded proteins, and CMA is a distinct pathway mediated by the chaperone protein HSC70, which recognizes suitable proteins and delivers them to a receptor called LAMP2A. The proteins then unfold and pass into the cell’s lysosomes for degradation. This process differs from macroautophagy, the pathway that delivers cellular material to lysosomes in tiny vesicles.
Previous research showed that CMA generally declines with age [2] and rises when cells enter senescence [3], suggesting that it mediates this transition. The researchers asked whether this failure to increase CMA alters the course of senescence onset and whether CMA decline also compromises immune clearance.
CMA mediates senescence and macrophage function
The researchers isolated ear fibroblasts from 4-month-old (young) and 23-month-old (old) mice. The old fibroblasts were not initially more senescent according to the markers used. Both young and old cells could be induced into senescence with the drug palbociclib, but young fibroblasts increased CMA after senescence induction, while old fibroblasts started with lower activity levels and failed to increase them.
The team then reduced LAMP2A in mouse fibroblasts to ask whether CMA loss itself causes senescence. CMA-deficient cells acquired some senescence-like features but remained proliferative until given a senescence-inducing treatment. After palbociclib treatment, both normal and CMA-deficient cells stopped proliferating, but their overall marker profiles differed. This suggests that while CMA deficiency could not cause growth arrest by itself, it changed the resulting senescent phenotype.
Disabling CMA in young cells reproduced many of the changes found in old cells, both before and after senescence induction. Normally, cells entering senescence remove certain proteins and reorganize their metabolism. Both old and CMA-deficient cells partially failed in that reorganization. This suggests that CMA decline contributes to the aging-associated altered senescent state.
Once induced into senescence, CMA-deficient cells developed a distinct secretory profile. The researchers investigated its effect by applying a medium conditioned by these cells onto normal fibroblasts for five days. Secretions from CMA-deficient cells induced senescence-associated changes in neighboring normal cells, even when the donor cells had not themselves been turned senescent.
The researchers then wanted to see whether these altered secretions suppress CMA and cell-clearing activity in macrophages, immune cells that help remove unwanted cells. Macrophages from old mice already had lower CMA activity than those from young mice. Moreover, the medium conditioned from senescent fibroblasts suppressed CMA in young macrophages. Secretions from CMA-deficient fibroblasts – even non-senescent – were particularly inhibitory.
The researchers then co-cultured senescent fibroblasts with either normal or CMA-deficient macrophages. When the macrophages lacked CMA, they were able to clear fewer fibroblasts, regardless of whether the fibroblasts themselves had functional CMA. This suggests that CMA-deficient cells secrete molecules that compromise CMA and function in the immune cells needed to clear them. The researchers then confirmed this decline in macrophage cell-removing abilities with a series of experiments.
Increasing CMA slows lung fibrosis
The researchers next examined mice in which LAMP2A was selectively deleted in macrophages and some other immune cells. Late in life, these mice showed an increased senescence burden across several tissues, although this varied by sex and measurement.
Since senescent cells participate in wound clearing, the researchers created skin wounds in these mice. Mice with CMA-deficient immune cells healed more slowly and retained more senescent cells at the wound site. The team confirmed that the problem was decreased macrophage function rather than recruitment to the wound site.
What would happen if CMA were increased rather than suppressed in old mice? The researchers administered CA77.1, a drug known to activate CMA, to aged mice and found that these generally had lower senescence-associated measurements than untreated aged mice, with several results moving toward young-control levels. However, the effects differed across tissues, sexes, and markers.
The researchers then investigated idiopathic pulmonary fibrosis (IPF), a lung-scarring disease associated with senescence. Lysosomes isolated from human fibrotic lungs had reduced LAMP2 protein levels and impaired uptake of a CMA substrate.
Finally, the team induced lung fibrosis in mice. CA77.1 treatment started soon after injury (day 2), but not on day 7, preserved body weight and substantially reduced subsequent lung fibrosis, suggesting that early CMA activation limits disease progression.
“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 study leader Ana Maria Cuervo, M.D., Ph.D., co-director of the Institute for Geroscience at Einstein. “By restoring cellular recycling, we may be able to help the body’s own defenses clear these cells more effectively. The next challenge is determining whether this approach can eventually be developed into a safe treatment for age-related diseases in people.”
Literature
[1] Sereda, R., Lindenau, K., Diaz, A. et al. (2026). Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells. Nature Aging.
[2] Khawaja, R. R., Martín-Segura, A., Santiago-Fernández, O., Sereda, R., Lindenau, K., Mccabe, M., … & Cuervo, A. M. (2025). Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging. Nature Aging, 5(4), 691-708.
[3] Rovira, M., Sereda, R., Pladevall‐Morera, D., Ramponi, V., Marin, I., Maus, M., … & Serrano, M. (2022). The lysosomal proteome of senescent cells contributes to the senescence secretome. Aging cell, 21(10), e13707.
View the article at lifespan.io
