In mice, an age-related decline in selective protein breakdown impairs macrophage clearance of senescent cells, while the compound CA77.1 activates this process and limited their accumulation

In mice, an age-related decline in selective protein breakdown impairs macrophage clearance of senescent cells, while the compound CA77.1 activates this process and limited their accumulation

On October 5, Nature Aging published a study from Ana Maria Cuervo’s laboratory at Albert Einstein College of Medicine. In experiments with cells and mice, the authors described a self-reinforcing cycle: senescent cells suppress protein breakdown in macrophages, and macrophages with impaired protein breakdown become less effective at clearing senescent cells.

A senescent cell, sometimes called a “zombie” cell, has stopped dividing but remains alive and releases inflammatory substances. In a young organism, immune cells, including macrophages, clear these cells; in an old organism, they accumulate and contribute to disease. The authors investigated whether this accumulation involved chaperone-mediated autophagy (CMA), a process that selectively breaks down proteins using the LAMP2A receptor on lysosomes. CMA declines with age in most tissues.

A 2022 study coauthored by Cuervo showed that senescent cells increase CMA in cell culture. In the new study, the authors induced connective tissue cells from mice aged 4 and 23 months to stop dividing. CMA increased only in cells from young mice; cells from old mice had lower CMA activity, which did not increase. Disabling CMA in young cells reproduced almost half of the differences in protein composition seen in old cells. These cells continued to divide, but their secretions made healthy cells more likely to develop signs of senescence.

Secretions from senescent cells reduced CMA in young macrophages, and secretions from cells lacking CMA reduced it further. Bone marrow macrophages from old mice also had lower CMA activity than those from young mice. Macrophages lacking CMA were less effective at engulfing particles and dead cells and left more senescent cells in coculture.

To investigate why engulfment was impaired, the authors examined proteins whose lysosomal breakdown changed in the absence of CMA and selected SIRPα. This protein inhibits engulfment by receiving a “do not eat me” signal from CD47 on other cells. In the authors’ model, SIRPα accumulates when CMA is absent, as it does in macrophages from old mice. The signal then more strongly inhibits the cytoskeletal rearrangement required for engulfment. To test the role of macrophages, the authors used mice with CMA disabled in these cells. By 23 months, male mice had more cells positive for the senescence marker SA-β-gal in their adipose tissue, liver and lungs than controls.

The compound CA77.1 activates CMA by increasing production of the LAMP2A receptor. Starting at 18 months of age, mice received oral CA77.1 for five months. Treatment suppressed the age-related increase in SA-β-gal-positive cells in the same organs in both sexes, with the greatest effect in the lungs. The authors attribute part of this effect to macrophages: after 48 hours of exposure to CA77.1, bone marrow macrophages from 23-month-old mice engulfed particles as actively as those from six-month-old mice.

Pulmonary fibrosis, a buildup of scar tissue in the lungs, has been linked to senescent cells. In three of four sample sets, lung lysosomes from four patients with fibrosis contained less LAMP2 protein, which includes the LAMP2A receptor, than those from four healthy donors. For the mouse experiment, the authors used young males because pulmonary fibrosis is more common in men and CMA activity is lower in men and male mice. Mice received bleomycin to induce scarring, followed by CA77.1 starting on day 2 or day 7. Early treatment reduced scarring by 55%, and later treatment reduced it by 24%. With early treatment, lung macrophage numbers returned to normal.

In the college’s press release, Cuervo contrasts this approach with senolytics, which kill senescent cells:

We also found that we may be able to restore communication between zombie cells and the immune system, allowing the body to clear them naturally as an alternative to trying to kill them.