In Old Mice, Zombie Cells Dull the Immune Cells That Clear Them

A FIBROBLAST from a 4-month-old mouse, dosed with a drug that halts cell division, does the sensible thing and cranks up its protein-recycling machinery. The same kind of cell from a 23-month-old mouse doesn’t. Experiments on mice and cultured mouse cells at Albert Einstein College of Medicine in New York now show that old zombie cells, which have stopped dividing but linger in tissue, release a cocktail that dulls the very immune cells sent to clear them. Behind it sits a recycling pathway called chaperone-mediated autophagy, which declines with age.

Zombie cells, known formally as senescent cells, are hardly pure villains. During wound healing some injured cells go senescent on purpose and release signals that summon repair crews, after which macrophages (the immune system’s all-purpose scavengers) are supposed to eat them. In older bodies the eating falters, and the survivors are linked to chronic inflammation and disease.

Ana Maria Cuervo, a distinguished professor of developmental and molecular biology at Einstein who co-directs its Institute for Geroscience, has spent years on chaperone-mediated autophagy, in which a chaperone molecule grabs proteins carrying a short amino acid sequence and feeds them through a receptor into the lysosome, the cell’s digestive compartment, for breakdown. It fades with age. Her lab had already seen young cells turn the pathway up as they slide into senescence. What happens when old cells cannot had never been tested.

So the team, with first author Rebecca Sereda then a graduate student in Cuervo’s lab, took the pathway away. Young mouse fibroblasts engineered to lack it and then pushed into senescence ended up resembling old ones: their protein remodeling matched that of aged cells by 45 percent, and only 200 proteins separated the two groups despite the age gap. The altered cells also secreted a different mix of proteins and metabolites, one that nudged healthy neighbors in the dish toward senescence.

The Cleanup Crew Stops Eating

The secretions hit the cleanup crew too. Young mouse macrophages bathed in medium from senescent fibroblasts lost recycling activity (more so with medium from fibroblasts lacking the pathway), and their appetite for antibody-coated beads dropped with it. The macrophage side runs through a receptor that relays a do-not-eat-me signal: with the pathway stalled, the cells fail to pull that receptor in for disposal, its partner protein builds up, and the brake stays on.

That shifts the target, according to Cuervo. “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.”

Does it hold up in living animals? In 23-month-old mice whose macrophages specifically lack the pathway, males carried more senescent cells in gonadal fat, liver and lung than littermates with normal macrophages, though the difference was less evident in females. In a separate test on 12-month-old mice (8 controls and 7 with the deletion), wounds in the macrophage-deficient animals were still larger 15 days after injury, with more lingering senescent cells at the wound site and, oddly, more macrophages crowding in.

Restarting the Recycling in Old Mice

The lab’s own small-molecule activator of the pathway, delivered in sweetened gelatin pellets that mice finish in about two minutes after a week of training, let the team test the reverse. Starting at 18 months, old mice got the compound by mouth for 5 months. Compared with animals on vehicle pellets, treated mice (groups ran from 5 to 16 mice, depending on the tissue) escaped the age-related rise in senescent cells in gonadal fat, liver and lung, and fibrosis in liver and fat eased a little. In a dish, a 48-hour dose brought the appetite of macrophages from 23-month-old mice back to the level of those from 6-month-old mice.

Idiopathic pulmonary fibrosis, in which scar tissue slowly stiffens the lungs, made a natural next test because the disease is tied to senescence. Lysosomes isolated from patients’ lungs carried less of the pathway’s key receptor, a pattern seen in three of the four sets of lungs examined, and gene-activity scores for the pathway ran lower. In male mice given bleomycin, a lung-scarring drug (groups of 4 to 7), starting the compound 2 days afterward kept body weight up and reduced scarring by day 15; starting at 7 days did less.

The caveats stack up, and the release runs a little ahead of them. Its line that restoring the pathway lessened fibrosis holds for early treatment in male mice only, and its suggestion that senolytic drugs (compounds that kill senescent cells) may be misjudged in young-cell tests is an extrapolation, since the paper tested none. The human lung data are correlative and need validation in patients, fibroblasts were the main cell model, and the macrophage deletion may also disable the pathway in other myeloid cells. Einstein holds intellectual property on the approach and is seeking licensing partners, and the compound is under a patent held by Cuervo and a co-author.

For now this is a mouse result, built on a compound nobody has tested in a person. The next challenge, Cuervo says, is “determining whether this approach can eventually be developed into a safe treatment for age-related diseases in people.”

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