Their signal, PD-L2, rises in human blood with age. Old mice bred without it kept fewer of these cells and handled sugar better. No person has been treated.
Every day some of your cells wear out. They stop dividing, and your immune system removes many of them. With age, more of them stay. They sit in fat, skin and organs and leak substances that inflame the tissue around them.
A study published on 10 September 2026 in Cell Metabolism names one reason they stay (1). Worn-out cells raise a signal called PD-L2. It tells the immune cells sent to remove them to stand down. In old mice bred without the signal, fewer of these cells built up, and the mice handled sugar better and gripped harder.
In people, the evidence is narrower. Human cells make more of the signal as they wear out, and levels in the blood rise with age (1). Nobody has been treated with a PD-L2 blocker for aging, and no such trial is registered.
What Senescent Cells Are, and Why They Build Up
Senescent cells are cells that have stopped dividing for good but have not died. Some writers call them zombie cells. They build up with age partly because the immune system stops clearing them, and the new study names one of the signals that lets them escape.
The state is useful when it is brief. A cell that stops dividing cannot turn into a tumor, and senescent cells help with wound healing (3). The trouble starts when they linger. They release a mix of inflammatory substances that damages the tissue around them, which is why senescence is one of the hallmarks of aging.
The strongest evidence that they matter comes from mice. In a 2016 study in Nature, researchers built a genetic switch into mice that killed these cells when the mice were given a drug.
Clearing them twice a week from one year of age lengthened median lifespan, the age by which half the mice had died, by 24 and 27 percent in two strains (3). Tumors appeared later, and the kidneys and heart held up better.
That switch cannot be put into people. It showed the cells were worth removing. Our earlier piece on cellular senescence covers the biology and the first drugs in more depth.
How the Body Normally Clears Them
Immune cells find senescent cells and kill them. Killer immune cells punch holes in a target cell's membrane using a protein called perforin, and that is one of the ways the body gets rid of worn-out cells.
A 2018 study took that tool away. Mice bred without perforin carried more senescent cells in their tissues, had chronic inflammation, developed age-related disorders earlier and died sooner (4). When the cells were cleared with a drug, part of that damage eased in those mice.
So the build-up with age is not only about making more worn-out cells. It is also about clearing fewer of them. That points to the question the new study asked: what stops the immune system from finishing the job? For the inflammation side of this story, see inflammation and aging.
The Brake Signal Worn-Out Cells Use
The immune system has brakes, and they matter. Without them, immune cells attack healthy tissue. One brake is a protein called PD-1, which sits on the surface of T cells, the family of immune cells that includes the killers of infected and damaged cells. Tasuku Honjo's laboratory reported PD-1 in 1992 (6).
Other cells press the brake by carrying a matching signal. There are two. PD-L1 is the famous one. PD-L2 was found in 2001. In that first paper, working with T cells in the lab, PD-L2 pressing the brake "dramatically inhibits" them from multiplying and sending signals. When the T cells were strongly stimulated, it still dampened their signals but no longer stopped them multiplying (5).
Some tumors use this. They raise these signals, and the T cells that reach them stand down (12). Drugs that block the brake let the T cells attack, and that discovery won Honjo and James Allison the 2018 Nobel Prize in Physiology or Medicine (7).
Two earlier studies connected the brake to worn-out cells:
- PD-L1 in aging mice, 2022. Senescent cells carrying PD-L1 resisted killer T cells. Giving naturally aging mice an antibody against PD-1 lowered the number of these cells and eased several signs of aging (8).
- PD-L2 in tumors, 2024. After chemotherapy, worn-out cancer cells raised PD-L2 and survived inside tumors. Worn-out cancer cells without PD-L2 were cleared quickly, and blocking PD-L2 alongside chemotherapy made breast tumors in mice go into remission (9). The first author of that study, Selim Chaib, led the new one.
The open question was whether PD-L2 does the same job in ordinary aging, away from cancer.
What the New Study Found
The team was led from Cedars-Sinai Health Sciences University in Los Angeles, with the Mayo Clinic and groups elsewhere in the US, in Spain and in Japan. James Kirkland, whose group named the senolytic drugs, is the senior author (1, 10). The paper reports four things (1):
- Worn-out human cells make more PD-L2. Human cells grown in the lab raised it when they became senescent, and PD-L2 rose in some human tissues with age (1, 2).
- Senolytic drugs removed the cells with the most PD-L2. Senolytics are drugs designed to kill senescent cells.
- Old mice bred without PD-L2 were healthier. They carried fewer worn-out cells than normal old mice. Their insulin sensitivity was better, which means their bodies needed less insulin to bring blood sugar down. Their grip was stronger.
- An antibody against PD-L2 helped normal old mice. It restored their insulin sensitivity. The institution's release says "removing or blocking PD-L2" lowered the number of worn-out cells and the inflammatory substances they make (2). It does not separate the two, so we cannot say the antibody alone lowered the count.
"Our findings suggest that PD-L2 may help aging cells stay in the body when they would normally be removed by the immune system," Chaib said in the release (2).
What we could not check. The full paper is paywalled, and the copy held by the US National Institutes of Health is under embargo. So we have the paper's own summary, not its figures. We cannot tell you how many fewer cells the mice carried, how much stronger their grip was, how long the antibody was given, or whether it lowered the cell count. We give no number from this paper for that reason.
What the Human Evidence Shows, and Where It Stops
Three findings in this work come from people:
- Human cells raised PD-L2 when they became senescent in the lab (1).
- PD-L2 levels rose with age in some human tissues (2).
- In human blood, a free-floating form of PD-L2 "increases with aging and declines after senolytic treatment", in the paper's own words (1).
That last line matters most. If blood PD-L2 falls when worn-out cells are cleared, it could become a blood test for how many of these cells a person carries. The release names that use directly (2). But we could not see how many people were tested, which drug they took, or how far the levels fell.
Here is where the evidence stops. The hiding itself, PD-L2 protecting worn-out cells from immune attack, was shown in mice. The benefit of removing PD-L2 was shown in mice. We searched the ClinicalTrials.gov registry six ways on 25 September 2026 and found no trial of a PD-L2 blocker for aging, frailty or senescence (14). The PD-L2 studies we found there are cancer studies.
Why a Cancer Drug Is Not the Answer
Drugs that release this brake already exist. Pembrolizumab, sold as Keytruda, binds PD-1 and blocks it from meeting both PD-L1 and PD-L2 (12). So a reasonable question is whether one of these drugs could clear worn-out cells in healthy older adults.
The drug's own label is the answer. Releasing the brake everywhere lets immune cells attack healthy organs. Among 2,799 patients who received pembrolizumab, the label reports (12):
| Immune side effect | How many patients |
|---|---|
| Underactive thyroid | 8 percent (237 people) |
| Lung inflammation | 3.4 percent (94), fatal in 0.1 percent |
| Bowel inflammation | 1.7 percent (48) |
| Liver inflammation | 0.7 percent (19) |
| Type 1 diabetes | 0.2 percent (6) |
These are people with cancer, and the counts include mild cases, so they are not the rates a healthy person would see. The direction is what matters. In 6 of the 2,799 patients, releasing the brake everywhere led to type 1 diabetes, where the body no longer makes its own insulin. That is the opposite of what the mice gained.
The hope in the new paper is a narrower target: block the signal on worn-out cells rather than the brake on every T cell. The paper lists immune side effects among its keywords, so the authors discuss the problem (1). We could not read what they concluded. Whether blocking PD-L2 is any safer than blocking PD-1 is not known.
What This Changes for Senolytics
In 2015, Kirkland's group named a new class of drugs, senolytics, which kill senescent cells by switching off the survival defenses those cells rely on (10).
The first evidence that they work in people came in 2019. Nine people with diabetic kidney disease took dasatinib and quercetin for three days. Eleven days later, biopsies showed fewer senescent cells in their fat and skin (11). There was no placebo group, and the study measured cells, not health.
The human senolytic trials are still small, as our May article reported. The new study suggests a second route alongside those drugs: remove the cover and let the immune system do the clearing it already knows how to do.
"If we can find a way to block this protein, we may be able to help the immune system get rid of these cells and potentially improve health problems linked with aging," Kirkland said (2).
Note the words he chose. Can, may, potentially. That is the right amount of confidence for a mouse result, and we'd suggest reading it the same way.
What You Can Do Now
We found no supplement shown in a controlled human trial to clear senescent cells and improve health. The prescription combination tested in 2019 had no placebo group. Fisetin, the most popular supplement candidate, improved artery function in old mice, and no human trial of it for vascular aging has reported, as our fisetin article covers. The supplement landscape gives the wider picture.
Exercise has the best human evidence of anything you can do today. In a 2021 study, a 12-week structured exercise program in older adults lowered blood markers of cellular senescence, including in T cells, and improved physical function (13). Those were markers, not direct counts of senescent cells, and it was one study. Zone 2 training is a sensible place to start.
The insulin result also has a practical side. Good blood sugar control helps whatever the reason, and metabolic syndrome is common after 60. But better insulin sensitivity is not the same as slower aging. Our earlier analysis found the two can come apart, so read the mouse result as a health gain, not proof of younger tissue.
Do not seek a cancer immunotherapy drug to slow aging. If you already take one for cancer, nothing here changes that treatment. Talk to your doctor before changing anything.
Two things to watch for: the paper's full figures, once the embargo lifts, and a registered human trial.
Frequently Asked Questions
What are zombie cells?
Zombie cells is a popular name for senescent cells. They have stopped dividing but have not died, and they release inflammatory substances into the tissue around them. A few are useful, for example in wound healing. Too many, held for too long, damage tissue. They build up in many tissues with age.
Why do senescent cells build up as we age?
The body makes more of them with age and clears fewer of them. A September 2026 study found that worn-out cells raise a signal called PD-L2, which tells immune cells to stand down. In people, blood levels of the signal rise with age. In mice, removing it meant fewer of these cells built up.
How does the body get rid of senescent cells?
Mostly through the immune system. Killer immune cells recognize worn-out cells and destroy them, partly by punching holes in them with a protein called perforin. Mice bred without perforin carried more senescent cells, had more inflammation and died sooner. Signals like PD-L1 and PD-L2 help some worn-out cells escape this clearance.
Can a cancer immunotherapy drug slow aging?
No drug of this kind has been tested for aging in people, and none should be taken for it. Pembrolizumab blocks the same brake PD-L2 uses, but in 2,799 patients 8 percent developed an underactive thyroid and 0.2 percent developed type 1 diabetes. Researchers hope a narrower PD-L2 blocker could be safer. That is untested.
Are there supplements that clear senescent cells?
We found none shown to clear senescent cells and improve health in a controlled human trial. Fisetin and quercetin clear them in mice. A 2019 pilot in nine people used quercetin with the cancer drug dasatinib, which is a prescription medicine, not a supplement. Exercise lowered blood markers of senescence in a 2021 human study.
When could a PD-L2 treatment reach people?
Not soon. As of 25 September 2026, no trial of a PD-L2 blocker for aging is registered on ClinicalTrials.gov. A new drug usually needs safety trials, then trials that show a benefit, which takes years. The nearer use may be a blood test: blood PD-L2 falls after these cells are cleared, and the researchers name tracking them as a possible use.
Sources
- Chaib S, Langhi Prata LGP, Suda M, et al. Blocking PD-L2 prevents senescent cell accumulation and age-related dysfunction. Cell Metab. Published online 10 September 2026. PMID: 42721966. DOI: 10.1016/j.cmet.2026.08.014. Read from its summary, eTOC summary and declarations; the full text was unavailable to us
- Cedars-Sinai Health Sciences University. Blocking a protein may reduce buildup of harmful aging cells. News release, September 2026. Cedars-Sinai newsroom
- Baker DJ, Childs BG, Durik M, et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016;530(7589):184-189. PMID: 26840489. DOI: 10.1038/nature16932
- Ovadya Y, Landsberger T, Leins H, et al. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat Commun. 2018;9(1):5435. PMID: 30575733. DOI: 10.1038/s41467-018-07825-3
- Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268. PMID: 11224527. DOI: 10.1038/85330
- Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887-3895. PMID: 1396582. DOI: 10.1002/j.1460-2075.1992.tb05481.x
- The Nobel Prize in Physiology or Medicine 2018, awarded to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation". Nobel Prize
- Wang TW, Johmura Y, Suzuki N, et al. Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes. Nature. 2022;611(7935):358-364. PMID: 36323784. DOI: 10.1038/s41586-022-05388-4
- Chaib S, López-Domínguez JA, Lalinde-Gutiérrez M, et al. The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2. Nat Cancer. 2024;5(3):448-462. PMID: 38267628. DOI: 10.1038/s43018-023-00712-x. Author correction: Nat Cancer. 2026;7(7):1160, PMID: 42215656
- Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644-658. PMID: 25754370. DOI: 10.1111/acel.12344
- Hickson LJ, Langhi Prata LGP, Bobart SA, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446-456. PMID: 31542391. DOI: 10.1016/j.ebiom.2019.08.069. NCT02848131
- Merck Sharp & Dohme LLC. KEYTRUDA (pembrolizumab) prescribing information, sections 5.1 and 12.1. Label effective 10 July 2026. DailyMed
- Englund DA, Sakamoto AE, Fritsche CM, et al. Exercise reduces circulating biomarkers of cellular senescence in humans. Aging Cell. 2021;20(7):e13415. PMID: 34101960. DOI: 10.1111/acel.13415
- ClinicalTrials.gov, searched 25 September 2026 for PD-L2 with aging, senescence and frailty, and for anti-PD-L2, PDCD1LG2 and PD-L2 as an intervention. The PD-L2 studies returned are cancer studies, including NCT02812875 and NCT05803746
Funding Transparency
LSD is editorially independent. We receive no funding from pharmaceutical, supplement or longevity companies. These are the funding ties behind each study above, taken from each paper's own funding and conflict statements.
- Source 1 (Chaib, 2026): The first author holds patents or pending patents on PD-L2 at the Mayo Clinic and the Spanish National Cancer Research Center, some licensed to Rejuveron Senescence Therapeutics. Manuel Serrano is a shareholder of Senolytic Therapeutics, Life Biosciences, Rejuveron Senescence Therapeutics and Altos Labs. Six authors, including Kirkland, have a financial interest through Mayo Clinic patents on senolytic drugs. Funding named in the release: three US National Institutes of Health grants, the Connor Fund, Robert J. and Theresa W. Ryan, the Hevolution Foundation and the Noaber Foundation (2).
- Source 2 (Cedars-Sinai release): Written by the lead institution about its own study. We used it only for what the paper's summary does not say, and name it wherever we do.
- Source 3 (Baker, 2016): The National Institutes of Health, the Paul F. Glenn Foundation, the Ellison Medical Foundation, the Noaber Foundation and others. The authors declare competing financial interests: the senior author, Jan van Deursen, co-founded Unity Biotechnology, and two authors are inventors on patents licensed to Unity by the Mayo Clinic.
- Source 8 (Wang, 2022): Funding is not stated in the abstract, and the full text was unavailable to us.
- Source 9 (Chaib, 2024): Manuel Serrano holds the same shareholdings as in source 1. The first author has received royalties from Rejuveron, one co-author is a Rejuveron shareholder, another consults for it, and two authors, including Kirkland, hold interests in Mayo Clinic senolytic patents. In July 2026 the journal published a correction replacing two images in Figure 1a that had been reused from a 2019 paper that shares an author with this one.
- Source 10 (Zhu, 2015): The Mayo Clinic and six authors, including Kirkland, declare a financial interest in this research. Two other authors co-founded and hold equity in Aldabra Bioscience.
- Source 11 (Hickson, 2019): Funded by the NIH and foundations, as its summary states. Four authors, including Kirkland, declare a financial interest; the patents on senolytic drugs are held by the Mayo Clinic.
- Source 12 (KEYTRUDA label): Written by the manufacturer and approved by the US Food and Drug Administration.
- Source 13 (Englund, 2021): National Institute on Aging grants, the Pritzker Foundation and an American Federation for Aging Research award. The authors declare no conflicts of interest. No drug or supplement was tested.
- Sources 4, 5, 6 and 7: Academic research and the Nobel Foundation. No industry funding is relevant to the facts we cite from them.
Related Reading
- Cellular Senescence Leaves Cells That Will Not Die, the biology of these cells and the first drugs against them
- The 12 Hallmarks of Aging, and Exercise Hits Seven, where senescence sits among the causes of aging
- Inflammation & Aging, what the substances these cells release do to the body
- Fisetin Improved Artery Function in Old Mice, Not People, the most popular senolytic supplement
- Good Insulin Sensitivity Does Not Mean Slower Aging, why the insulin result needs care
- Zone 2 Exercise Builds the Fitness That Predicts Lifespan, the intervention with human evidence behind it
Worn-out cells do not outlast the immune system by being tougher. In mice, they outlast it by telling it to stand down, and that message can be blocked. In people, nobody has tried.
Written with the help of AI tools, shaped and verified by humans. Every result in this article was checked against the study's own paper, summary, label or registry entry.
This article is for information only and is not medical advice. Do not start or stop any medicine on the basis of an article.