LongeCityNews Last Updated: 07 April 2026 - 07:48 PM

Cellular senescence has been increasingly implicated in the development of pulmonary fibrosis, a largely irreversible condition with a poor prognosis under the current standard of care. An early clinical trial of first generation senolytic drugs to clear senescent cells showed promising results, but the condition remains a low priority among companies developing various forms of novel senolytics. Here, researchers discuss one of the primary mechanisms targeted by early senolytics, the BCL-2 protein known to be involved in preventing apoptosis in senescent cells, in the context of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease that develops in response to chronic epithelial injury. Unlike injury-induced homeostatic lung repair during which fibroblasts undergo apoptosis and clearance, the lungs of IPF patients continue to accumulate apoptosis-resistant, pro-fibrotic, extracellular matrix-producing fibroblasts.

Here, we show that prevention of PDGFRα+ fibroblast apoptosis by conditional BCL-2 expression leads to the emergence and persistence of senescent, pro-fibrotic fibroblasts along with enduring, pathologic fibrotic lung remodeling. Additionally, spatial transcriptomic studies of human IPF lungs confirmed the presence of senescent, BCL-2 expressing α-smooth muscle actin+ myofibroblasts in fibrotic regions.

Of translational significance, selective BCL-2 inhibition with ABT-199 in fibrotic mice re-engaged the apoptotic pathway in fibroblasts, reduced senescence, and promoted fibrosis resolution and lung regeneration. Our findings suggest that sustained BCL-2 expression in fibroblasts prevents homeostatic lung repair, drives persistent fibrosis and is a therapeutically relevant target to reverse persistent pulmonary fibrosis.

Link: https://doi.org/10.1038/s41467-026-69865-4

uPAR is expressed as a surface marker on senescent cells, and researchers have published the results of targeting chimeric antigen receptor (CAR) T cell therapies to uPAR in the context of clearing senescent cells from aged tissues. Absent an enormous reduction in cost, it is unlikely that CAR T therapies will see much use in this context, but they continue to be used in cancer therapy. Here, researchers show that targeting uPAR-expressing cells in and around solid tumors enables CAR T therapy to work in this context. CAR T therapy was developed for leukemia and has so far struggled to make the jump to the more complex environment of solid tumors; different approaches are needed, and this one seems to be producing positive results so far.

The urokinase plasminogen activator receptor - or uPAR - is a protein found on the outside of cells. In healthy tissue, very few cells have uPAR on their surface; it's primarily found on myeloid immune cells, and helps with processes associated with wound healing. But in cancer, which co-opts the body's normal wound healing programs, both tumor cells and cells in the fibrous "niche" that support the tumor produce a lot more uPAR. By focusing on uPAR, the new approach allows researchers to target cells in a particular state rather than a specific type of cell.

The CAR T cells that target CD19 in leukemia and lymphoma, for example, primarily target B cells - including cancer cells that develop from B cells. uPAR, on the other hand, tends to show up on the most dangerous, identity-shifting cancer cells - as well as on nearby support cells that are stuck in a constant wound-healing mode, building scar tissue and suppressing the immune response. In the study, researchers found uPAR was elevated in 12 of the 14 human cancer types they analyzed, with especially high levels in some types of ovarian, pancreatic, colon, lung, and brain cancers.

In preclinical experiments, uPAR-targeted CAR T cells were effective at killing cancer cells across multiple cancer models. And their effect could be further enhanced by combining them with senescence-inducing treatments such as the chemotherapy agent cisplatin, which raised uPAR levels and made tumor cells easier for the engineered T cells to attack. In a mouse model of ovarian cancer, for example, uPAR-targeting CAR T cells were able to wipe out metastases, leading to durable remissions. And mice whose tumors had been eliminated also resisted developing new tumors when researchers tried to introduce cancer again later, indicating the CAR T cells remained active.

Link: https://www.mskcc.org/news/cell-surface-protein-upar-may-hold-key-to-targeting-solid-tumors-with-car-cell-therapy

Rapamycin is increasingly prescribed off-label by anti-aging physicians based on animal studies and very limited human data (even including the relatively recent crowdfunded PEARL trial) for it to improve late-life metabolism. Rapamycin and other mTOR inhibitors are calorie restriction mimetics, provoking a greater level of autophagy to improve cell maintenance. In mice, rapamycin results in a ~20-25% increase in life span, a sizable fraction of the ~40% that is possible via calorie restriction. We know that human calorie restriction is beneficial to health in many ways, but doesn't add more than a few years to life span - while no actual assessment has been carried out, it would be hard for an effect of more than five years or so to remain hidden from interested epidemiologists and scientists across the course of history.

Rapamcyin can be prescribed off-label because it has long been used as an immunosuppressant drug at much higher doses than the anti-aging use, and the safety profile for that use is well mapped. The drug has existed for long enough that it is now generic, outlasted its patent protection. Generic drugs tend to see little further formal clinical trial activity because they cannot produce enough income to sustain the high costs imposed by regulatory authorities. That doesn't stop academics from sometimes managing to obtain enough funding to explore unanswered questions, however.

While enough people are presently using rapamycin off-label at anti-aging doses for a recent study to find more than 300 individuals who were willing to provide information on their rapamycin use, in general this sort of use generates next to no actually useful, robust data. To obtain that data clinical trials of some sort, at the very least run by a reputable organization, remain needed. At present, there is no great consensus that any of the present range of anti-aging doses used in the community are in fact the optimal dose for humans. There are also remaining questions as to the dose at which undesirable immunosuppressive or hyperglycemic effects begin to emerge, and how prevalent they are. So it is good to see that an academic group has found the funds needed to run an initial set of trials aimed at answering these questions.

Large rapamycin clinical trial launches

Researchers are launching a multi-phase clinical study to better understand the biological effects of rapamycin in older adults. The study reflects a shift toward evidence-based dosing, safety, and long-term outcomes rather than off-label and speculative use of rapamycin. "Rapamycin is widely discussed in popular culture as a longevity drug. But there's a difference between something that is biologically plausible and something that has been rigorously tested in people."

The current study is structured as a series of interconnected sub-studies, each designed to answer a specific question. The translational pipeline will move from biological benchmarks to long-term clinical observation. The first sub-study establishes a reference point by examining immune and metabolic markers in younger adults. These measurements help define what "optimal" function looks like before aging-related changes begin.

The second sub-study will determine the optimal rapamycin dosage for older adults that will safely bring them back to the optimal functioning seen in the younger population. The dosage used for transplant patients may be too high for safe use in generally healthy older adults, so the scientists are testing different dosing schedules to determine how much rapamycin is needed to reach biological targets without negative side effects. "This phase is about precision. We're asking how much drug it actually takes to achieve a desired biological effect, not more than that."

The third sub-study is the largest cohort and will run the longest. It is a randomized, placebo-controlled clinical trial involving approximately 84 older adults who will receive either daily rapamycin, intermittent dosing, or a placebo. Participants will be treated for six months and followed for an additional six months to assess both short-term effects and sustained effects after treatment ends.

Researchers have discovered a potential treatment for post-operative delirium, which accelerates cognitive decline in older people.

A common problem with long-term effects

Roughly a quarter of older people suffer from delirium after surgery [1], which rises to around half if the surgery is particularly invasive or high-risk [2]. This increases the length of hospital stays and roughly triples mortality risk [3].

Furthermore, post-operative delirium is linked to further permanent damage to already damaged brains [4]. Nearly two-thirds of people with existing mild cognitive impairment went on to develop full-blown Alzheimer’s disease within three years of experiencing delirium after surgery [5]. This team noted that little work has been done in analyzing why this occurs.

For their own investigations, they turned to microglia, the immune cells of the brain. Previous research has noted that these cells are overactivated in cases of post-operative delirium [6], which occurs alongside metabolic reprogramming that is linked to Alzheimer’s disease [7]. This is linked to the formation of stress granules, a protective mechanism that goes out of control during neurodegeneration [8].

These researchers have previously discovered that knocking down RUVBL2 increases ATP in cells, leading to more rapid dissolution of these granules and restoring function in a rat model [9]. This paper builds upon that work, focusing on RUVBL2’s role in metabolic reprogramming in the context of post-operative delirium.

Anaesthetic surgery causes hippocampal changes

In their first experiment, the researchers conducted surgery on 8-month- to 9-month-old rats in which they used a 3% sevoflurane anaesthetic for three hours, then conducted cognitive tests to determine its effects. Compared to a control group and a sham surgery group, the pro-inflammatory cytokine IL-1β was increased in the sevoflurane group while the anti-inflammatory cytokine IL-10 was decreased.

The treated rats also had significantly worse performance on the Barnes maze and novel object recognition tests, which occurred alongside metabolic differences in the hippocampus. This brain region was overactivated, with a metabolic shift from oxidative phosphorlylation to glycolysis. Further analysis found that this occurred alongside a more inflammatory profile in the microglia, with fewer microglia branches and an increase in CD86. Unsurprisingly in light of their previous work, the researchers also found increases in RUVBL2 alongside an increase in stress granule formation in the treatment group.

Suppressing RUVBL2 has significant effects

The researchers then chose to investigate RUVBL2 more directly. In an older rat model of mild cognitive impairment, the researchers confirmed the function of two lentiviruses, one of which increases RUVBL2 expression and the other of which decreases it. These rats were then subjected to the same anaesthetic surgery as the younger rats.

As expected, the rats with increased RUVBL2 expression performed worse on the novel object and Barnes maze tests. Suppressing RUVBL2 had dramatic benefits for both tests alongside a significant decrease in inflammation. The glycolytic metabolic shift was attenuated, available ATP was increased, and the number and size of stress granules were decreased. “In conclusion, these data suggest that reduced RUVBL2 expression inhibits metabolic reprogramming progression and effectively alleviates postoperative cognitive deficits in aged MCI rats subjected to sevoflurane anesthesia and surgical trauma.”

With these data in hand, these researchers believe that RUVBL2 is a therapeutic target worthy of further investigation. However, they note the study’s limitations, a major one of which is that microglia are highly heterogenous and that significantly more in-depth study may be required to understand the full effects of anaesthesia on microglial function and how RUVBL2 fits into this dynamic. If a therapy can be created from this line of research, performing significant surgery on older people may become much less dangerous for their long-term cognitive health.

Literature

[1] Wildes, T. S., Mickle, A. M., Ben Abdallah, A., Maybrier, H. R., Oberhaus, J., Budelier, T. P., … & Avidan, M. S. (2019). Effect of electroencephalography-guided anesthetic administration on postoperative delirium among older adults undergoing major surgery: the ENGAGES randomized clinical trial. Jama, 321(5), 473-483.

[2] Adelaars, S., Te Pas, M. E., Jansen, S. W., van der Linden, C. M., Oosterbos, E., van de Kerkhof, D., … & Bouwman, R. A. (2025). Incidence of delirium post cardiac surgery: Discrepancy between clinical observation, DOS scores, and single‑lead EEG. Journal of Clinical Anesthesia, 106, 111896.

[3] Lander, H. L., Dick, A. W., Joynt Maddox, K. E., Oldham, M. A., Fleisher, L. A., Mazzeffi, M., … & Glance, L. G. (2025). Postoperative delirium in older adults undergoing noncardiac surgery. JAMA Network Open, 8(7), e2519467.

[4] Goldberg, T. E., Chen, C., Wang, Y., Jung, E., Swanson, A., Ing, C., … & Moitra, V. (2020). Association of delirium with long-term cognitive decline: a meta-analysis. JAMA neurology, 77(11), 1373-1381.

[5] Olofsson, B., Persson, M., Bellelli, G., Morandi, A., Gustafson, Y., & Stenvall, M. (2018). Development of dementia in patients with femoral neck fracture who experience postoperative delirium—A three‐year follow‐up study. International journal of geriatric psychiatry, 33(4), 623-632.

[6] Ishii, T., Wang, T., Shibata, K., Nishitani, S., Yamanashi, T., Wahba, N. E., … & Shinozaki, G. (2025). Glial contribution to the pathogenesis of post-operative delirium revealed by multi-omic analysis of brain tissue from neurosurgery patients. bioRxiv, 2025-03.

[7] Guillot-Sestier, M. V., Araiz, A. R., Mela, V., Gaban, A. S., O’Neill, E., Joshi, L., … & Lynch, M. A. (2021). Microglial metabolism is a pivotal factor in sexual dimorphism in Alzheimer’s disease. Communications biology, 4(1), 711.

[8] Cui, Q., Liu, Z., & Bai, G. (2024). Friend or foe: The role of stress granule in neurodegenerative disease. Neuron, 112(15), 2464-2485.

[9] Wang, Z., Yang, C., Wang, X., Liao, H., Liu, X., Liu, H., … & Wang, H. (2025). Knockdown of RUVBL2 improves hnRNPA2/B1‐stress granules dynamics to inhibit perioperative neurocognitive disorders in aged mild cognitive impairment rats. Aging Cell, 24(3), e14418.