Highlights
- Researchers compared 21 senolytic compounds and found that the top two compounds were:
- ABT263: which inhibits the BCL2 protein whose function is to prevent programmed cell death (apoptosis)
- ARV825: which inhibits a class of proteins called BET that promote gene expression
- Neither drug is approved at present for human use
- While ABT263 and ARV825 were the most effective, even the best senolytics left behind a resistant population of 20-30% of senescent cells
- Further analysis indicated that these resistant cells survived by clearing out their damaged mitochondria more efficiently
- But shifting cellular metabolism such that mitochondria in these cells were now forced to generate more energy, made senescent cells more vulnerable to senolytics
- In aging mice, ketogenic diet or the diabetes drug dapagliflozin (SGLT2 inhibitor) boosted effectiveness of senolytic treatment
Cellular senescence drives age-associated chronic diseases
Accumulation of senescent cells as we age, is one of the key causes of organ dysfunction, disability and age-related diseases. Atherosclerosis, osteoarathritis, sarcopenia, chronic kidney dissease, metabolic syndrome are just a few examples of age-associated chronic diseases where the gradual accumulation of senescent cells in organs and tissues drive these diseases. While senescence appears to be a defense mechanism to prevent cancer development, these cells accumulate with age and secrete a pro-inflammatory mix of molecules known as the SASP, or senescence-associated secretory phenotype. These cells stop dividing, but they do not simply sit quietly. They can promote chronic inflammation, tissue dysfunction, fibrosis, and pradoxically, they can even support tumor progression.
In mouse studies, senolytic drugs, treatments that selectively remove senescent cells from the body, reverse many age-associated dysfunctions (i.e. improve healthspan) and increase lifespan even when given to old mice. While human clinical data is still lacking, studies where senescent cells were removed by multiple mechanisms (drugs, or genetic manipulation) has convincingly showed that age-associated disabilities can be halted or reversed by removing these cells.
These findings have made senolytics, drugs designed to selectively kill senescent cells, one of the most attractive intervention classes in healthspan research. But the field has had a basic unresolved problem: many senolytic compounds have been reported, yet there has been no clean head-to-head comparison showing which ones are actually the most potent and specific.
In this Nature Aging study, researchers compared 21 senolytic candidates by testing them in senescent fibroblast and epithelial cells. They found that two compounds stood out: ABT263, a Bcl-2 family inhibitor, and ARV825, a BET protein degrader. But even these top performers failed to eliminate all senescent cells. This led to an important question: why do some senescent cells survive?
Mitochondrial quality control is the escape route for senescent cell survival
The study found that the senescent cells that resisted ABT263 or ARV825 were not random survivors. They maintained stronger mitochondrial integrity and were better able to clear damaged mitochondria.
A key player was the protein complex V-ATPase, an intracellular proton pump involved in cellular waste handling and mitochondrial quality control. Resistant senescent cells showed higher expression of V-ATPase-related genes. These cells were better able to remove damaged mitochondria, avoid excessive buildup of damaging reactive oxygen species (ROS), and escape senolytic-induced death.
By contrast, senescent cells with lower V-ATPase expression accumulated more mitochondrial damage, lost mitochondrial membrane potential, built up reactive oxygen species, and were more likely to die when exposed to ABT263 or ARV825.
The study found that:
- Among 21 senolytic candidates, ABT263 and ARV825 had the highest senolytic specificity across the tested in vitro models. Notably, two widely used senolytics among healthspan enthusiasts: 1) Fisetin, and 2) Dasatinib+Quercetin, performed only modestly in these tests.
- Even after prolonged treatment, roughly 20–30% of senescent cells survived
- The resistant cells showed evidence of preserved mitochondrial function and stronger mitochondrial quality control
- Higher V-ATPase activity helped resistant cells clear damaged mitochondria and limit ROS accumulation
- The researchers increased mitochondrial work load by lowering blood glucose
- Ketogenic diet: Old mice on a ketogenic diet cleared senescent cells better when treated with these drugs
- Diabetes drug: Mice with cancer, cleared chemotherapy-induced senescent cells more efficiently when given the diabetes drug (SGLT2 inhibitor) dapagliflozin to lower their blood sugar
Could lowering blood sugar make senolytics work better?
The researchers next tested an important hypothesis on how to better clear the resistant cells: if the resistant senescent cells survive by maintaining mitochondrial integrity, then forcing theses cells to rely more heavily on their mitochondria as the primary energy source, should increase their vulnerability to cell clearing.
That is exactly what happened. In cell culture, the researchers used a drug that blocks glucose transport into cells (GLUT1 inhibitor BAY876) to suppress glycolysis and push cells toward energy production through mitochondrial oxidative phosphorylation. This increased mitochondrial workload. When senescent cells were treated with BAY876 together with ABT263 or ARV825, mitochondrial membrane potential fell further, ROS increased, and senescent cell killing improved substantially.
This suggests that senolytic efficacy is not just about the drug itself. It also depends on the metabolic state of the target cell. Senescent cells that can buffer mitochondrial stress survive better. Cells forced into higher mitochondrial workload become easier to clear using senolytic drugs.
Ketogenic diet or diabetes drug separately boosted senescent cell clearance in mice
The most provocative part of the study was the mouse studies. The researchers tested whether lowering carbohydrate availability and forcing the body to use mitochondria for energy could improve senolysis in mice.
In aged mice (equivalent to roughly 60 years for humans), combining a ketogenic diet with ABT263 or ARV825 reduced lung senescence markers more than the senolytic drugs alone. It also reduced expression of SASP-associated factors such as Cxcl2 and Cxcl12, and decreased melanoma cell accumulation in the lungs.
Cancer chemotherapy is known to cause cellular senescence. The researcher wanted test if they could clear these cells also using the blood sugar lowering method in combination with the senolytic drugs. In a mouse tumor study, the authors turned to a diabetes drug SGLT2 inhibitor (dapagliflozin) to lower blood sugar because mice with tumors could not tolerate a ketogenic diet.
When SGLT2 inhibition was combined with ABT263 or ARV825 after chemotherapy-induced senescence, tumor growth was suppressed more strongly than with either intervention alone.
In the mouse studies, the combination strategies led to:
- Lower senescence markers in aged lung tissue
- Reduced expression of SASP-related inflammatory factors
- Reduced metastatic tumor accumulation in lungs of aged mice
- Stronger inhibition of tumor growth when SGLT2 inhibition was combined with ABT263 or ARV825
Safety considerations
This paper is exciting, but it is not yet a ready-made senolytic protocol.
First, the work was done in cultured cells and in mice. Second, even in the animal experiments, the metabolic interventions were clearly context dependent. The ketogenic diet improved senolytic efficacy in aged-mouse setting, but in the cancer chemotherapy mouse model it caused severe problems and many mice died. The team specifically shifted to SGLT2 inhibition in that model because it lowered blood glucose without harming the mice. Also raising questions about the benefits of a ketogenic diet, is a recent study in mice that found ketogenic diet induces cellular senescence in multiple organs such as the heart and the kidney.
It is also important that ABT263 is known to have toxicity concerns, and this study was not designed as a human healthspan trial. So while the paper strongly supports the idea that mitochondrial state determines senolytic sensitivity, it does not yet establish a safe or effective senolytic regimen for healthy humans.
What it does suggest is something highly relevant for the field: senolytics may work much better when paired with interventions that increase mitochondrial workload or reduce blood glucose. That could eventually help explain why senolytic responses are so inconsistent across tissues and people.
Wakita, M., Ito, K., Fujii, K. et al. Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance. Nature Aging (2026). https://doi.org/10.1038/s43587-025-01057-z
Lushchak, O., Schosserer, M., & Grillari, J. (2023). Senopathies—Diseases Associated with Cellular Senescence. Biomolecules, 13(6), 966. https://doi.org/10.3390/biom13060966
Xu, M., Pirtskhalava, T., Farr, J. N., Weigand, B. M., Palmer, A. K., Weivoda, M. M., et al. (2018). Senolytics improve physical function and increase lifespan in old age. Nature Medicine, 24, 1246–1256. https://doi.org/10.1038/s41591-018-0092-9
Sun, Y., Li, Q., & Kirkland, J. L. (2022). Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging. Life Medicine, 1(2), 103–119. https://doi.org/10.1093/lifemedi/lnac030
Wei, S. J., Schell, J. R., Chocron, E. S., et al. (2024). Ketogenic diet induces p53-dependent cellular senescence in multiple organs. Science Advances, 10(20), eado1463. https://doi.org/10.1126/sciadv.ado1463