A Supplement Kills Senescent Cells and Extends Life in Mice

A new study shows healthspan and lifespan increases in male mice following late-life treatment with vanadyl sulfate, a food-derived molecule marketed as an over-the-counter supplement [1].

Searching for vulnerabilities

Cellular Senescence

As your body ages, more of your cells become senescent. Senescent cells do not divide or support the tissues of which they are part; instead, they emit potentially harmful chemical signals, collectively known as the senescence-associated secretory phenotype (SASP), which encourages nearby cells to enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related ...
Read More

In a new study published in Nature Aging, a group of researchers from the University of Chicago has described the senolytic activity of a mineral called vanadyl sulfate (VS). It is naturally found in food, such as shellfish, mushrooms, and soybeans, and it is sold as an over-the-counter supplement. Previous research suggests that VS might assist in glucose processing [2].

The laboratory of Jin Cheng, PhD, Janet Davison Rowley Distinguished Service Professor of Medicine and a senior author of the new study, has previously created a library of nutrients, metabolites, and dietary supplements to investigate how individual diet-related compounds affect cellular functions [3]. In this study, the researchers started from identifying new potentially senolytic compounds that would also be safe for non-senescent cells. Their in vitro screens revealed 68 candidates, with VS among the top hits.

Fitness and lifespan increase

The researchers then moved to experiments with naturally aged mice. 76-week-old animals received VS in drinking water for 13 weeks. 12-week-old mice were used as a reference group. Most measurements included 12 to 15 mice per group.

The treatment improved fitness (hanging endurance), body composition (reduced fat accumulation), and glucose tolerance. The treatment group also had better liver and kidney markers along with less kidney inflammation. These improvements were accompanied by reductions in senescence markers: SA-β-gal, p16, p21, and inflammatory gene expression.

Moreover, 90-day treatment that was started in male mice at about 71 weeks of age (late adulthood) increased median lifespan from 887 to 952 days, or by 7.4%. This result is made more impressive by the late start and the short duration of the treatment as well as by relatively long-lived controls. The cohort, however, was small (about 20 mice per group), and the lifespan increase barely reached statistical significance.

In an interesting additional experiment, aged mice received VS for six weeks before either continuing treatment or switching back to ordinary water. While circulating vanadium returned to baseline after withdrawal, improvements in fitness, fat accumulation, glucose tolerance, and several tissue measurements were largely retained until the end of follow-up. These results are compatible with lasting changes in tissue composition, such as removal of senescent cells, but they do not prove it.

Aged female mice also showed improved endurance and metabolic measurements and reduced senescence-associated markers after three months of treatment. However, female lifespan was not tested.

Next, the researchers asked whether VS could affect diseases in which senescent cells have been implicated. VS treatment indeed improved disease-associated metrics in mouse models of diabetes, liver fibrosis, atherosclerosis, and lung fibrosis.

Impaired protein recycling

Having established these effects, the researchers turned to the mechanism – how exactly does VS kill senescent cells? Working with senescent fibroblasts in vitro, they learned that VS quickly disrupts protein handling in senescent cells, eventually leading to controlled self-destruction (apoptosis), which senescent cells normally evade.

The researchers found signs of protein aggregation and impaired removal of misfolded proteins. Blocking the cell’s protein removal machinery boosted VS’ senolytic effect, while enhancing it partially restored viability. Nonsenescent cells showed much smaller responses to VS, suggesting that the compound exploits a vulnerability specific to senescent cells.

One important protein folding mechanism involves cysteine, an amino acid with a sulfur-containing chemical group. Two cysteines can form a strong disulfide bond between them. When formed in the correct place, it helps stabilize the protein’s structure. However, incorrect bonds can distort a protein’s shape or link separate proteins into abnormal aggregates.

Direct chemical experiments showed that VS, acting basically as a mild oxidant, promoted formation of disulfide bonds. Apparently, healthy cells were able to successfully deal with it, but for senescent cells, this was a death sentence.

When two cysteines form a bisulfate bond, they become less available to other reactions; therefore, the researchers analyzed the proteins that showed decreased cysteine reactivity. Among such proteins, those related to protein folding were enriched. They were also enriched among protein aggregates.

Finally, the team linked the senescent cell-specific vulnerability to the metabolism of glutathione, a major antioxidant, which exists in a reduced form, GSH, and an oxidized form, GSSG. They found that senescent cells accumulate GSSG due to the scarcity of the enzyme glutathione reductase. This imbalance apparently creates the conditions for VS-mediated stress.

Literature

[1] Wu, R., Yang, F., Li, J., Wu, T., Lyu, R., Xiang, J., … & Chen, J. (2026). Altered protein cysteine reactivity in senescent cells is a vulnerability for senolysis to ameliorate aging. Nature Aging, 1-24.

[2] Cusi, K., Cukier, S., DeFronzo, R. A., Torres, M., Puchulu, F. M., & Redondo, J. P. (2001). Vanadyl sulfate improves hepatic and muscle insulin sensitivity in type 2 diabetes. The Journal of Clinical Endocrinology & Metabolism, 86(3), 1410-1417.

[3] Fan, H., Xia, S., Xiang, J., Li, Y., Ross, M. O., Lim, S. A., … & Chen, J. (2023). Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity. Nature, 623(7989), 1034-1043.