Senolytics

Drugs that selectively kill senescent cells, promising in mice and still at the stage of small early phase human trials.

The idea

Senescent cells resist apoptosis by upregulating specific survival pathways. Senolytics exploit that dependence to kill them selectively, leaving healthy cells alone. The best studied combination is dasatinib, a cancer drug, with quercetin, a plant flavonoid.

Because the cells are not dividing, the drugs do not need to be present continuously. That is why senolytics are given intermittently, which is a genuinely novel dosing concept.

What the mouse data show

In aged mice, intermittent senolytic treatment improved physical function and extended remaining lifespan, and clearing senescent cells improved outcomes in models of osteoarthritis, atherosclerosis and lung fibrosis. These are strong preclinical results.

What the human data show

Very little so far, and everyone honest says so. The first open label pilot in idiopathic pulmonary fibrosis enrolled 14 patients and reported feasibility with modest changes in physical function. A pilot in diabetic kidney disease showed reduced senescent cell markers in tissue. Both were small, short and uncontrolled.

No randomized trial has yet shown that senolytic treatment improves a hard outcome in humans. Trials are running, including in Alzheimer's disease and osteoarthritis.

The practical position

The gap between the mouse data and the human data is still wide. Dasatinib is a chemotherapeutic with a real side effect profile, and quercetin supplements are not standardized between brands.

This is a field worth following closely and not worth buying yet.

Baseline does not offer senolytics. When randomized human outcome data exist, that position changes.

References

  1. Justice JN, et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine. 2019.
  2. Hickson LJ, 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.
  3. Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020.