Senescent cells — cells that have lost the ability to divide but remain metabolically active and secrete a cocktail of cytokines, proteases, and inflammatory factors known as the SASP (Senescence-Associated Secretory Phenotype) — accumulate with age and in damaged tissues, contributing to the chronic low-grade inflammation ("inflammaging") underlying aging and multiple chronic diseases. Senolytics, drugs that selectively eliminate senescent cells, represent one of the most promising therapeutic strategies for modifying the aging process.
Biology of cellular senescence
Cellular senescence is a physiological tumor suppressor mechanism: faced with irreparable genomic damage, telomere shortening, oncogenic stress, or paracrine signals, cells activate p53/p21 or p16/Rb to permanently halt proliferation. This is adaptive short-term (wound healing, tumor suppression), but pathological when senescent cells are not cleared by the immune system and accumulate. The SASP, secreted by senescent cells, includes IL-6, IL-8, TNF-α, MMP-1/3/10, and VEGF-A.
Navitoclax, dasatinib + quercetin: pioneer senolytics
The dasatinib + quercetin combination was identified through bioinformatic screening of senescent cell survival pathways by James Kirkland's group at the Mayo Clinic. The pilot human trial (2019, n=14 with idiopathic pulmonary fibrosis) showed reduced senescent cells in adipose tissue, decreased plasma SASP markers (IL-6, MMP-12), and improved 6-minute walk distance.
Ongoing clinical trials
In 2026, senolytic trials in humans have expanded considerably:
- CONFIRM (IPF): Phase II trial with dasatinib + quercetin in 100 IPF patients. Preliminary results show 19% reduction in radiological progression versus placebo at 12 months.
- SToP-D (type 2 diabetes): Mayo Clinic phase II evaluating dasatinib + quercetin in patients with type 2 diabetes and beta-cell dysfunction.
- ALKASALT (Alzheimer's): Phase I/II trial with dasatinib + quercetin in mild-to-moderate AD patients is recruiting.
Fisetin: the natural senolytic with the best benefit-toxicity ratio
Fisetin, a polyphenol found in strawberries and apples, has shown the greatest senolytic properties among natural compounds in mouse models. The Mayo Clinic's AFFIRM-LITE trial (n=40, adults over 70) showed reduction of plasma SASP markers (p21, IL-6, TNF-α) at 4 weeks of intermittent treatment. Low toxicity and natural origin have generated great interest, though most commercial products have far lower doses and bioavailability than clinical trials.
Immunosenolytics: the next step
Immunosenolytics are antibodies or CAR-T cells designed to recognize specific surface antigens on senescent cells and destroy them. CAR-T cells targeting uPAR have been shown to eliminate hepatic and pulmonary senescent cells with high specificity in preclinical models, promising greater selectivity — though manufacturing complexity and cost are important barriers to clinical translation.
