Cellular Senescence: What “Zombie Cells” Are and What the Human Evidence Shows
Senescent cells have permanently stopped dividing but resist dying. They accumulate with age and at the sites of many chronic diseases,3 and through a mix of secreted signals called the SASP they can cause chronic inflammation.2
- Senescence is triggered by stresses such as telomere shortening, DNA damage and cancer-promoting gene activity. It starts as a protective response that stops damaged cells from multiplying; the trouble is that senescent cells build up with age.
- The SASP (senescence-associated secretory phenotype) includes inflammatory signals, protein-degrading enzymes and growth factors, and it has been linked to chronic disease and frailty.2
- Senolytics are drugs that selectively clear senescent cells; the first ones discovered were dasatinib, quercetin, fisetin and navitoclax.3 In an open-label pilot in 9 people with diabetic kidney disease, three days of dasatinib plus quercetin reduced senescent cells in fat tissue and skin, along with some circulating SASP factors.5
- In a first-in-human open-label pilot (with no placebo group) in 14 people with idiopathic pulmonary fibrosis, dasatinib plus quercetin was followed by better walking distance, gait speed and chair-stand times; lung function was unchanged, and the authors called for randomized trials.4
- A major review concludes that it is too early for senolytics to be used outside clinical trials.3 The first placebo-controlled trial in older adults was negative on its main measure: in 60 postmenopausal women, intermittent dasatinib plus quercetin did not reduce bone breakdown, the primary endpoint, over 20 weeks, though exploratory analyses hinted at effects in women with many senescent cells.7
What Cellular Senescence Is and Why It Matters
Cellular senescence was first described by Leonard Hayflick and Paul Moorhead in 1961, who found that normal human cells grown in culture could divide only a limited number of times before stopping for good.1 This limit acts as a brake on cancer, because it stops cells with accumulated damage from multiplying indefinitely. What it did not reveal was the harm that non-dividing senescent cells might do as they accumulate.
Senescent cells are metabolically active, and the most harmful ones resist programmed cell death by switching on survival pathways that protect them from their own inflammatory secretions.3 The immune system clears some senescent cells, but with age they accumulate, and they are found at the sites of many chronic disorders.3
The SASP: Local Inflammation Going Systemic
Through the SASP, senescent cells can drive chronic inflammation, and they have been linked to many chronic diseases and to frailty. That has made them a target for drugs that might delay several age-related diseases at once.2
SASP signals can also push neighbouring cells into senescence in laboratory studies, which may help explain how the burden builds up; how much this matters in people is not yet known.
Senolytics: What Has Been Tested
Senolytics briefly disable the survival pathways of senescent cells, causing them to die. Because senescent cells take weeks to reaccumulate, senolytics can be given intermittently, a “hit-and-run” approach. In preclinical models they delayed, prevented or alleviated a wide range of conditions, from frailty to heart, kidney and lung disease.3
In mice, fisetin was the most potent senolytic of 10 flavonoids tested, and giving it to old mice reduced age-related damage and extended median and maximum lifespan.6 Whether it does anything similar in people has not been shown; see our Supplement Evidence Database.
Human evidence is limited to small pilots. In 14 people with idiopathic pulmonary fibrosis, an open-label course of dasatinib plus quercetin was followed by better walking distance, gait speed and chair-stand times, but lung function and frailty scores were unchanged, effects on circulating SASP factors were inconclusive, and one serious adverse event was reported.4 In 9 people with diabetic kidney disease, three days of the combination reduced senescent cells in fat and skin and lowered some circulating SASP factors, including IL-6.5 A 2020 review listed trials in diabetes, idiopathic pulmonary fibrosis, Alzheimer's disease and several other conditions, and concluded that until they are done, it is too early for senolytics to be used outside clinical trials.3
References
- 1HAYFLICK L, MOORHEAD PS. "The serial cultivation of human diploid cell strains." Exp Cell Res. 1961;25:585-621. PubMed · DOI
- 2Tchkonia T, et al. "Cellular senescence and the senescent secretory phenotype: therapeutic opportunities." J Clin Invest. 2013;123(3):966-72. PubMed · DOI
- 3Kirkland JL, Tchkonia T. "Senolytic drugs: from discovery to translation." J Intern Med. 2020;288(5):518-536. PubMed · DOI
- 4Justice JN, et al. "Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study." EBioMedicine. 2019;40:554-563. PubMed · DOI
- 5Hickson 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;47:446-456. PubMed · DOI
- 6Yousefzadeh MJ, et al. "Fisetin is a senotherapeutic that extends health and lifespan." EBioMedicine. 2018;36:18-28. PubMed · DOI
- 7Farr JN, et al. "Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial." Nat Med. 2024;30(9):2605-2612. PubMed · DOI
