Aging & Longevity

Revitalizing Aging: Clearing Troublesome Senescent Cells with Senolytics for Optimal Health

Senolytics selectively eliminate senescent cells — non-proliferative cells that release inflammatory molecules to surrounding tissue triggering otherwise healthy cells to enter senescence.

(Senolytics | Shutterstock)
By Bennett M. Sherman

Key Points

  • Several senolytic agents have been established to reduce age-related organ dysfunction and deterioration by selectively eliminating aged, non-proliferative senescent cells.
  • Supplementing mice with the senolytic fisetin increases their average lifespan by as much as 25%.

As we grow older, the number of aged, non-proliferative senescent cells that release a milieu of inflammatory molecules to surrounding cells increases throughout our bodies. The molecule combination that senescent cells release (the senescence-associated secretory phenotype [SASP]) also induces healthy cells that come into contact with them to become senescent. Although most cells reach a point where they undergo programmed cell death (apoptosis), as we get older, more and more cells become senescent and survive molecular apoptosis cues. Since our immunity wanes with age, our immune systems also have a more difficult time disposing of senescent cells.

This age-associated accumulation of senescent cells facilitates tissue inflammation and organ damage. Intriguingly, some researchers propose age-related senescent cell accumulation is one of the reasons we age.

(Sun et al., 2022 | Life Medicine) Senescent cells have a heavy impact on aging and associated diseases. As organisms grow older and cells age, the cells frequently enter a state of non-proliferation where they emit inflammatory molecules called senescence. Senescent cell accumulation contributes to organ dysfunction and disease in aged organisms.

Senolytics Explained

Scientists have considered eliminating senescent cells as a way to counter the adverse effects of aging, namely to reduce inflammation and improve tissue function. For this purpose, researchers have recently developed a new class of supplements called senolytics, the majority of which are derived from a class of molecules found in fruits and vegetables called polyphenols. These new drugs can selectively trigger cell death (apoptosis) in senescent cells without considerably damaging healthy cells.

Senolytics work by targeting pro-survival pathways, which senescent cells use to evade apoptosis. A big challenge to eliminating senescent cells is that there are multiple types of these cells coming from different tissues, which rely on different pathways for apoptosis evasion. For this reason, the use of multiple senolytics, each targeting different pathways, may be necessary to terminate large swaths of senescent cells. Furthermore, some senescent cells play essential roles in wound healing, so figuring out what each senescent cell population does is critical before deciding which to target.

Examples of Senolytics and Their Preclinical Trials

Within the last decade, researchers have begun putting more stock into the idea that getting rid of senescent cells can counter some of aging’s adverse effects. Along those lines, a number of rodent studies have given positive results, propelling enthusiasm for senolytics.

Examples include the use of the senolytic agents dasatinib and quercetin, a combination that was found to improve cardiac function in naturally aged and atherosclerosis mouse models. Another study using dasatinib and quercetin found the senolytic combination enhanced exercise capacity and radiation-damaged mice. The dasatinib and quercetin senolytic combination also delayed the onset of physical dysfunction in prematurely aging mice. These studies are among some of the major findings from animal studies using the senolytic agents dasatinib and quercetin.

Fisetin, a plant flavonoid found in foods like strawberries and onions, has garnered positive findings when applied in mouse studies. Fisetin attenuates age-related pathologies and increases healthy mouse average lifespan by ~25%. The question remains how well the dasatinib and quercetin along with fisetin findings in rodent studies will translate to humans.

(Yousefzadeh et al., 2018 | EBioMedicine) Fisetin-infused diets drive ~25% increase in average mouse lifespan. A diet including fisetin (orange line) drives increased survival such that the median lifespan (asterisk) is ~25% longer compared to mice that consumed a normal diet (black line).

Active and Planned Senolytic Human Trials

Data from early pilot human trials indicate that senolytics potently eliminate senescent cells, alleviate inflammation and reduce frailty in humans. Clinical trials for Alzheimer’s disease, COVID-19, diabetes, eye disorders, lung fibrosis, osteoarthritis, osteoporosis, bone marrow transplantation, and childhood cancer survivors are currently underway. Until the conclusion of such studies, it’s too early to say how effective senolytics will be for aged people.

The first senolytic clinical trial demonstrated improved physical function in patients with lung scarring (idiopathic pulmonary fibrosis) who took dasatinib and quercetin. Another human trial reported dasatinib and quercetin treatment reduces senescent cell burden in fat tissues (adipose tissue) of patients developing diabetic kidney disease. Moreover, circulating SASP factors inducing inflammation were reduced in these patients.

More recently, a phase I clinical trial of dasatinib and quercetin for Alzheimer’s disease reported that intermittent senolytic administration decreases a hallmark of Alzheimer’s disease pathology — tau protein aggregates. The same study showed dasatinib and quercetin reduce neuroinflammation, preserve neurons, and partly restore blood flow to the brain.

Given the promising findings associated with senolytics and their solid safety profiles, a number of new trials investigating their clinical potential have been initiated. Such studies with dasatinib and quercetin include those for mild cognitive impairment and Alzheimer’s disease, liver disease, and cancer. Fisetin is also being investigated for conditions like cancer, COVID-19, and Carpal Tunnel syndrome. If these trials produce positive results, using senolytic agents against age-related physiological decline may become more and more common.

While the effects of senescent cell accumulation in the body as we get older is under investigation, the evidence showing this accumulation plays a key role in aging makes it a promising target for anti-aging drugs. As such, senolytics present a promising new option to selectively eliminate senescent cells for inflammation reduction and improving tissue health.


Fuhrmann-Stroissnigg H, Ling YY, Zhao J, McGowan SJ, Zhu Y, Brooks RW, Grassi D, Gregg SQ, Stripay JL, Dorronsoro A, Corbo L, Tang P, Bukata C, Ring N, Giacca M, Li X, Tchkonia T, Kirkland JL, Niedernhofer LJ, Robbins PD. Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun. 2017 Sep 4;8(1):422. doi: 10.1038/s41467-017-00314-z. PMID: 28871086; PMCID: PMC5583353.


Gonzales MM, Garbarino VR, Marques Zilli E, Petersen RC, Kirkland JL, Tchkonia T, Musi N, Seshadri S, Craft S, Orr ME. Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD): A Pilot Clinical Trial. J Prev Alzheimers Dis. 2022;9(1):22-29. doi: 10.14283/jpad.2021.62. PMID: 35098970; PMCID: PMC8612719.


Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, Herrmann SM, Jensen MD, Jia Q, Jordan KL, Kellogg TA, Khosla S, Koerber DM, Lagnado AB, Lawson DK, LeBrasseur NK, Lerman LO, McDonald KM, McKenzie TJ, Passos JF, Pignolo RJ, Pirtskhalava T, Saadiq IM, Schaefer KK, Textor SC, Victorelli SG, Volkman TL, Xue A, Wentworth MA, Wissler Gerdes EO, Zhu Y, Tchkonia T, Kirkland JL. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019 Sep;47:446-456. doi: 10.1016/j.ebiom.2019.08.069. Epub 2019 Sep 18. Erratum in: EBioMedicine. 2020 Feb;52:102595. PMID: 31542391; PMCID: PMC6796530.


Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, Prata L, Masternak MM, Kritchevsky SB, Musi N, Kirkland JL. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019 Feb;40:554-563. doi: 10.1016/j.ebiom.2018.12.052. Epub 2019 Jan 5. PMID: 30616998; PMCID: PMC6412088.


Roos CM, Zhang B, Palmer AK, Ogrodnik MB, Pirtskhalava T, Thalji NM, Hagler M, Jurk D, Smith LA, Casaclang-Verzosa G, Zhu Y, Schafer MJ, Tchkonia T, Kirkland JL, Miller JD. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016 Oct;15(5):973-7. doi: 10.1111/acel.12458. Epub 2016 Aug 5. PMID: 26864908; PMCID: PMC5013022.


Sun Y, Li Q, Kirkland JL. Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging. Life Med. 2022 Aug 9;1(2):103-119. doi: 10.1093/lifemedi/lnac030. PMID: 36699942; PMCID: PMC9869767.


van Deursen JM. The role of senescent cells in ageing. Nature. 2014 May 22;509(7501):439-46. doi: 10.1038/nature13193. PMID: 24848057; PMCID: PMC4214092.


Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28. doi: 10.1016/j.ebiom.2018.09.015. Epub 2018 Sep 29. PMID: 30279143; PMCID: PMC6197652.


Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, Pirtskhalava T, Giorgadze N, Johnson KO, Giles CB, Wren JD, Niedernhofer LJ, Robbins PD, Kirkland JL. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 2016 Jun;15(3):428-35. doi: 10.1111/acel.12445. Epub 2016 Mar 18. PMID: 26711051; PMCID: PMC4854923.

To The Top