Senolytics & Cellular Senescence: Clearing the “Zombie Cells”

July 17, 2025

Aging is not merely the passage of time, it is a gradual accumulation of cellular damage that ultimately impairs tissue function and fosters chronic inflammation. A key contributor to this process is cellular senescence: a state in which cells permanently exit the cell cycle yet remain metabolically active and secrete a cocktail of pro-inflammatory factors known as the senescence-associated secretory phenotype (SASP). These “zombie cells” resist apoptosis, accumulate in tissues over time, and drive local and systemic dysfunction. At Redox Medical Group, we focus on advanced cellular strategies that improve your cellular redox which then leads to improved cellular senescence. Senolytic therapies, which target and remove senescent cells, present a promising strategy to counteract chronic low-grade inflammation associated with aging, enhance tissue repair, and promote improved healthspan. In this article, we’ll explore the mechanisms of cellular senescence, examine dietary and pharmacologic senolytics, highlight clinical applications, and outline practical protocols for integrating senolytic strategies into a comprehensive cellular medicine approach.

What Is Cellular Senescence?

The Senescence Phenotype

Cellular senescence is a stress response characterized by a permanent cessation of cell division triggered by various insults such as telomere shortening, DNA double-strand breaks, oxidative stress, oncogene activation, and mitochondrial dysfunction. Hallmarks of Cellular Senescence:

  • Cell Cycle Arrest: Upregulation of cyclin-dependent kinase inhibitors (p16^INK4a^, p21^CIP1/WAF1^) forces cells to remain in the G1 or G2 phase, preventing DNA replication and further cell division.
  • Senescence-Associated β-Galactosidase (SA-β-Gal) Activity: Elevated SA-β-Gal activity is a widely used histochemical marker of senescent cells, reflecting increased lysosomal content and metabolic activity. It is important to recognize that cellular senescence cannot be diagnosed by a single clinical marker.
  • Resistance to Apoptosis: Senescent cells often upregulate anti-apoptotic proteins (such as BCL-2 and BCL-xL), which allows them to survive and accumulate despite cellular damage.
  • Senescence-Associated Secretory Phenotype (SASP): Senescent cells secrete a complex mix of factors, including pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), chemokines (CCL2, CXCL8), growth factors (VEGF), and matrix metalloproteinases (MMPs), that profoundly alter the tissue microenvironment and influence neighboring cells.

While transient senescence, such as that induced during wound healing, can be beneficial (limiting malignant transformation and coordinating tissue repair), chronic senescent cell accumulation promotes local inflammation, extracellular matrix (ECM) degradation, and impaired stem cell function. Over time, this “senescent burden” contributes to age-related pathologies: osteoarthritis, atherosclerosis, pulmonary fibrosis, and neurodegeneration. Senescent cells also secrete factors that reinforce senescence in neighboring cells via paracrine signaling, creating a vicious cycle that amplifies tissue dysfunction, a concept aligned with the redox and inflammatory themes in [Unpacking Inflammaging: What It Is, Why It Matters, and How to Manage It].

Mechanisms Driving Senescence

  1. Telomere Attrition: Each cell division shortens telomeres, which are protective DNA-protein structures at the ends of chromosomes. When telomeres become critically short they trigger a DNA damage response (DDR). The DDR activates key tumor suppressor proteins, such as p53, which enforce cellular senescence. Fun fact: Elephants have 20 p53 genes and humans only have 1!
  2. DNA Damage & Genotoxic Stress: Reactive oxygen species (ROS), produced during mitochondrial respiration or induced by external toxins, cause DNA strand breaks. When repair mechanisms fail, cells enter senescence to prevent malignant transformation. Ensuring robust mitochondrial function and redox balance (as detailed in [What Is Cellular Redox and Why It Needs To Be YOUR Long Term Health Goal] and [The TCA Cycle: Deciding Cell Fate and Function and More]) is critical for mitigating ROS-induced senescence.
  3. Oncogene-Induced Senescence (OIS): Rapid activation of oncogenes (e.g., RAS, BRAF) triggers an acute senescence program to block neoplastic progression, mediated by p16^INK4a^ and p53 pathways.
  4. Mitochondrial Dysfunction: Damaged or dysfunctional mitochondria produce elevated levels of ROS and release mitochondrial DNA into the cytosol, activating cGAS-STING pathways that promote SASP. NAD⁺ depletion exacerbates mitochondrial inefficiency; supporting NAD⁺ levels by optimizing cellular efficiency (refer to [Why NAD Supplementation Isn’t Beneficial]) can delay senescence onset. NOTE: Supplementing endogenous NAD⁺ can promote the survival and secretory activity of senescent cells, thereby increasing the overall senescent cell burden!

Persistent senescent cells adopt a pro-inflammatory, tissue-destructive SASP, undermining nearby healthy cells. In cartilage, SASP factors degrade collagen and proteoglycans, accelerating osteoarthritis; in vasculature, endothelial senescence fosters atherogenesis; in skin, epidermal and dermal senescence contribute to wrinkles and impaired barrier function. The challenge is to selectively eliminate these cells without harming normal tissues, a task that senolytics aim to achieve.

Senolytic Agents: Dietary & Pharmacologic Interventions

Dietary Senolytics: Nature’s Allies

Certain phytochemicals naturally induce apoptosis in senescent cells by interfering with their anti-apoptotic defenses. Key dietary senolytics include:

  • Quercetin: A flavonoid abundant in onions, apples, and berries. It exerts senolytic effects by interacting with PI3K isoforms and downregulating anti-apoptotic BCL-2 family proteins, such as BCL-2 and BCL-xL, leading to apoptosis of senescent cells. In mouse models, a combination of quercetin (50 mg/kg) plus dasatinib (5 mg/kg) has been shown to selectively eliminate senescent cells, reduce their burden, and improve organ function, including cardiovascular parameters
  • Fisetin: Found in strawberries, apples, and cucumbers. Fisetin exerts senolytic activity by inhibiting BCL-2 family proteins and modulating multiple kinase pathways. In aged mice, oral fisetin (100 mg/kg for two consecutive days) reduced senescent markers in adipose and liver tissues, improved cognition, and extended median lifespan. Human-equivalent dosing (~20 mg/kg) is being explored in early-phase trials.
  • Curcumin & Ginkgolic Acid: While curcumin (from turmeric) primarily acts as a senomorphic (reduce secretion of SASP), ginkgolic acid (from Ginkgo biloba) exhibits direct pro-apoptotic activity in senescent cells by disrupting mitochondrial membrane potential. Dosing for efficacy in humans remains under investigation.

Although dietary senolytics provide a gentler approach to targeting senescent cells, their bioavailability is often limited. Enhancing absorption, such as using quercetin phytosome formulations or co-administering curcumin with piperine, is important to improve systemic exposure. Additionally, dietary senolytics tend to be most effective when administered intermittently in targeted pulses, mimicking pharmacological senolytic dosing schedules. This strategy helps minimize off-target effects while maintaining a baseline anti-inflammatory environment.

Pharmacologic Senolytics: Precision Therapies

More potent senolytics have emerged from repurposed oncology drugs and experimental compounds. Leading agents include:

  • Dasatinib (D) + Quercetin (Q): Dasatinib (D) was designed as a multi-kinase inhibitor for chronic myeloid leukemia and targets EphA receptors, among others to induce apoptosis in senescent human preadipocytes. In combination with quercetin (Q), which inhibits BCL-2 family proteins, the D+Q cocktail has demonstrated synergistic senolytic effects in both preclinical research and early human trials. A landmark pilot study (Phase I clinical trial) in IPF patients, intermittent D (100 mg/day) + Q (1250 mg/day) for three days/week over three weeks reduced senescence markers (notably p16^INK4a^ in blood mononuclear cells) and led to significant improvements in physical functioning, with effects lasting at least several weeks after treatment
  • Navitoclax (ABT-263): A BCL-2/BCL-xL inhibitor originally trialed for hematologic malignancies. Navitoclax selectively induces apoptosis in senescent human umbilical vein endothelial cells (HUVECs) and senescent erythroid progenitors. However, its clinical use is limited by thrombocytopenia, as platelets rely on BCL-xL for survival and navitoclax inhibits BCL-xL. To mitigate thrombocytopenia while maintaining senolytic efficacy, lower-dose and intermittent schedules (e.g., 50 mg every other day for two weeks) are being tested to mitigate platelet loss while retaining senolytic efficacy.
  • Fisetin: As noted above, fisetin is both a dietary flavonoid and a potent senolytic at pharmacologic doses. A Phase I trial (AFFIRM-LITE) uses 20–30 mg/kg fisetin daily for two consecutive days monthly, aiming to reduce senescent cell burden in older adults with early cognitive impairment. The approach is experimental and under active study for safety and long-term effectiveness.
  • Other Emerging Compounds:
    • FOXO4-DRI Peptide: A synthetic D-retro-inverso peptide specifically engineered to disrupt the interaction between the transcription factor FOXO4 and the tumor suppressor p53. By interfering with the FOXO4-p53 binding, FOXO4-DRI triggers p53-mediated apoptosis selectively in senescent cells, leaving healthy, non-senescent cells largely unaffected. Preclinical studies in mice demonstrate improved hair density, renal function, and exercise capacity after systemic administration.
    • Procyanidin C1: A flavanol from grape seeds shown to act as a senolytic by inducing apoptosis in senescent human fibroblasts and adipocytes, primarily through upregulation of apoptotic pathways. Early data suggest synergy with quercetin or D + Q regimens.

Pharmacologic senolytics require precise dosing to avoid off-target cytotoxicity. Unlike chronic pharmaceuticals, senolytics are administered intermittently, commonly in “senolytic pulses”, to clear accrued senescent cells, followed by recovery and regenerative phases. This intermittent approach reduces the risk of damaging proliferative stem cells and limits adverse events.

Clinical & Therapeutic Applications

Osteoarthritis & Musculoskeletal Aging

Senescent chondrocytes in cartilage secrete high levels of MMP-13, ADAMTS5, and inflammatory cytokines that degrade collagen type II and aggrecan, contributing to osteoarthritis. Preclinical studies show that intra-articular injection of dasatinib plus quercetin (D+Q) reduces senescent cell burden, limits cartilage degradation, and relieves pain in aged and post-traumatic osteoarthritis mouse models. A small open-label trial in 12 patients with knee osteoarthritis administering D+Q (dasatinib 100 mg and quercetin 1,250 mg once weekly for three weeks) reported reduced pain and improved function at 12 weeks, with only mild transient cytopenias as side effects.

Remember, don’t overlook simple yet important options like native collagen, which can be a valuable supplement for arthritis!

Cardiovascular Disease & Atherosclerosis

Senescent endothelial cells accumulate in atherosclerotic plaques and secrete senescence-associated secretory phenotype (SASP) factors, such as pro-inflammatory cytokines and chemokines. These factors fuel vascular inflammation and drive monocyte recruitment, worsening plaque instability and vascular dysfunction. In murine models of atherosclerosis (ApoE^−/−^ mice), a single D + Q regimen reduced senescent-cell markers in the endothelium, decreased plaque burden by ~25%, and improved vascular reactivity. Translational studies in humans are in progress to determine if periodic senolytic dosing can stabilize atherosclerotic plaques, improve coronary flow reserve, and lower circulating indicators of vascular injury and inflammation, such as endothelial microparticles and interleukin-6 (IL-6).

For high-risk patients, such as those with metabolic syndrome, hypertension, or a history of angioplasty, it’s important to support overall cellular efficiency through a comprehensive approach. While senolytics can help reduce senescent cell burden, other cellular modalities that enhance mitochondrial function, metabolic health, and redox balance are also vital. Additionally, senomodulators may help modulate cell activity and promote tissue repair. Combining these strategies offers a balanced, flexible approach to improving cellular function and reducing inflammation.

Pulmonary Fibrosis & Chronic Obstructive Pulmonary Disease (COPD)

Idiopathic pulmonary fibrosis (IPF) involves the accumulation of senescent alveolar epithelial cells and fibroblasts, which drive ongoing fibrogenesis through transforming growth factor-beta (TGF-β) signaling and the senescence-associated secretory phenotype (SASP). In a pilot Phase I trial, IPF patients received D + Q (dasatinib 100 mg + quercetin 1,000 mg daily for three days), resulting in reduced circulating senescent markers (p16^INK4a^ mRNA in PBMCs) and modest improvements in six-minute walk distance at 3 months.

Peptides can show promise in mitigating fibrosis by regulating collagen synthesis, reducing inflammation, and modulating pro-fibrotic pathways such as TGF-β. When used following senolytic treatments, these peptides may help clear residual fibrotic tissue, promote tissue repair, and restore healthy extracellular matrix balance. Although primarily supported by preclinical data, combining these peptides with senolytics represents a promising strategy to enhance lung regeneration and reduce fibrosis progression.

Neurodegeneration & Cognitive Decline

Senescent glial cells secrete pro-inflammatory factors that compromise neuronal function and synaptic plasticity. In Alzheimer’s disease (AD) mouse models, genetic ablation of senescent cells or senolytic treatment (D + Q) reduced amyloid-beta accumulation, improved cognitive performance in maze tests, and decreased microgliosis. Although human trials are in nascent stages, targeting brain senescence holds promise for early MCI (mild cognitive impairment) and AD. Combining senolytic pulses and trehalose (which enhances autophagy, per [Trehalose – The Sugar that Is Actually Good For You]) may synergistically clear senescent glia and aggregate-prone proteins.

Because the blood-brain barrier (BBB) limits some senolytic penetration, exploring intranasal or nanoparticle-based delivery of FOXO4-DRI peptides is an emerging frontier. Patients with Down syndrome, who exhibit accelerated brain senescence, may especially benefit from early senolytic interventions to delay neurodegenerative onset.

Metabolic Syndrome & Diabetes

Senescent adipocytes and hepatic stellate cells contribute to insulin resistance, hepatic steatosis, and low-grade inflammation. In diet-induced obese mice, D + Q treatment reduced senescent cell accumulation in adipose tissue, improved insulin sensitivity (HOMA-IR decreased by ~30%), and decreased hepatic triglyceride content. Human pilots are exploring whether intermittent senolytic pulses can complement lifestyle interventions, calorie restriction (see [Intermittent Fasting & Calorie Restriction: Cellular Pathways to Longevity]) and high-fiber diets (see [Fiber: A Cornerstone of Cellular Health and Longevity]), to achieve greater metabolic improvements.

GLP-1 receptor agonists are proving to be important tools in this space due to their ability to enhance metabolic flexibility at the cellular level. By improving how cells utilize and shift between different energy substrates, GLP-1s create a domino effect that supports mitochondrial health, reduces oxidative stress, and drives broad improvements in metabolic and inflammatory processes downstream, therefore decreasing cellular senescence. Integrating GLP-1 receptor agonists into multi-modal strategies can therefore further strengthen metabolic resilience and outcomes in patients with metabolic dysfunction.

Practical Considerations

Patient Selection & Screening

  1. Clinical Assessment: Identify individuals with age-related, senescence-driven conditions such as osteoarthritis, IPF, early AD, or metabolic syndrome refractory to lifestyle changes. Evaluate baseline inflammatory markers (CRP, IL-6), measure senescent-cell proxies (p16^INK4a^ expression in PBMCs), and conduct functional tests (six-minute walk distance for IPF, WOMAC index for osteoarthritis).
  2. Safety Screening: It is essential to stress that using senolytic therapies, agents aimed at eliminating senescent cells, should only be pursued under the direct guidance of a qualified healthcare professional. Senolytics, whether pharmaceutical (such as dasatinib or navitoclax) or high-dose nutraceutical (like fisetin or quercetin), can carry significant risks, including: cytopenia, impact liver or kidney function, drug-drug interaction (e.g., CYP3A4 substrates for dasatinib) and exacerbation of underlying medical conditions. Women of childbearing potential should use effective contraception during and one week after dosing.
  3. Safety Emphasis: Senolytics Require Medical Supervision: Never attempt senolytic treatments without professional medical oversight. Always consult your physician before making decisions about senolytic use or related protocols, as the risks can be significant without expert evaluation and supervision.

Senolytic Pulse Protocols

  • Dasatinib + Quercetin (D + Q)
    • Dosage: Dasatinib 100 mg + Quercetin 1,000 mg orally once daily for two consecutive days.
    • Frequency: Monthly pulses (every 30 days) for three months, then reassess. Some patients may require maintenance pulses every 6–12 months depending on biomarkers and clinical response.
    • Monitoring: Check CBC, liver panel, and markers of senescence (p16^INK4a^ in PBMCs) two weeks and four weeks post-pulse. Evaluate functional outcomes (e.g., WOMAC, six-minute walk) at three months.
  • Fisetin Pulse
    • Dosage: Fisetin 20 mg/kg/day (orally, in divided doses) for two consecutive days. For a 70 kg adult, this equals roughly 1,400 mg per day.
    • Frequency: Quarterly pulses (every 90 days), pending biomarker assessments.
    • Monitoring: Weekly CBC and metabolic panel for two weeks to detect any cytopenias or hepatic enzyme elevations. Functional measures (cognition tests, endurance tests) at three months.
  • Navitoclax (ABT-263)(Investigational Use)
    • Dosage: 50 mg orally every other day for two weeks, co-administered with a platelet growth factor if needed.
    • Frequency: Single course or repeated twice annually under trial protocols.
    • Monitoring: Weekly CBC focusing on platelets; liver function tests; and assessments of senescent exposure (SASP cytokine panel) monthly for three months.
  • Note on Supplementation at Redox: While dietary senolytics such as quercetin, fisetin, curcumin, Navitoclax and ginkgolic acid are frequently discussed in the literature on cellular senescence, it’s important to recognize that these are not typically supplements we recommend or routinely use at Redox. When reading about senescence, you will commonly encounter these compounds mentioned in research and wellness articles, but they do not represent the standard supplement protocols in our practice.

Adjunctive Regenerative Support

  1. Signaling Agent Therapies
    • Certain signaling agents may be considered as part of strategies to support healthy cellular senescence. These peptides have shown potential in promoting tissue repair, reducing inflammation, and modulating pathways associated with cellular aging.
    • Improving metabolic flexibility and supporting cellular health can have beneficial downstream effects on senescence-related processes.
  2. Redox Support:
    • Glutathione & Antioxidants: N-acetylcysteine (600 mg twice daily) and alpha-lipoic acid (300 mg twice daily) for four weeks post-pulse to buffer ROS and support detoxification pathways—complementing redox strategies outlined in [Why NAD Supplementation Isn’t Beneficial].

Practical Takeaways & Cautions

  1. Intermittent Dosing Maximizes Safety
    • Senolytics are not intended for chronic daily use. Instead, brief “pulses” allow for preferential clearance of senescent cells while giving healthy tissues time to recover. Monthly or quarterly dosing balances efficacy with minimizing adverse events.
  2. Comprehensive Monitoring Is Essential
    • Repeat CBC, metabolic panels, and senescence biomarkers (p16^INK4a^, SASP cytokines) to assess efficacy and early toxicity. Functional outcomes (mobility tests, cognitive assessments) should guide ongoing need for additional pulses. Remember, cellular senescence cannot be diagnosed by a single clinical marker.
  3. Tailor to Individual Risk Profiles
    • Older patients with multiple comorbidities may require lower dosing or extended intervals between pulses. Women of childbearing potential should avoid senolytics due to limited safety data in pregnancy.
  4. Combine with Nutritional & Lifestyle Interventions
  5. Work with a Multidisciplinary Team
    • Senolytic therapy involves nuanced decision-making. Collaboration between cellular medicine specialists, rheumatologists (for osteoarthritis), pulmonologists (for IPF), and neurologists (for cognitive decline) ensures safety and maximizes benefits.

Conclusion & Call to Action

Cellular senescence underlies many age-related conditions, from osteoarthritis and cardiovascular disease to neurodegeneration and metabolic syndrome. Senolytics, whether dietary flavonoids like fisetin and quercetin, repurposed oncology drugs like dasatinib, or emerging peptides, offer a targeted approach to clear senescent cells, reduce chronic inflammation, and restore tissue function.

At Redox, we go far beyond a generic or protocol-driven style of care by taking a deeply individualized, science-based approach that operates at the cellular and pathway level. We recognize that cellular senescence is a complex, multifaceted process and that the underlying drivers differ significantly from person to person. Factors such as lifestyle, genetics, metabolic health, and even previous environmental exposures all shape why and how senescence burdens arise in each individual.

Our process begins with building a strong foundation tailored to the patient’s unique biology. We focus first on addressing root contributors to senescence that are unique with each patient such as; restoring metabolic balance, mitochondrial function and cellular resilience. We don’t jump right into senolytic therapies. Senescence is not “one size fits all”; everyone’s pathway to, and out of, cellular aging is unique. By thoroughly evaluating and addressing your individual drivers, Redox aims to lay a sturdy foundation for cellular health and resilience. Only then do we strategically add advanced interventions (like senolytics, peptides, or targeted antioxidant strategies) to accelerate regeneration and extend health span, ensuring that each element of care is purposeful and optimally timed.

Ready to take the next step in your personalized journey to cellular health? Book a consultation with Dr. Seeds today. Together, we’ll evaluate your senescence burden, design an evidence-based senolytic protocol tailored to your unique biology, and coordinate adjunctive therapies, empowering you to clear “zombie cells” and support lasting cellular rejuvenation built on a strong, individualized foundation.