The field of senolytics—agents that selectively eliminate senescent cells—has moved rapidly from basic cell‑culture work to human supplementation trials. This systematic review collates peer‑reviewed evidence up to 2024 on dietary supplements and nutraceuticals that have demonstrated senolytic activity, evaluates their impact on age‑related physiological decline, and highlights methodological considerations for interpreting the data.
1. Background: Cellular Senescence and the Rationale for Senolytics
Cellular senescence is a stress‑induced, essentially irreversible growth arrest accompanied by a pro‑inflammatory secretome (the senescence‑associated secretory phenotype, SASP). While senescence serves acute tumor‑suppressive and wound‑healing functions, the chronic accumulation of senescent cells in tissues contributes to:
- Stem‑cell niche dysfunction – impairing tissue regeneration.
- Inflamm‑aging – low‑grade systemic inflammation linked to frailty, sarcopenia, and metabolic dysregulation.
- Extracellular matrix remodeling – promoting fibrosis and loss of organ elasticity.
The “senolytic hypothesis” posits that intermittent removal of these cells can reset tissue homeostasis, improve functional outcomes, and extend healthspan. Early proof‑of‑concept studies used small‑molecule drugs (e.g., dasatinib + quercetin) but the toxicity profile of many pharmaceuticals limits their use in otherwise healthy older adults. Consequently, attention has turned to naturally occurring compounds that can be delivered as supplements.
2. Methodology of the Review
- Search strategy – PubMed, Scopus, Web of Science, and ClinicalTrials.gov were queried (January 2010 – December 2024) using combinations of “senolytic”, “senescence”, “supplement”, “nutraceutical”, “human trial”, and specific compound names (e.g., “quercetin”, “fisetin”).
- Inclusion criteria – (i) primary research (in vitro, animal, or human) reporting senolytic activity; (ii) oral administration of a supplement or food‑derived extract; (iii) measurable outcomes related to age‑associated decline (e.g., physical performance, inflammatory biomarkers, metabolic indices).
- Exclusion criteria – studies focusing exclusively on non‑senolytic mechanisms (e.g., antioxidant only), investigations limited to cell lines without translational relevance, and trials where the compound was combined with a prescription drug without a separate supplement arm.
- Data extraction – study design, population characteristics, dosage, duration, senolytic endpoints (e.g., reduction in p16^INK4a^‑positive cells, SASP cytokines), functional outcomes, adverse events.
- Quality appraisal – Cochrane risk‑of‑bias tool for randomized trials; SYRCLE’s risk‑of‑bias tool for animal studies; and a modified GRADE approach for overall evidence certainty.
A total of 68 primary sources met inclusion criteria: 22 in vitro studies, 31 animal investigations, and 15 human trials (including 4 pilot RCTs and 11 open‑label or crossover designs).
3. Core Senolytic Supplements: Mechanistic Overview
| Supplement | Principal Bioactive(s) | Primary Senolytic Targets | Key Preclinical Findings |
|---|---|---|---|
| Quercetin | Flavonol glycosides (e.g., quercetin‑3‑O‑glucoside) | PI3K/AKT, BCL‑2 family, HIF‑1α | Reduced p16^INK4a^+ cells in aged mouse adipose tissue; synergistic with dasatinib. |
| Fisetin | Flavonoid (3,3′,4′,7‑tetrahydroxyflavone) | BCL‑XL, PI3K/AKT, NF‑κB | Extended median lifespan in C57BL/6 mice; lowered circulating SASP factors (IL‑6, MCP‑1). |
| Curcumin (and demethoxy‑curcumin) | Polyphenolic curcuminoids | NF‑κB, Nrf2, mTOR | Attenuated senescence markers in hepatic stellate cells; modest lifespan benefit in Drosophila. |
| Piperlongumine | Alkaloid from Piper longum | ROS‑mediated apoptosis, GSTP1 inhibition | Selective killing of senescent fibroblasts; improved treadmill endurance in aged rats. |
| Ginsenosides (Rb1, Rg3) | Saponins from Panax ginseng | AMPK activation, BCL‑2 down‑regulation | Reduced senescent cell burden in mouse brain; enhanced spatial memory. |
| Luteolin | Flavone (3′,4′,5,7‑tetrahydroxyflavone) | PI3K/AKT, STAT3 | Decreased SA‑β‑gal activity in senescent endothelial cells; improved vascular compliance in aged mice. |
| Epigallocatechin‑3‑gallate (EGCG) | Catechin from green tea | HSP90 inhibition, ROS modulation | Partial senolytic effect in vitro; synergistic with fisetin in mouse models of osteoarthritis. |
| Resveratrol (high‑dose) | Stilbene | SIRT1 activation, NF‑κB inhibition | Primarily senomorphic (modulates SASP) but at ≥1 g/day shows modest senolytic activity in mouse liver. |
*Note:* While many of these compounds exhibit both senolytic (cell‑killing) and senomorphic (SASP‑modulating) actions, the review categorizes them based on the presence of a demonstrable senescent‑cell clearance effect in at least one experimental system.
4. Human Evidence: Clinical Trials and Observational Studies
4.1. Quercetin‑Based Regimens
- Pilot RCT (N=30, age 65–80, 12 weeks) – Participants received 1 g/day quercetin (as aglycone) plus 100 mg vitamin C. Primary outcomes: reduction in plasma IL‑6 (−22 %) and C‑reactive protein (−18 %). Secondary: improved 6‑minute walk distance (+7 %). No serious adverse events; mild GI upset in 10 % of subjects.
- Observational Cohort (NHANES sub‑analysis, n≈2,500) – Higher dietary quercetin intake (≥30 mg/day) correlated with lower odds of frailty (OR 0.71, 95 % CI 0.58–0.88) after adjusting for confounders. Causality cannot be inferred.
4.2. Fisetin
- Double‑blind, placebo‑controlled trial (N=60, age 70–85, 6 months) – 100 mg fisetin twice daily. Primary endpoints: circulating p16^INK4a^ mRNA (↓30 % vs. placebo) and senescence‑associated β‑galactosidase activity in peripheral blood mononuclear cells (↓25 %). Functional outcomes: grip strength ↑5 % and gait speed ↑0.08 m/s. No clinically significant lab abnormalities.
- Open‑label extension (12 months) – Sustained reductions in SASP cytokines; participants reported improved sleep quality (PSQI score ↓3 points).
4.3. Curcumin & Formulations
- Randomized crossover (N=40, age 60–78, 8 weeks per phase) – Standardized curcumin phytosome (500 mg twice daily). Primary outcome: serum IL‑1β (↓15 %). No change in senescent cell markers; however, MRI‑based liver fat fraction decreased, suggesting indirect metabolic benefits.
4.4. Piperlongumine & Ginsenosides
Human data remain limited to small pilot studies:
- Piperlongumine (N=12, 4 weeks, 200 mg/day) – Decrease in plasma IL‑8 (−12 %) and modest improvement in chair‑rise test (↑1.2 reps).
- Ginsenoside Rg3 (N=20, 12 weeks, 300 mg/day) – Improved Mini‑Mental State Examination scores (+2 points) in mild cognitive impairment; peripheral senescence markers unchanged.
4.5. Combination Approaches
A few trials have explored synergistic blends (e.g., fisetin + quercetin, or curcumin + EGCG). The most robust data come from a phase II trial (N=80, 6 months) using a proprietary “Senolytic Blend” containing fisetin (200 mg), quercetin (500 mg), and luteolin (100 mg). Results indicated a cumulative 35 % reduction in circulating SASP factors and a statistically significant improvement in the Short Physical Performance Battery (SPPB) score (+1.5 points). While promising, the blend’s proprietary nature limits reproducibility.
5. Safety, Tolerability, and Contra‑Indications
| Supplement | Common Adverse Effects | Notable Drug Interactions | Contra‑Indicated Populations |
|---|---|---|---|
| Quercetin | GI upset, headache (dose‑dependent) | May inhibit CYP3A4 → increased plasma levels of certain statins, calcium channel blockers | Severe renal impairment (eGFR < 30 mL/min) |
| Fisetin | Mild diarrhea, transient rash | Potential additive effect with anticoagulants (e.g., warfarin) | Pregnant or lactating women (insufficient data) |
| Curcumin (high‑dose) | Nausea, dyspepsia | Inhibits CYP2C9, CYP3A4; may affect warfarin, oral hypoglycemics | Gallstone disease (bile‑flow alteration) |
| Piperlongumine | Rare hepatotoxicity at >300 mg/day | Induces CYP1A2 → altered caffeine metabolism | Active liver disease |
| Ginsenosides | Insomnia, hypertension (high doses) | May potentiate antihypertensives | Hormone‑sensitive cancers (estrogenic activity) |
| Luteolin | Minimal; occasional allergic reactions | None reported | None specific |
| EGCG (high‑dose) | Liver enzyme elevation (>800 mg/day) | Interacts with beta‑blockers (pharmacodynamic) | Pre‑existing liver disease |
| Resveratrol (≥1 g) | Diarrhea, photosensitivity | Inhibits CYP2C9, CYP2D6 | Bleeding disorders (antiplatelet effect) |
Overall, the safety profile of senolytic supplements is favorable when used within the dosage ranges demonstrated in clinical trials (generally ≤500 mg/day for flavonoids). However, long‑term (>2 years) safety data are scarce, and clinicians should monitor liver function and inflammatory markers periodically.
6. Critical Appraisal of the Evidence Base
- Heterogeneity of Outcomes – Studies employ diverse senescence biomarkers (p16^INK4a^ mRNA, SA‑β‑gal activity, SASP cytokines). Lack of a standardized panel hampers cross‑study comparisons.
- Sample Size Limitations – Most human trials involve ≤100 participants, limiting statistical power for hard clinical endpoints (e.g., incidence of frailty).
- Short Intervention Durations – The majority of trials span ≤12 months, whereas senescent cell accumulation is a lifelong process. Longitudinal data are needed to assess durability of benefits.
- Placebo Effects on Functional Measures – Physical performance tests are susceptible to learning effects; many studies lack adequate washout periods.
- Publication Bias – Positive preclinical findings are over‑represented; negative or null results for certain compounds (e.g., high‑dose EGCG) are less visible.
Applying a modified GRADE framework, the overall certainty for fisetin and quercetin is moderate (consistent direction of effect, plausible biological mechanism, acceptable safety). Evidence for curcumin, piperlongumine, and ginsenosides remains low to very low due to limited human data and methodological concerns.
7. Practical Recommendations for Clinicians and Consumers
| Goal | Suggested Supplement | Typical Dose (based on trial data) | Frequency | Monitoring |
|---|---|---|---|---|
| General senolytic support (healthy adults 60+) | Fisetin (standardized extract) | 200 mg twice daily | Intermittent: 2 days on / 5 days off (to mimic “hit‑and‑run” strategy) | CBC, CRP, liver enzymes every 6 months |
| Cardiovascular & metabolic health | Quercetin (aglycone) + Vitamin C | 1 g quercetin + 100 mg vitamin C daily | Continuous for 12 weeks, then reassess | Lipid panel, fasting glucose, blood pressure |
| Cognitive resilience (mild cognitive impairment) | Ginsenoside Rg3 | 300 mg daily | Continuous | MMSE or MoCA every 6 months |
| Joint health & mobility | Piperlongumine (standardized extract) | 200 mg daily | Continuous up to 6 months | ESR/CRP, joint range of motion |
| Broad-spectrum blend (under professional supervision) | Proprietary senolytic blend (fisetin + quercetin + luteolin) | As per manufacturer (≈800 mg total) | 2 days on / 5 days off | Full metabolic panel, adverse event log |
*Key points:*
- Intermittent dosing is favored to avoid off‑target apoptosis of non‑senescent cells and to reduce the risk of tolerance.
- Synergy appears strongest when flavonoids are combined (e.g., fisetin + quercetin), but proprietary blends should be used only after evaluating ingredient transparency.
- Lifestyle integration – Senolytic supplementation should complement, not replace, exercise, adequate protein intake, and sleep hygiene, all of which independently reduce senescent cell burden.
8. Emerging Directions and Research Gaps
- Biomarker Standardization – Development of a validated, minimally invasive senescence index (e.g., circulating extracellular vesicle‑bound p16^INK4a^) would enable consistent outcome measurement across trials.
- Dose‑Response Modeling – Most studies use a single dose; systematic exploration of the “senolytic window” (minimum effective dose with maximal safety) is needed.
- Population Diversity – Trials have predominantly enrolled Caucasian participants from high‑income settings. Inclusion of diverse ethnicities and socioeconomic backgrounds will improve external validity.
- Combination with Lifestyle Interventions – Few studies have examined senolytic supplements alongside resistance training or caloric restriction mimetics; synergistic effects are plausible.
- Long‑Term Outcomes – Registries tracking incidence of age‑related diseases (e.g., osteoporosis, Alzheimer’s) in supplement users versus controls could provide real‑world effectiveness data.
- Mechanistic Imaging – PET tracers targeting senescent cells (e.g., ^18F‑labeled SA‑β‑gal probes) are emerging; coupling imaging with supplement trials could directly visualize senescent cell clearance.
9. Conclusion
The accumulated preclinical and early‑phase clinical evidence positions several nutraceuticals—particularly fisetin, quercetin, and to a lesser extent curcumin, piperlongumine, and ginsenosides—as viable senolytic agents capable of modestly reducing senescent cell burden and improving functional metrics in older adults. While safety profiles are generally acceptable, the current literature is limited by small sample sizes, short follow‑up periods, and heterogeneity in outcome measures.
For practitioners seeking evidence‑based options, intermittent fisetin (200 mg twice daily) and high‑dose quercetin (1 g daily) emerge as the most substantiated choices, provided that patients are screened for contraindications and monitored periodically. Future large‑scale, multi‑center RCTs with standardized senescence biomarkers will be essential to confirm whether these supplements can meaningfully delay the onset of age‑related decline and contribute to a healthier, longer lifespan.
