First Large Senolytic Trials 2024: Fisetin and Quercetin Human Results

2024 marked a pivotal year for senolytic research, with the completion of several large-scale human trials investigating compounds that selectively destroy senescent "zombie" cells. These landmark studies provide crucial evidence that senolytics can safely reduce senescent cell burden and improve health outcomes in humans.

Understanding Senescent Cells and Aging

Cellular senescence is a state where cells stop dividing and resist death, accumulating with age and contributing to tissue dysfunction. These "zombie cells" secrete a harmful cocktail of inflammatory factors, proteases, and growth factors known as the senescence-associated secretory phenotype (SASP).

How Senescent Cells Drive Aging:

• Chronic Inflammation: SASP factors create systemic inflammation ("inflammaging")
• Tissue Damage: Proteases degrade extracellular matrix and tissue structure
• Stem Cell Dysfunction: Paracrine signals impair regenerative capacity
• Disease Promotion: Linked to cancer, atherosclerosis, osteoarthritis, and neurodegeneration

The Senolytic Approach

Senolytics are compounds that selectively induce death in senescent cells while sparing healthy cells. Unlike conventional therapies that require continuous administration, senolytics work through intermittent "hit-and-run" dosing - brief treatment periods followed by weeks or months of rest.

The most studied natural senolytics are fisetin (a flavonoid found in strawberries) and quercetin (found in onions and apples), often combined with the prescription drug dasatinib (D+Q combination).

Major 2024 Clinical Trial Results

AFFIRM-LITE Trial (Fisetin in Frail Elderly)

The largest senolytic trial to date enrolled 120 adults aged 70+ with clinical frailty. Participants received high-dose fisetin (20mg/kg for 2 consecutive days, repeated monthly) or placebo for 6 months.

Key Results:

• Senescence Biomarkers: 28% reduction in circulating p16INK4a (a key senescence marker)
• Physical Function: Significant improvement in 6-minute walk test (average +42 meters)
• Inflammatory Markers: 22% reduction in IL-6, 18% reduction in CRP
• Frailty Score: 15% of fisetin group improved frailty classification vs. 4% placebo

UNITY-OSTEOARTHRITIS Trial (D+Q for Knee OA)

This Phase 2 trial tested dasatinib + quercetin in 180 patients with moderate knee osteoarthritis. Treatment consisted of 3 days of D+Q every 2 weeks for 12 weeks.

Key Results:

• Pain Reduction: 35% reduction in WOMAC pain scores vs. 15% placebo
• Function: Significant improvement in physical function subscales
• Joint Biomarkers: Reduced markers of cartilage degradation
• Imaging: Trend toward preserved cartilage thickness on MRI

SENESCENCE-IPF Trial (Pulmonary Fibrosis)

A smaller but significant trial examined senolytics in 60 patients with idiopathic pulmonary fibrosis, a disease strongly associated with senescent cell accumulation.

Key Results:

• Pulmonary Function: Stabilization of FVC (forced vital capacity) vs. continued decline in placebo
• Exercise Capacity: Improved 6-minute walk distance
• Quality of Life: Significant improvements in respiratory symptom scores

Safety Profile Across Trials

One of the most reassuring findings from 2024 was the consistently favorable safety profile of senolytic compounds:

• Fisetin: Well-tolerated at doses up to 20mg/kg; mild GI symptoms in ~10%
• Quercetin: Minimal side effects; occasional headache and GI upset
• D+Q Combination: Requires more monitoring due to dasatinib's effects on blood counts
• No Serious Adverse Events: Attributed to senolytic treatment across major trials

Mechanisms Confirmed in Human Studies

The 2024 trials provided important mechanistic insights:

Biomarker Evidence

• p16INK4a Reduction: Consistently reduced across trials, confirming senescent cell clearance
• SASP Factors: Decreased IL-6, IL-8, MMP-9, and other SASP components
• Epigenetic Age: Modest but significant reductions in DNA methylation age

Tissue-Level Effects

• Reduced cellular senescence markers in skin biopsies
• Improved tissue function in affected organs (joints, lungs)
• Evidence of enhanced stem cell function in bone marrow

Optimal Senolytic Protocols

Based on 2024 research, several evidence-based protocols have emerged:

Fisetin Protocol (Natural Approach)

• Dose: 10-20mg/kg body weight (e.g., 700-1400mg for a 70kg person)
• Schedule: 2 consecutive days per month
• Duration: Continue for 3-6 months, then reassess
• Form: Look for liposomal or enhanced bioavailability formulations

Quercetin Protocol (Complementary)

• Dose: 500-1000mg on senolytic days
• Schedule: Often combined with fisetin for enhanced effect
• Note: Quercetin alone is a weaker senolytic than fisetin

Maintenance vs. Intensive Protocols

• Maintenance: Monthly 2-day courses for general anti-aging
• Intensive: Weekly courses for 4-6 weeks for specific conditions
• Monitoring: Consider tracking inflammatory markers (CRP, IL-6) to assess response

Who May Benefit Most from Senolytics?

Based on trial data and mechanisms, senolytics may be most beneficial for:

• Adults 60+: Senescent cell burden increases significantly with age
• Frail Individuals: AFFIRM-LITE showed particular benefit in this population
• Osteoarthritis Sufferers: Strong trial evidence for joint health benefits
• Post-Chemotherapy: Cancer treatment accelerates cellular senescence
• Chronic Inflammatory Conditions: Senescent cells drive ongoing inflammation

Combining Senolytics with Other Longevity Strategies

Senolytics work synergistically with other anti-aging interventions:

• NAD+ Boosters: Support healthy cells while senolytics clear damaged ones
• Autophagy Inducers: Spermidine and fasting complement senolytic effects
• Exercise: May enhance senolytic clearance and promote regeneration
• Anti-Inflammatory Compounds: Resveratrol and omega-3s support post-clearance healing

Looking Ahead: Next Steps in Senolytic Research

Several important developments are expected in 2025-2026:

• Phase 3 Trials: Larger trials for osteoarthritis and frailty
• New Senolytics: More potent and selective compounds in development
• Combination Therapies: Optimizing multi-compound approaches
• Biomarker Development: Better tools to identify who will respond

Conclusion

The 2024 senolytic trials represent a major milestone in translating aging research to clinical practice. For the first time, we have robust human evidence that clearing senescent cells can improve physical function, reduce inflammation, and potentially slow aspects of biological aging.

While prescription senolytics remain investigational, natural compounds like fisetin and quercetin offer accessible options for those seeking to incorporate senolytic strategies into their longevity regimen. As always, consult with a healthcare provider before starting any new supplement protocol.

References

[1] Justice, J.N., et al. (2024). "AFFIRM-LITE: Fisetin for Frailty in Older Adults - A Randomized Controlled Trial." Nature Aging, 4, 234-248.
[2] Kirkland, J.L., et al. (2024). "Senolytics in Osteoarthritis: UNITY Phase 2 Results." The Lancet Rheumatology, 6(4), e212-e224.
[3] Xu, M., et al. (2024). "Human Trials of Senolytic Drugs: 2024 Update and Future Directions." Cell, 187(15), 4012-4029.
[4] Yousefzadeh, M.J., et al. (2024). "Fisetin is a Senotherapeutic that Extends Health and Lifespan." EBioMedicine, 89, 104483.