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Animal studies + Phase 1 human trial
Cell

Senolytic Drugs: Clearing Senescent Cells Reverses Aspects of Aging

Groundbreaking research demonstrates that the senolytic combination of **dasatinib plus quercetin (D+Q)** selectively eliminates senescent cells, extending healthspan and lifespan in animal models while showing promising results in early human trials for age-related conditions.

August 17, 2018

Core Finding

Senolytic agents—drugs that selectively induce death of senescent cells—extended median lifespan by 25-35% in naturally aged mice and reversed physical dysfunction by 40-50%. In the first human trial of D+Q, patients with idiopathic pulmonary fibrosis showed significant improvement in physical function after 3 weeks.

The Senescent Cell Theory of Aging

Aging was long considered an inevitable, intractable process. However, the discovery of cellular senescence as a driver of age-related dysfunction has opened new therapeutic possibilities. Senescent cells are cells that have stopped dividing but don't die—they accumulate with age and secrete a toxic cocktail of inflammatory factors called the senescence-associated secretory phenotype (SASP).

The SASP includes pro-inflammatory cytokines (IL-6, IL-8), growth factors, and proteases that damage surrounding healthy cells, promote tissue dysfunction, and create a chronic inflammatory state dubbed "inflammaging." Senescent cells accumulate in multiple tissues with aging and are found at sites of age-related pathology including osteoarthritis plaques, atherosclerotic lesions, and diabetic kidneys.

The senolytic hypothesis proposes that selectively eliminating these harmful cells could delay, prevent, or treat age-related diseases. Unlike interventions targeting single diseases, senolytics address a fundamental aging mechanism that underlies multiple conditions simultaneously.

Study at a Glance

Study Overview

Source: Cell (2018)

Design: Animal studies + Phase 1 human trial

Animal findings: 25-35% lifespan extension in aged mice

Human trial: 14 patients with idiopathic pulmonary fibrosis

Intervention: Dasatinib + Quercetin, 3 intermittent doses

How senolytics work:

  • SCAPs: Senescent cells rely on specific "senescent cell anti-apoptotic pathways" to survive
  • Dasatinib: Targets tyrosine kinases, particularly effective against senescent adipose progenitor cells
  • Quercetin: Flavonoid targeting BCL-2 family proteins, effective against senescent endothelial cells
  • Combination: Broader coverage across senescent cell types than either agent alone

Intermittent dosing is effective because senescent cells are slow to reaccumulate. This allows periodic treatment rather than continuous medication, reducing side effects.

Therapeutic Window

Normal cells don't depend on SCAPs for survival, so senolytics selectively target senescent cells while sparing healthy cells. This selectivity is the key to their safety profile.

The Senescent Cell Burden in Human Disease

Senescent cells contribute to multiple age-related conditions:

Senescent Cell Contributions by Condition

Osteoarthritis Senescent chondrocytes drive joint degeneration

Atherosclerosis Senescent endothelial cells promote plaque formation

Type 2 Diabetes Senescent adipocytes cause insulin resistance

Kidney Disease Senescent podocytes drive glomerulosclerosis

Alzheimer's Disease Senescent glial cells promote neuroinflammation

Osteoporosis Senescent osteocytes disrupt bone remodeling

This central role explains why senolytics show potential across diverse age-related conditions simultaneously—targeting one fundamental aging process affects multiple disease pathways.

Current Senolytic Agents

Pharmaceutical Senolytics

Current Senolytic Agents

Dasatinib + Quercetin

  • Status: Most studied, Phase 2 trials ongoing
  • Target Tissues: Broad spectrum

Navitoclax (ABT-263)

  • Status: Potent but thrombocytopenia limits use
  • Target Tissues: Hematopoietic, solid tumors

Fisetin

  • Status: Natural senolytic, Phase 2 trials
  • Target Tissues: Multiple tissues

Piperlongumine

  • Status: Preclinical, potent
  • Target Tissues: Various cancers

Natural Senolytics

Several natural compounds show senolytic properties, though with weaker evidence:

  • Quercetin: Flavonoid found in apples, onions, capers
  • Fisetin: Flavonoid in strawberries, apples
  • Piperlongumine: From long pepper
  • Curcumin: Turmeric compound (weak senolytic)

Evidence Caveats

  • Most human evidence remains preliminary (Phase 1/2 trials)
  • Optimal dosing, frequency, and duration not established
  • Long-term safety data in humans limited
  • Effects on normal stem cells under investigation
  • Commercial products vary widely in quality and bioavailability

Clinical Applications and Future Directions

Current Status

Senolytics are entering Phase 2 clinical trials for multiple conditions:

  • Idiopathic pulmonary fibrosis
  • Diabetic kidney disease
  • Alzheimer's disease
  • Osteoarthritis
  • Frailty syndrome

Potential Applications

Development Timeline

Near-term (1-3 years) Senescence-associated diseases (IPF, DKD)

Mid-term (3-7 years) Multiple age-related conditions, geriatric syndromes

Long-term (7+ years) Preventive use in healthy aging (more controversial)

Challenges

  1. Biomarker development: Need better ways to measure senescent cell burden
  2. Clinical trial design: Traditional disease-focused trials may not capture benefits
  3. Regulatory pathway: FDA not designed for aging as an indication
  4. Combination approaches: Senolytics may work best with other geroprotectors
  5. Safety monitoring: Long-term effects of senescent cell clearance unknown

Practical Considerations

For Patients Considering Senolytics

Important Warnings

  • Dasatinib is a prescription chemotherapy drug with significant potential side effects
  • Over-the-counter quercetin supplements are NOT equivalent to clinical-grade quercetin
  • Self-experimentation with senolytics carries risks, especially with dasatinib
  • Medical supervision is essential, particularly for those on multiple medications

Natural Alternatives

For those interested in senolytic approaches without prescription medications:

  1. Quercetin supplements: 500-1000 mg/day (though bioavailability varies)
  2. Fisetin-rich foods: Strawberries, apples, persimmons
  3. Fasting protocols: May enhance natural senescent cell clearance
  4. Exercise: Reduces senescent cell accumulation in some tissues
  5. Sleep optimization: Supports natural cellular cleanup processes

FAQ

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Senolytic Drugs: Clearing Senescent Cells Reverses Aspects of Aging | Paper Interpretation