Mayo Clinic researchers characterize cardiac aging markers in GRZ killifish using echocardiography, swim tests, and molecular assays, demonstrating that dasatinib and quercetin treatment reduces senescence and preserves heart function.
Key points
GRZ killifish serve as a rapid vertebrate model for cardiac aging using EF% and E/A ratio echocardiography.
Senescence markers SA-β-gal, p15/p16, γ-H2A.X, and SASP transcripts increase in aged fish hearts.
Oral dasatinib and quercetin (D+Q) senolytic therapy reduces senescent cell burden and preserves heart function.
Why it matters:
This work provides a fast, vertebrate platform to evaluate anti-aging therapies and highlights senolytics’ potential to protect the aging heart.
Q&A
What makes the killifish GRZ strain ideal for aging studies?
How do echocardiography measurements reflect cardiac aging?
What is cellular senescence and why is it harmful to the heart?
How do dasatinib and quercetin eliminate senescent cells?
Read full article
Academy
Cellular Senescence
Definition: Cellular senescence is a state in which cells permanently stop dividing in response to stress, DNA damage, or telomere shortening. While initially protective against cancer, accumulation of senescent cells disrupts tissue function over time.
Mechanisms:
- Senescence triggers include DNA damage, oxidative stress, and oncogene activation.
- Key markers are senescence-associated β-galactosidase (SA-β-gal), p15/p16^INK4a, and γ-H2A.X foci in nuclei.
- Senescent cells secrete a pro-inflammatory profile called the senescence-associated secretory phenotype (SASP), containing cytokines (e.g., IL-6, IL-8), growth factors, and proteases.
Impact on Aging: Over time, senescent cells accumulate in organs including the heart, brain, and skin. Their SASP factors promote chronic inflammation, fibrosis, and impaired regenerative capacity, accelerating age-related decline.
Detection:
- SA-β-gal staining on tissue sections identifies senescent cells by blue coloration.
- Immunostaining for cell cycle inhibitors p15/p16 and DNA damage marker γ-H2A.X highlights senescence foci.
- Quantitative PCR measures upregulation of SASP transcripts such as IL-6, TNF-α, and matrix metalloproteinases.
Senolytic Drug Therapy
Overview: Senolytics are compounds that selectively induce apoptosis in senescent cells, alleviating their detrimental effects. The dasatinib plus quercetin (D+Q) combination is a widely studied senolytic regimen.
Components:
- Dasatinib: A tyrosine kinase inhibitor originally developed for cancer, which disrupts pro-survival signaling in senescent cells.
- Quercetin: A natural flavonoid with antioxidant and anti-inflammatory properties, enhancing dasatinib’s killing of senescent cells.
Administration: In preclinical models, D+Q is given intermittently (e.g., twice weekly) via oral gavage or injection, minimizing toxicity while clearing senescent cells.
Benefits:
- Reduces senescent cell burden in tissues.
- Decreases systemic and local inflammation by lowering SASP factors.
- Improves organ function—such as cardiac output and muscle strength—in aged animals.
Clinical Potential: Early human trials of senolytics target age-related diseases including idiopathic pulmonary fibrosis and chronic kidney disease. Understanding dosing, safety, and long-term outcomes remains a key research priority.
Future Directions:
- Development of second-generation senolytics with greater selectivity.
- Combination therapies targeting multiple aging hallmarks (e.g., autophagy enhancers, mitochondrial protectors).
- Biomarker-driven trials to identify patients who will benefit most from senolytic interventions.
