Academy

Geroscience and Senolytics

Geroscience investigates the biological underpinnings of aging, focusing on hallmarks like cellular senescence and chronic inflammation. Senolytics are therapeutic agents designed to selectively target and eliminate senescent cells, which accumulate with age and contribute to tissue dysfunction. This field aims to extend healthspan by restoring cellular function and preventing age-related diseases.

Hallmarks of Aging

• Cellular Senescence: Process where aged cells stop dividing but secrete harmful inflammatory factors.
• Telomere Shortening: Progressive loss of protective chromosome ends leading to genomic instability.
• Accumulation of Damage: Build-up of DNA mutations, protein aggregates, and mitochondrial dysfunction.

Senolytic Mechanisms

Senolytics act by inhibiting survival pathways in senescent cells, such as BCL-2 family proteins, PI3K/AKT signaling, or FOXO pathways. Examples include Dasatinib combined with Quercetin and novel small molecules targeting anti-apoptotic mechanisms. By inducing apoptosis, these drugs clear dysfunctional cells.

Key Senolytic Compounds and Trials

Several senolytic compounds have entered clinical evaluation. Dasatinib plus quercetin (D+Q) is one of the earliest combinations tested in humans, showing safety and preliminary efficacy in pilot trials for pulmonary fibrosis and diabetic kidney disease. Navitoclax (a BCL-2 inhibitor) and fisetin (a flavonoid) are under investigation for cognitive decline and osteoarthritis. Preclinical models in mice show lifespan extension after intermittent dosing.

Clinical Implementation and Biomarkers

Translation to human therapy requires reliable biomarkers to measure senescent cell clearance. Researchers are validating panels of circulating proteins (e.g., IL-6, GDF15) and imaging techniques to track tissue-level senescence. Combining biomarker assays with functional assessments, such as gait speed and lung capacity, evaluates both molecular and clinical outcomes. Personalized dosing schedules and intermittent treatment cycles minimize off-target effects and maintain benefits.

Applications in Longevity

1. Improved Tissue Function: Rejuvenates tissues by reducing inflammatory secretions.
2. Disease Prevention: Targets conditions like osteoarthritis, atherosclerosis, and neurodegeneration.
3. Enhanced Repair: Clearing senescent cells promotes regeneration through stem cell activation.

Challenges and Ethical Considerations

Challenges include ensuring specificity to avoid harming healthy cells and balancing risks such as impaired wound healing. Regulatory pathways must evolve to recognize aging-related endpoints, and long-term safety requires extensive trials. Ethical issues around access, cost, and equitable distribution are critical as therapies enter practice.

Future Research Directions

Advances in single-cell sequencing and spatial transcriptomics are uncovering new senescence markers, enabling next-generation senolytics with improved precision. Synergistic combinations with regenerative therapies, such as stem cell transplantation and gene editing, are under study. Multidisciplinary collaborations integrating computational models and wet-lab work will accelerate discovery and personalized regimens for healthy aging.

Collaboration and Investment Models

Public–private partnerships between academic institutions, biotech startups, and venture capital firms fuel innovation in senolytic research. Investment funds focusing on longevity channel resources into early-stage companies, while philanthropic organizations support basic science and translational studies. Collaborative networks standardize protocols, share data, and align regulatory strategies for global approval of senolytic therapies.