What approach should be taken for an older adult with a history of chronic diseases who is being considered for senolytic therapy?

Senolytic Therapy in Older Adults with Chronic Diseases

Senolytic therapy should NOT be used outside of clinical trials in older adults with chronic diseases, regardless of their multimorbidity burden, as these agents remain investigational with insufficient safety and efficacy data in humans. 1, 2

Current Evidence Status

Preclinical Promise vs. Clinical Reality

• Senolytics are drugs that selectively eliminate senescent cells, which accumulate with aging and contribute to inflammation and age-related diseases 1, 3
• In preclinical animal models, senolytics have shown benefit for over 40 conditions including frailty, cardiovascular disease, diabetes, osteoporosis, pulmonary fibrosis, and neurodegenerative disorders 1, 2, 3
• However, only early pilot trials in humans have been conducted, showing preliminary evidence of reducing senescent cells and inflammation 1

Why Senolytics Are Not Ready for Clinical Use

The evidence base remains fundamentally inadequate for several critical reasons:

• Clinical trials are only now underway or beginning for specific conditions (diabetes, idiopathic pulmonary fibrosis, Alzheimer's disease, osteoarthritis, and others), with no completed Phase III data available 1
• The leading senolytic agents (dasatinib, quercetin, fisetin, navitoclax) are repurposed anticancer drugs with significant potential toxicities, including thrombocytopenia and dose-limiting adverse effects 4
• Issues of drug selectivity, resistance mechanisms, and long-term safety in older adults remain unresolved 5

Appropriate Clinical Context

When Senolytics Might Be Considered (Within Trials Only)

If an older adult with chronic diseases is being evaluated for senolytic therapy, this should only occur within the context of a properly designed clinical trial that includes: 6

• Cancer survivors experiencing accelerated biological aging after treatment, where senolytics may protect against treatment-related aging acceleration 6
• Patients with localized accumulation of senescent cells in specific disease states (e.g., idiopathic pulmonary fibrosis, osteoarthritis) 2
• Individuals with accelerated aging-like conditions or potentially fatal diseases associated with senescent cell accumulation 2

Critical Exclusion Criteria

Older adults who should never receive senolytics, even in trials:

• Those with significant polypharmacy burden where drug-drug interactions cannot be adequately assessed 6
• Patients with thrombocytopenia or bleeding disorders, given the hematologic toxicity of agents like dasatinib and navitoclax 4
• Frail elderly with limited life expectancy where the risk-benefit ratio is unfavorable 6

Alternative Evidence-Based Approaches

Proven Interventions for Biological Aging

Rather than experimental senolytics, older adults with chronic diseases should receive established gero-protective interventions: 6

• Smoking cessation and increased physical activity, which have direct evidence for decelerating biological aging 6
• Obesity reduction, improved sleep health, and reduction of socioenvironmental stressors 6
• Optimization of existing medication regimens through systematic deprescribing using validated tools like STOPP/START criteria 6

Medication Management Priority

For older adults with multimorbidity, the immediate priority should be:

• Careful medication review to identify and discontinue therapies with unfavorable risk-benefit ratios in the context of limited life expectancy 6
• Avoidance of polypharmacy-related adverse effects, which are well-documented and preventable 6
• Focus on functional status and quality of life rather than adding experimental agents 6

Common Pitfalls to Avoid

• Do not prescribe senolytics based on preclinical animal data alone—the translation to human benefit remains unproven 1, 2
• Avoid the misconception that "anti-aging" drugs are universally beneficial—older adults with frailty may experience net harm from additional pharmacotherapy 6
• Do not neglect proven lifestyle interventions in favor of experimental pharmacotherapy 6
• Never assume safety based on short-term pilot studies—long-term toxicity data in older adults are completely absent 1, 4

Research Participation Considerations

If clinical trial enrollment is being considered:

• Ensure the trial includes appropriate geriatric assessment measures and functional status endpoints 6
• Verify that the protocol includes adequate monitoring for drug-specific toxicities (e.g., complete blood counts for dasatinib) 4
• Confirm that the trial design accounts for the patient's biological age rather than chronological age alone 6
• Ensure informed consent addresses the investigational nature and unknown long-term risks 1