Targeting Senescence: Senolytics and Senomorphics in Anti-Aging Interventions

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Introduction

The global demographic shift towards an aging population has intensified the search for interventions that can extend healthspan—the period of life free from serious disease and disability. At the cellular level, aging is driven by a series of hallmarks, among which cellular senescence has emerged as a fundamentally targetable process. Cellular senescence is a state of stable cell cycle arrest triggered by various stressors, such as DNA damage and oncogene activation. While this process serves beneficial roles in early life—including tumor suppression, wound healing, and tissue remodeling—the chronic accumulation of senescent cells with age becomes profoundly detrimental. The primary mechanism of this harm is the senescence-associated secretory phenotype (SASP), a potent and complex mixture of pro-inflammatory cytokines, chemokines, growth factors, and proteases. The persistent SASP fosters a state of chronic, low-grade inflammation termed "inflammaging," which disrupts tissue structure, impairs stem cell function, and drives the pathogenesis of a wide spectrum of age-related conditions, from osteoarthritis and atherosclerosis to neurodegeneration and cancer. In response, two principal therapeutic strategies have been developed: senolytics, which selectively eliminate senescent cells, and senomorphics, which modulate the harmful SASP without killing the cells. This review examines the mechanisms, efficacy, clinical landscape, and limitations of these pioneering approaches, evaluating their potential to translate the science of aging into clinical strategies for enhancing healthspan.

Senolytics: Selective Clearance and Clinical Translation

Senolytics are a class of drugs designed to selectively induce apoptosis in senescent cells by exploiting their unique vulnerabilities, specifically their reliance on pro-survival pathways known as senescent cell anti-apoptotic pathways (SCAPs).

The first-generation senolytic combination, dasatinib and quercetin (D+Q), demonstrated that clearing senescent cells could improve physical function and reduce tissue dysfunction in aged mice. Clinically, D+Q has progressed to human trials, showing promise in early-phase studies for idiopathic pulmonary fibrosis (IPF) and diabetic kidney disease (DKD). In these trials, intermittent administration led to improved physical function and reductions in senescence biomarkers, providing initial proof-of-concept in humans. A major focus has been on the BCL-2 family of anti-apoptotic proteins. Inhibitors like navitoclax (ABT-263) are potent senolytics but cause dose-limiting thrombocytopenia, which has hindered its clinical development for aging; however, it remains under investigation in oncology contexts. Other strategies, such as the FOXO4-p53 disrupting peptide, have shown efficacy in preclinical models but have not yet advanced significantly in clinical trials.

Beyond synthetic compounds, natural products like fisetin have shown broad senolytic activity. Fisetin is currently being evaluated in several clinical trials (e.g., NCT03675724) for alleviating frailty and inflammatory markers in older adults, positioning it as a potentially safer and more accessible candidate. To improve specificity, emerging approaches utilize precision delivery systems. For instance, antibody-drug conjugates (ADCs) that bind to senescence-enriched surface markers like β2-microglobulin (B2M) are in preclinical development and represent a next-generation strategy aimed at minimizing off-target effects, though they have not yet entered clinical trials.

Senomorphics: Modulation and Clinical Applicability

Senomorphics offer an alternative strategy by suppressing the deleterious effects of the SASP without inducing cell death, which is advantageous in tissues where senescent cells may retain beneficial functions.

Senomorphic agents target key signaling pathways that regulate SASP production. mTOR inhibitors, such as rapamycin (sirolimus), have been shown to dampen SASP expression and extend lifespan in model organisms. Clinically, rapamycin and its analogs (rapalogs) have a well-established safety profile from use in organ transplantation and oncology, which facilitates their repurposing for aging. Early-stage trials, such as the PEARL trial, are directly exploring low-dose rapamycin for mitigating age-related decline in humans. Similarly, JAK inhibitors (e.g., ruxolitinib, baricitinib) block signaling from SASP cytokines like IL-6 and IL-8. JAK inhibitors are already FDA-approved for myeloproliferative disorders and rheumatoid arthritis, and are now being investigated in geroscience contexts for reducing inflammation and improving hematopoietic function in aged individuals. Other pathways, such as NF-κB and p38 MAPK, are targeted by experimental compounds that remain primarily in preclinical stages.

A critical consideration is the temporal evolution of the SASP, which shifts from an early, pro-fibrotic profile to a late, pro-inflammatory one. This dynamism implies that therapeutic modulation must be timed appropriately. Natural compounds, such as luteolin from Salvia haenkei extract, have demonstrated senomorphic potential in preclinical models but have not yet entered structured clinical trials for aging. The clinical goal for next-generation senomorphics is to achieve selective SASP modulation, silencing harmful components while preserving beneficial signals, potentially through repurposed drugs with known safety profiles.

Comparative Challenges and Limitations

Despite their promise, both strategies face significant hurdles. The profound heterogeneity of senescent cells across tissues means a universal therapy is unlikely, complicating drug development and leading to inconsistent efficacy. Pharmacologically, senolytics like navitoclax suffer from off-target toxicities, while senomorphics can have pleiotropic effects that disrupt essential biological processes beyond the SASP. Furthermore, senomorphics do not remove senescent cells, risking SASP rebound upon treatment cessation.

Translational challenges are exacerbated by the lack of robust, non-invasive biomarkers for human trials. Without reliable biomarkers like validated blood-based SASP factors, patient selection and efficacy monitoring remain difficult. Finally, conceptual risks exist, as indiscriminate targeting could impair beneficial roles of senescence in wound healing and tumor suppression, necessitating nuanced, context-aware application.

Future Directions and Conclusion

The future of senescence-targeting interventions lies in enhancing precision and integration. Next-generation therapeutics, such as tissue-specific nanoparticles and improved ADCs, aim to minimize off-target effects and are moving toward early-stage clinical testing. The integration of multi-omics data and artificial intelligence is accelerating the creation of detailed senescence "atlases," which will guide biomarker discovery and personalized senotherapy. Combinatorial approaches—such as using senomorphics to precondition tissues before senolytic clearance—are being explored preclinically to enhance efficacy and safety.

Clinical trial design must evolve to incorporate surrogate endpoints like epigenetic clocks and frailty indices to capture healthspan benefits. Several senolytic and senomorphic agents are now in early-phase trials for age-related conditions such as Alzheimer's disease, osteoarthritis, and frailty, signaling a critical transition from bench to bedside.

In conclusion, targeting cellular senescence with senolytics and senomorphics represents a paradigm shift in geroscience. While challenges regarding specificity and safety remain substantial, the ongoing clinical evaluation of these therapies, coupled with advances in precision delivery and diagnostics, paints a promising future. Through continued effort, senescence-targeting strategies are poised to become cornerstone interventions for extending human healthspan and compressing morbidity.

Reference

Saliev T, Singh PB. Targeting Senescence: A Review of Senolytics and Senomorphics in Anti-Aging Interventions. Biomolecules. 2025 Jun 13;15(6):860. doi: 10.3390/biom15060860. PMID: 40563501; PMCID: PMC12190739.