Senolytics Show Promise in Restoring Liver Function and Improving Survival in Sepsis: Mouse Studies Demonstrate

Senescence in Sepsis

Senescence is a distinct cellular fate, diverging from apoptosis or necrosis, and is characterized by altered gene and protein expression that confers resistance to apoptosis. Senescent cells (SnCs) accumulate with age and are widely present in organs, often contributing to dysfunction, particularly in age-related immunosenescence, which disrupts innate, T, and B cell function. This process closely resembles immune dysregulation in sepsis—a severe, inflammatory response to infection leading to organ failure—suggesting shared mechanisms or age-linked predispositions to sepsis.

SnCs secrete cytokines and chemokines, components of the senescence-associated secretory phenotype (SASP), which overlap with sepsis mediators and amplify immune dysfunction. Triggered by stressors like DNA damage, key senescence-associated genes (SAGs) like p53 and p21 are upregulated in sepsis, worsening immune impairment and increasing susceptibility to infections. Senolytic drugs, such as fisetin, show promise in targeting SnCs to reduce inflammation and restore immune function, improving outcomes in animal models of sepsis. Fisetin, a natural senolytic, has demonstrated safety and efficacy in reducing mortality and multi-organ dysfunction in preclinical sepsis models and is now undergoing trials in humans. Developing biomarkers based on SAGs could enable early detection and stratified, personalized treatments for sepsis, highlighting senescence as a promising target in sepsis management.

Aging, Senescence, and Sepsis: Unraveling the Complex Interplay

Aging increases susceptibility to sepsis due to immunosenescence, which diminishes both innate and adaptive immune functions, impacting cells like T and B lymphocytes, neutrophils, and macrophages. This immune decline weakens infection responses in the elderly, who often show pro-inflammatory states not adequately counterbalanced by anti-inflammatory mechanisms, raising the risk of severe sepsis. Additional risk factors include chronic diseases, frequent hospitalizations, frailty, and malnutrition, all of which heighten infection risk.

Sepsis symptoms in older adults may present atypically, often as confusion rather than fever, which can delay diagnosis and treatment, contributing to higher mortality. Managing sepsis in the elderly is complex due to comorbidities and requires prompt recognition and aggressive treatment, emphasizing the need for preventive strategies like vaccinations. Understanding these aging-related impacts on sepsis is essential for better care and tailored treatments in this vulnerable population.

Dr. Raju elaborated:

“Our study shows that there are common molecular signatures with aging and sepsis, and we propose that methods to reduce the senescence burden can minimize organ dysfunction and improve outcomes following sepsis. Further studies are needed to evaluate whether senescence markers correlate with sepsis severity and their significance in diagnosis. Several diseases and conditions are presented with increasing proportions of senescent cells, and we need to understand more about the context-dependent role of senescent cells in the biology of these diseases before targeting them.”

Senescence and Sepsis: How Senolytics Improve Liver Function and Survival Outcomes

The study from Dr. Raju’s laboratory investigated the role of acute senescence induction in sepsis, focusing on liver damage in a murine model of sepsis induced by cecal ligation and puncture (CLP). Rapid senescence was observed, particularly marked by a significant increase in the senescence marker p21, alongside elevated oxidative stress and pro-inflammatory markers. The presence of senescent cells in hepatocytes, endothelial cells, and macrophages was associated with a heightened senescence-associated secretory phenotype (SASP), including elevated cytokines (IL-6, IL-1β, TNF-α) and chemokines, exacerbating inflammation and liver dysfunction.

Single cell RNA sequencing, a state-of-the-art technique to profile gene expression in each cell separately, further showed widespread senescence across liver cell types, with macrophages shifting toward a pro-inflammatory M1 phenotype, likely driven by p21-upregulated CXCL14. This inflammatory-senescent cycle appears to worsen liver impairment, suggesting that senescence may contribute significantly to sepsis pathophysiology.

To assess therapeutic strategies, the study evaluated the senolytic drug combination dasatinib and quercetin (D+Q) for its effects on sepsis outcomes. Treatment with D+Q improved survival rates, reduced inflammation, and lowered liver markers of senescence (p21 and p16) as well as oxidative stress indicators like ALT, MDA, and MPO. This aligns with previous findings of D+Q’s senolytic effects in other conditions and supports the hypothesis that p21-driven senescence plays a central role in sepsis-induced liver dysfunction.

While D+Q treatment partially reduced senescence markers in both young and aged mice, the aged group showed a lesser response, indicating that age-related senescence burden might require higher doses. Dr. Raju added:

“Our mouse model showed that combination therapy with Dasatinib and Quercetin (D+Q) effectively improved organ function and mortality following sepsis. Several agents like D+Q can reduce the senescence burden by killing senescent cells (senolytics) or others by reducing the bad effects of senescent cells (senostats). There is a need to do more systematic studies to identify agents that show efficacy while safe for the subjects.”

Potential Future Clinical Applications of this Study

1. Senolytic Therapy for Sepsis: Developing senolytic drugs, such as dasatinib and quercetin (D+Q), could provide a targeted treatment approach for sepsis, especially for reducing liver dysfunction.
2. Personalized Sepsis Treatment: By understanding the role of senescence in sepsis progression, treatments could be tailored based on individual senescence profiles, considering age-related differences in senescence response.
3. Biomarker Development: Markers like p21 and p16 have potential as biomarkers for assessing sepsis severity and treatment response, enabling more accurate monitoring of disease progression and therapeutic efficacy.
4. Preventive Strategies: For high-risk groups, such as the elderly or those with chronic diseases, senolytic therapies may be explored as preventive measures to reduce the risk of developing sepsis.
5. Combination Therapies: Investigating senolytics alongside standard sepsis treatments could potentially improve overall therapeutic outcomes.
6. Organ-Specific Treatments: Based on this study’s focus on liver dysfunction, senolytic treatments could be developed for organ-specific damage caused by sepsis in other vital organs.
7. Age-Tailored Dosing: Observing different responses between young and aged models suggests age-specific dosing regimens for senolytic drugs, which may enhance their efficacy and safety in clinical settings.
8. Extended Applications: These findings may inspire the use of senolytic therapies in other acute inflammatory conditions beyond sepsis, broadening therapeutic applications.
9. Immunomodulation Strategies: Insights into macrophage phenotype shifts could lead to new immunomodulatory approaches for more effective sepsis treatments.
10. Long-Term Benefits for Sepsis Survivors: Future studies could explore whether reducing acute senescence in sepsis has lasting benefits, potentially lowering the risk of post-sepsis syndrome.

These applications underscore the potential for translating these preclinical insights into clinical practice, promising advancements in sepsis management and patient outcomes.

Further Reading

1. Senescence landscape in the liver following sepsis and senolytics as potential therapeutics
2. Comprehensive analysis of senescence-associated genes in sepsis based on bulk and single-cell sequencing data
3. Senolytics To slOw Progression of Sepsis (STOP-Sepsis) in elderly patients: Study protocol for a multicenter, randomized, adaptive allocation clinical trial
4. Immunosenescence: A Critical Factor Associated With Organ Injury After Sepsis
5. Sepsis and Immunosenescence in the Elderly Patient: A Review
6. Immune Cell Number, Phenotype, and Function in the Elderly with Sepsis
7. Severe sepsis and septic shock in the elderly: An overview