Scientists have proposed innovative organ rejuvenation strategies to address the critical issue of organ donor shortages. These strategies focus on revitalizing aging organs, transforming thousands of discarded donor organs into viable, life-saving grafts. The key to this approach lies in understanding cellular aging and developing targeted treatments to combat senescence, the process of cellular aging. By targeting senescent cells and their harmful secretions, researchers aim to restore organ function and improve transplant outcomes.
Cellular Aging and Ischemic Reperfusion Injury
Aging organs are particularly susceptible to ischemic reperfusion injury (IRI), a complex process that occurs when blood flow is interrupted and then restored. During ischemia, oxygen and nutrient deprivation disrupts mitochondrial function, leading to energy loss. In young cells, mitochondria maintain their resilience, ensuring ATP production and mitigating damage. However, in older cells, ATP depletion is more pronounced, forcing cells to rely on anaerobic metabolism, which results in lactate buildup, pH reduction, and cellular stress.
When blood flow is restored during reperfusion, mitochondria generate excessive reactive oxygen species (ROS), triggering oxidative stress and inflammation. Young cells possess robust antioxidant systems, compensating for these events and maintaining cellular integrity. In contrast, older cells struggle with impaired antioxidant defenses, leading to unregulated ROS production, membrane damage, organelle collapse, and DNA damage. Additionally, older cells release pro-inflammatory genes, exacerbating local inflammation.
Underperformance of Older Donor Organs
The underperformance of older donor organs is primarily attributed to IRI. Clinical studies reveal higher rates of primary graft dysfunction in livers, kidneys, hearts, and lungs from donors aged 50 and older. Aging reduces mitochondrial reserves, increases microvascular fragility, and lowers the expression of protective proteins that normally dampen inflammation. As a result, older organs sustain more structural damage and struggle to recover after IRI.
Immune Activation and Rejection Risks
Older grafts provoke stronger immune responses and are more likely to be rejected, especially within the first year. The combination of IRI, senescent cell-secreted factors (SASP), and impaired anti-inflammatory capacity enhances the release of danger-associated molecular patterns (DAMPs), including circulating mitochondrial DNA. These signals intensify inflammation, attract immune cells, and heighten alloimmune activation.
Machine Perfusion and Preservation Advances
Machine perfusion technologies play a pivotal role in organ rejuvenation. Normothermic and hypothermic machine perfusion allow for ex vivo assessment of organ viability, targeted delivery of therapeutics, and metabolic recovery before transplantation. Subnormothermic storage at 10°C is another promising technique, preserving mitochondrial function and reducing IRI across organ types.
Senolytic Drug Strategies
Senolytics are a class of drugs that selectively eliminate senescent cells and reduce SASP-driven inflammation. The combination of dasatinib and quercetin targets anti-apoptotic pathways in senescent cells. Preclinical studies demonstrate improved function in multiple tissues, including the heart, and reductions in circulating mitochondrial DNA. Other senolytics, such as fisetin and navitoclax, induce apoptosis in senescent cells and have shown benefits in reducing fibrosis and hypertrophy.
Senomorphic and Metabolic Modulators
Senomorphics, on the other hand, do not kill senescent cells but dampen the harmful effects of SASP. Metformin reduces SASP by lowering inflammation and oxidative stress, improving ATP production and reducing injury in liver perfusion and transplant models. Rapamycin, an immunosuppressant, prevents senescent cell accumulation and preserves graft structure. Resveratrol enhances mitochondrial function and reduces oxidative stress, showing promise in improving metabolic and inflammatory profiles.
Anti-Fibrotic and Regenerative Approaches
Anti-fibrotic compounds, such as losartan, blebbistatin, nattokinase, and lumbrokinase, may reduce established fibrosis in older organs. Stem-cell-based strategies, including mesenchymal stromal cells (MSCs) delivered during machine perfusion, show potential to reduce inflammation, enhance regeneration, and improve microvascular function in aged grafts.
Anti-Inflammatory Interventions
Given the significant contribution of aging-associated inflammation to graft dysfunction, anti-inflammatory drugs may help prepare older organs for transplantation. Corticosteroids are commonly used in recipients, but experimental evidence suggests that treating donor organs before transplantation may also reduce inflammation and improve outcomes. Nonsteroidal anti-inflammatory drugs (NSAIDs) may offer additional benefits, although evidence in aged organs is still limited.
Future Outlook for Organ Rejuvenation
The underuse of older donor organs significantly contributes to the global organ shortage. Aging increases susceptibility to IRI, functional decline, and immunogenicity, but new strategies, including senolytics, senomorphics, anti-inflammatory therapies, machine perfusion platforms, mitochondrial modulators, anti-fibrotic treatments, and stem-cell-based interventions, show strong potential to rejuvenate aging organs.
However, the review emphasizes that most interventions remain in early-stage or preclinical development and require rigorous safety and efficacy testing. Future progress will depend on integrating biomarkers, refining allocation frameworks, and validating the proposed two-phase rejuvenation strategy in clinical trials. Continued research may substantially expand the donor pool and improve transplant outcomes, helping bridge the gap between organ supply and clinical need.
