Effects of Long-Term Low-Dose Intermittent Rapamycin Administration on Glucose Metabolism and Immune System of SAMP8 and SAMR1 Mice

Luiz Adriano Damasceno De QueirozRAFAEL BARROSJosiane AssisCamille Cristine Caldeira SilvaWalter Miguel TuratoSofia BustiaStephen Fernandes RodriguesAnderson Sa-NunesJoilson O. Martins^*

• University of São Paulo, São Paulo, Brazil

Aging involves a gradual decline in physiological integrity, and rapamycin (RAPA) has demonstrated potential as an anti-aging agent. Nonetheless, its effects on glucose metabolism and immune function may vary based on dosage and administration regimen. This study investigates the impact of intermittent low-dose RAPA on glucose metabolism and immune function in Senescence-Accelerated Mouse Prone 8 (SAMP8) and Senescence-Accelerated Mouse Resistant 1 (SAMR1) mice. Twelve-week-old male SAMP8 and SAMR1 mice were treated with RAPA (0.78 µg/kg) every five days for six months. Glucose uptake, mitochondrial respiratory capacity, spleen and thymus immunophenotype, lymphoproliferation, and cytokine profiles were evaluated. Our findings indicate that RAPA reduced glucose uptake in the bladder and the percentage of FoxP3+ lymphocytes in the spleen of SAMP8 mice, while improving mitochondrial respiratory Control and ATP production. In SAMR1 mice, RAPA administration led to a decrease in CD3+ thymocytes and splenic lymphoproliferative capacity, while also enhanced mitochondrial performance. Comparisons between Control groups revealed that SAMP8 mice exhibited higher glucose uptake in several tissues, lower lymphocyte populations in spleen and thymus, altered CD4+/CD8+ ratios, and reduced IL-4 expression compared with SAMR1 mice. The findings reinforce the potential of RAPA to modulate aging-related processes, highlighting improvements in mitochondrial function and energy metabolism across strains with different aging processes. However, the immunosuppressive effects of RAPA remain evident, even at low doses administered intermittently, in an age-and strain-specific manner. These findings emphasize the therapeutic potential of RAPA while underscoring the need for customized dosing strategies to balance efficacy and safety. These data highlight mitochondrial metabolic improvements as the primary benefit of intermittent low-dose RAPA and suggest potential clinical relevance for conditions involving compromised mitochondrial energy metabolism.