# Effects of Long-term low-dose intermittent rapamycin administration on glucose metabolism and immune system of SAMP8 and SAMR1 mice

## TL;DR

This study shows that low-dose rapamycin improves liver mitochondria and energy metabolism in aging mice but also suppresses parts of the immune system.

## Contribution

The novel finding is that intermittent low-dose rapamycin improves mitochondrial function in aging mice while causing strain-specific immunosuppressive effects.

## Key findings

- RAPA enhanced mitochondrial respiratory control and ATP production in the liver of both SAMP8 and SAMR1 mice.
- RAPA reduced FoxP3+ lymphocytes in the spleen of SAMP8 mice and decreased CD3+ thymocytes in SAMR1 mice.
- SAMP8 mice showed higher glucose uptake in multiple tissues and altered immune cell ratios compared to SAMR1 mice.

## Abstract

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 enhancing mitochondrial respiratory control and ATP production in liver. 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.

This study evaluated how rapamycin treatment affects hepatic metabolism and immunological parameters in SAMR1 and SAMP8 mice. We measured in vivo glucose uptake, hepatic mitochondrial function, and lymphocyte profiles in the thymus and spleen. We found that the treatment increased mitochondrial capacity in the liver and affected the profile of regulatory T cells. In untreated animals, differences were identified in lymphocyte populations in the spleen and thymus, as well as in glucose uptake in muscle, liver, heart, and bladder in the SAMP8 model (characterized by accelerated senescence) compared with the SAMR1 control group.The abstract should ideally be structured according to the IMRaD format (Introduction, Methods, Results and Discussion). Provide a structured abstract if possible. If your article has been copyedited by us, please provide the updated abstract based on this version.

Diagram depicting the effects of glucose intake and aging on mice, organs, and specific biomarkers. In vivo glucose intake increases in liver, muscle, heart, and bladder. The thymus and spleen show changes in CD3, CD4, CD8, FOXP3, and CD19 levels. Control and RAPA treatment effects are analyzed in SAM-R1 and SAM-P8 mice, showing differences in mitochondrial capacity and lymphoproliferation in the liver, thymus, and spleen. Arrows indicate increases or decreases in the specified parameters.