Department of Pathogen Biology, School of Medicine, Jinan University, Guangzhou, China.
Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Guangzhou, China.
Gerontology. 2024;70(1):90-101. doi: 10.1159/000534863. Epub 2023 Nov 10.
The discovery of longevity molecules that delay aging and prolong lifespan has always been a dream of humanity. Sitagliptin phosphate (SIT), an oral dipeptidyl peptidase-4 (DPP-4) inhibitor, is an oral drug commonly used in the treatment of type 2 diabetes (T2D). In addition to being antidiabetic, previous studies have reported that SIT has shown potential to improve health. However, whether SIT plays a role in the amelioration of aging and the underlying molecular mechanism remain undetermined.
Caenorhabditis elegans (C. elegans) was used as a model of aging. Lifespan assays were performed with adult-stage worms on nematode growth medium plates containing FUdR with or without the specific concentration of SIT. The period of fast body movement, body bending rates, and pharyngeal pumping rates were recorded to assess the healthspan of C. elegans. Gene expression was confirmed by GFP fluorescence signal of transgenic worms and qPCR. In addition, the intracellular reactive oxygen species levels were measured using a free radical sensor H2DCF-DA.
We found that SIT significantly extended lifespan and healthspan of C. elegans. Mechanistically, we found that several age-related pathways and genes were involved in SIT-induced lifespan extension. The transcription factors DAF-16/FOXO, SKN-1/NRF2, and HSF-1 played important roles in SIT-induced longevity. Moreover, our findings illustrated that SIT-induced survival benefits by inhibiting the insulin/insulin-like signaling pathway and activating the dietary restriction-related and mitochondrial function-related signaling pathways.
Our work may provide a theoretical basis for the development of anti-T2D drugs as antiaging drugs, especially for the treatment of age-related disease in diabetic patients.
发现能延缓衰老、延长寿命的长寿分子一直是人类的梦想。磷酸西他列汀（SIT）是一种口服二肽基肽酶-4（DPP-4）抑制剂，是治疗 2 型糖尿病（T2D）的常用口服药物。除了具有抗糖尿病作用外，先前的研究还表明 SIT 具有改善健康的潜力。然而，SIT 是否在改善衰老中发挥作用以及潜在的分子机制仍未确定。
使用秀丽隐杆线虫（C. elegans）作为衰老模型。在含有 FUdR 的线虫生长培养基平板上，用成年期线虫进行寿命测定，有或没有特定浓度的 SIT。记录快速身体运动、身体弯曲率和咽部抽吸率，以评估 C. elegans 的健康寿命。通过转绿色荧光蛋白（GFP）的转基因线虫的 GFP 荧光信号和 qPCR 确认基因表达。此外，使用自由基传感器 H2DCF-DA 测量细胞内活性氧（ROS）水平。
我们发现 SIT 显著延长了 C. elegans 的寿命和健康寿命。从机制上讲，我们发现几个与年龄相关的途径和基因参与了 SIT 诱导的寿命延长。转录因子 DAF-16/FOXO、SKN-1/NRF2 和 HSF-1 在 SIT 诱导的长寿中发挥重要作用。此外，我们的研究结果表明，SIT 通过抑制胰岛素/胰岛素样信号通路和激活与饮食限制相关和与线粒体功能相关的信号通路，诱导生存获益。
我们的工作可能为开发抗 2 型糖尿病药物作为抗衰老药物提供理论依据，特别是对糖尿病患者与年龄相关疾病的治疗。
