Ye Shi-Wei, Song Shuang-Di, Liu Xi-Juan, Luo Yun, Cai Shi-Qing
Institute of Neuroscience and State key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
Aging Cell. 2025 Mar;24(3):e14411. doi: 10.1111/acel.14411. Epub 2024 Nov 18.
The risk of many human diseases including cardiovascular diseases, cancer, neurodegenerative diseases, and musculoskeletal disorders rises significantly in the elderly. With the increase in the aging population, it is becoming increasingly important to understand the biology of healthy aging and develop interventions that slow down the aging process or prevent age-related diseases. In this study, by a high-throughput screen in Caenorhabditis elegans (C. elegans), we identified 11 small molecules that promote healthy aging. Among them, Carbamazepine (a voltage-gated channels inhibitor) and Calmagite (a calcium and magnesium indicator) enhanced serotonin (5-HT) and dopamine (DA) levels, extended lifespan, and preserved several important behaviors in aging C. elegans. These behaviors include slowing responses to food, pharyngeal pumping, locomotion, and male mating. Interestingly, we further found that administration of Carbamazepine or Calmagite alleviated hyperexcitability of aging male diagonal muscles and improved behavioral performance by ameliorating Ca homeostasis. Mechanistically, administration of Carbamazepine or Calmagite induced nuclear translocation of the transcription factor DAF-16 and thus up-regulated its downstream genes numr-1/-2, which are known to promote resistance to metal-induced stresses and longevity. Taken together, our study offers a way for the discovery of drugs that promote healthy aging, and provides potential interventions for preventing behavioral deterioration in the elderly.
包括心血管疾病、癌症、神经退行性疾病和肌肉骨骼疾病在内的许多人类疾病的风险在老年人中显著上升。随着老龄化人口的增加，了解健康衰老的生物学机制并开发减缓衰老过程或预防与年龄相关疾病的干预措施变得越来越重要。在这项研究中，我们通过对秀丽隐杆线虫（C. elegans）进行高通量筛选，鉴定出11种促进健康衰老的小分子。其中，卡马西平（一种电压门控通道抑制剂）和钙镁试剂（一种钙镁指示剂）提高了血清素（5-HT）和多巴胺（DA）水平，延长了寿命，并保留了衰老的秀丽隐杆线虫的几种重要行为。这些行为包括对食物的反应减慢、咽部蠕动、运动和雄性交配。有趣的是，我们进一步发现，给予卡马西平或钙镁试剂可减轻衰老雄性对角肌的过度兴奋，并通过改善钙稳态来改善行为表现。从机制上讲，给予卡马西平或钙镁试剂可诱导转录因子DAF-16的核转位，从而上调其下游基因numr-1/-2，已知这些基因可促进对金属诱导应激的抗性和长寿。综上所述，我们的研究为发现促进健康衰老的药物提供了一种方法，并为预防老年人行为退化提供了潜在的干预措施。
