Jiang Wei, Ding Kaixi, Yang Maoyi, Hu Zhipeng, Yue Rensong
School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Department of Clinical Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
J Gerontol A Biol Sci Med Sci. 2025 Mar 7;80(4). doi: 10.1093/gerona/glaf007.
Glucagon-like peptide-1 receptor agonists (GLP1RAs) are widely used in managing type 2 diabetes mellitus and weight control. Their potential in treating aging-related diseases has been gaining attention in recent years. However, the long-term effects of GLP1RAs on these diseases have yet to be fully revealed.
Using a genetic variant in the GLP1R gene to model the long-term effects of GLP1RAs, this Mendelian randomization (MR) study systematically explored potential causal associations between GLP1R agonism and 12 aging-related diseases and indicators. Genetic summary data sets used in this study were obtained from previous genome-wide association studies.
The primary MR analysis results suggested that GLP1R agonism was potentially positively causally associated with appendicular lean mass (Beta = 0.246, 95% confidence interval [CI] = 0.096-0.396), whole-body fat-free mass (Beta = 0.202, 95% CI = 0.048-0.355), and lung function (forced vital capacity [FVC]; Beta = 0.179, 95% CI = 0.152-0.205; p < .05). Additionally, a potential negative causal association was observed with myocardial infarction (odds ratio = 0.430, 95% CI = 0.249-0.745; p < .05).
The present MR study provides exploratory evidence suggesting potential causal associations between GLP1R agonism and appendicular lean mass, whole-body fat-free mass, lung function (FVC), and myocardial infarction. Given the exploratory nature of these findings and the limitations of the MR methodology, further research is needed to validate these results and investigate the underlying biological mechanisms.
胰高血糖素样肽-1受体激动剂（GLP1RAs）被广泛用于治疗2型糖尿病和控制体重。近年来，其在治疗与衰老相关疾病方面的潜力受到关注。然而，GLP1RAs对这些疾病的长期影响尚未完全揭示。
本孟德尔随机化（MR）研究利用GLP1R基因中的一个遗传变异来模拟GLP1RAs的长期影响，系统地探索了GLP1R激动与12种与衰老相关疾病及指标之间的潜在因果关联。本研究中使用的遗传汇总数据集来自先前的全基因组关联研究。
主要的MR分析结果表明，GLP1R激动可能与上肢瘦体重（β = 0.246，95%置信区间[CI] = 0.096 - 0.396）、全身去脂体重（β = 0.202，95% CI = 0.048 - 0.355）和肺功能（用力肺活量[FVC]；β = 0.179，95% CI = 0.152 - 0.205；p <.05）呈正因果关联。此外，观察到与心肌梗死存在潜在的负因果关联（比值比 = 0.430，95% CI = 0.249 - 0.745；p <.05）。
本MR研究提供了探索性证据，表明GLP1R激动与上肢瘦体重、全身去脂体重、肺功能（FVC）和心肌梗死之间存在潜在因果关联。鉴于这些发现的探索性质以及MR方法的局限性，需要进一步研究来验证这些结果并探究潜在的生物学机制。
