Chen Zhihe, Wu Xueyan, Yang Qianqian, Zhao Huiling, Ying Hui, Liu Haoyu, Wang Chaoyue, Zheng Ruizhi, Lin Hong, Wang Shuangyuan, Li Mian, Wang Tiange, Zhao Zhiyun, Xu Min, Chen Yuhong, Xu Yu, Lu Jieli, Ning Guang, Wang Weiqing, Luo Shan, Au Yeung Shiu Lun, Bi Yufang, Zheng Jie
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Shanghai Digital Medicine Innovation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
J Clin Endocrinol Metab. 2025 Mar 17;110(4):1096-1104. doi: 10.1210/clinem/dgae635.
An observational study suggested sodium-glucose cotransporter 2 (SGLT2) inhibitors might promote healthy aging. However, whether brain-related phenotypes mediate this association is still a question. We applied Mendelian randomization (MR) to investigate the effect of SGLT2 inhibition on chronological age, biological age, and cognition and explore the mediation effects of brain imaging-derived phenotypes (IDPs).
We selected genetic variants associated with both expression levels of SLC5A2 (Genotype-Tissue Expression and eQTLGen data; n = 129 to 31 684) and hemoglobin A1c (HbA1c) levels (UK Biobank; n = 344 182) and used them to proxy the effect of SGLT2 inhibition. Aging-related outcomes, including parental longevity (n = 389 166) and epigenetic clocks (n = 34 710), and cognitive phenotypes, including cognitive function (n = 300 486) and intelligence (n = 269 867) were derived from genome-wide association studies. Two-step MR was conducted to explore the associations between SGLT2 inhibition, IDPs, and aging outcomes and cognition.
SGLT2 inhibition was associated with longer father's attained age [years of life increase per SD (6.75 mmol/mol) reduction in HbA1c levels = 6.21, 95% confidence interval (CI) 1.27-11.15], better cognitive function (beta = .17, 95% CI 0.03-0.31), and higher intelligence (beta = .47, 95% CI 0.19-0.75). Two-step MR identified 2 IDPs as mediators linking SGLT2 inhibition with chronological age (total proportion of mediation = 22.6%), where 4 and 5 IDPs were mediators for SGLT2 inhibition on cognitive function and intelligence, respectively (total proportion of mediation = 61.6% and 68.6%, respectively).
Our study supported that SGLT2 inhibition increases father's attained age, cognitive function, and intelligence, which was mediated through brain images of different brain regions. Future studies are needed to investigate whether a similar effect could be observed for users of SGLT2 inhibitors.
一项观察性研究表明，钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可能促进健康衰老。然而，与大脑相关的表型是否介导了这种关联仍是一个问题。我们应用孟德尔随机化（MR）来研究SGLT2抑制对实际年龄、生物学年龄和认知的影响，并探索脑成像衍生表型（IDP）的中介作用。
我们选择了与SLC5A2表达水平（基因型-组织表达和eQTLGen数据；n = 129至31684）和糖化血红蛋白（HbA1c）水平（英国生物银行；n = 344182）相关的基因变异，并使用它们来代表SGLT2抑制的作用。与衰老相关的结果，包括父母的寿命（n = 389166）和表观遗传时钟（n = 34710），以及认知表型，包括认知功能（n = 300486）和智力（n = 269867），均来自全基因组关联研究。进行了两步MR以探索SGLT2抑制、IDP与衰老结果和认知之间的关联。
SGLT2抑制与父亲达到的年龄更长相关[HbA1c水平每降低1个标准差（6.75 mmol/mol），寿命增加的年数 = 6.21，95%置信区间（CI）1.27 - 11.15]，认知功能更好（β = 0.17，95% CI 0.03 - 0.31），以及智力更高（β = 0.47，95% CI 0.19 - 0.75）。两步MR确定了2个IDP作为将SGLT2抑制与实际年龄联系起来的中介（总中介比例 = 22.6%），其中分别有4个和5个IDP是SGLT2抑制对认知功能和智力的中介（总中介比例分别为61.6%和68.6%）。
我们的研究支持SGLT2抑制可增加父亲达到的年龄、认知功能和智力，这是通过不同脑区的脑图像介导的。未来需要研究SGLT2抑制剂使用者是否能观察到类似的效果。
