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Background <p>Glucagon-like peptide-1 receptor (GLP1R) agonists and dual glucose-dependent insulinotropic polypeptide receptor/glucagon-like peptide-1 receptor (GIPR/GLP1R) agonists are established treatments for diabetes and obesity, but their potential effects on biological aging remain uncertain.</p> Methods <p>In this drug target Mendelian randomization study, we assessed the associations of genetically proxied modulation of GLP1R, GIPR, and dual GIPR/GLP1R pathways with four aging phenotypes, including frailty index, phenotypic age (PhenoAge) acceleration, telomere length, and longevity.</p> Results <p>Glycated hemoglobin (HbA1c) lowering via GIPR, modeling the glucose-lowering effect of variants in GIPR loci, was consistently associated with a lower frailty index (primary dataset: β = − 0.10 [95% CI: − 0.18, − 0.02]; replication dataset: − 0.14 [− 0.27, − 0.01]), reduced PhenoAge acceleration (primary: − 0.82 [− 1.17, − 0.48]; replication − 1.04 [− 1.81, − 0.27]), longer telomere length (primary: 0.06 [0.003, 0.11]; replication: 0.09 [0.002, 0.19]), and greater odds of longevity (primary: odds ratio [OR] = 2.90 [95% CI: 1.93, 4.36]; replication: 6.54 [2.92, 14.65]). Body mass index (BMI) lowering via GIPR, modeling appetite-suppressing and weight-reducing effects of variants, was associated with a lower frailty index (primary: − 0.07 [− 0.13, − 0.01]; replication: − 0.19 [− 0.35, − 0.04]) and higher odds of longevity (primary: 2.11 [1.22, 3.66]). In contrast, HbA1c lowering via GLP1R was associated exclusively with longevity (primary: OR = 3.72 [2.25, 6.18]; replication: 16.53 [4.28, 63.80]), whereas BMI lowering via GLP1R was not associated with any aging phenotype. Analyses of dual GIPR/GLP1R yielded results broadly similar to those for GIPR, with the exception of a null effect on frailty index.</p> Conclusions <p>Genetically proxied HbA1c- and BMI-lowering effects through GLP1R- and GIPR-related pathways were favorably associated with aging phenotypes, with broader associations observed for HbA1c lowering. Further clinical studies are warranted to clarify the relevance of these pathways to healthy aging.</p> Graphical abstract <p></p>

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Genetically proxied glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor pathway modulation is associated with favorable aging phenotypes: a drug-target Mendelian randomization study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月22日

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  • Jiang Li,
  • Jie Li,
  • Xiaoqin Xu,
  • Ningjian Wang,
  • Yingli Lu,
  • Bin Wang

摘要

Background

Glucagon-like peptide-1 receptor (GLP1R) agonists and dual glucose-dependent insulinotropic polypeptide receptor/glucagon-like peptide-1 receptor (GIPR/GLP1R) agonists are established treatments for diabetes and obesity, but their potential effects on biological aging remain uncertain.

Methods

In this drug target Mendelian randomization study, we assessed the associations of genetically proxied modulation of GLP1R, GIPR, and dual GIPR/GLP1R pathways with four aging phenotypes, including frailty index, phenotypic age (PhenoAge) acceleration, telomere length, and longevity.

Results

Glycated hemoglobin (HbA1c) lowering via GIPR, modeling the glucose-lowering effect of variants in GIPR loci, was consistently associated with a lower frailty index (primary dataset: β = − 0.10 [95% CI: − 0.18, − 0.02]; replication dataset: − 0.14 [− 0.27, − 0.01]), reduced PhenoAge acceleration (primary: − 0.82 [− 1.17, − 0.48]; replication − 1.04 [− 1.81, − 0.27]), longer telomere length (primary: 0.06 [0.003, 0.11]; replication: 0.09 [0.002, 0.19]), and greater odds of longevity (primary: odds ratio [OR] = 2.90 [95% CI: 1.93, 4.36]; replication: 6.54 [2.92, 14.65]). Body mass index (BMI) lowering via GIPR, modeling appetite-suppressing and weight-reducing effects of variants, was associated with a lower frailty index (primary: − 0.07 [− 0.13, − 0.01]; replication: − 0.19 [− 0.35, − 0.04]) and higher odds of longevity (primary: 2.11 [1.22, 3.66]). In contrast, HbA1c lowering via GLP1R was associated exclusively with longevity (primary: OR = 3.72 [2.25, 6.18]; replication: 16.53 [4.28, 63.80]), whereas BMI lowering via GLP1R was not associated with any aging phenotype. Analyses of dual GIPR/GLP1R yielded results broadly similar to those for GIPR, with the exception of a null effect on frailty index.

Conclusions

Genetically proxied HbA1c- and BMI-lowering effects through GLP1R- and GIPR-related pathways were favorably associated with aging phenotypes, with broader associations observed for HbA1c lowering. Further clinical studies are warranted to clarify the relevance of these pathways to healthy aging.

Graphical abstract