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Updated: Jun 29, 2025
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Identification of prospective aging drug targets via Mendelian randomization analysis
Rui Mao1,2,3, Ji Li1,2,3, Wenqin Xiao1,2,3
1Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
Abstract:
Aging represents a multifaceted process culminating in the deterioration of biological functions. Despite the introduction of numerous anti-aging strategies, their therapeutic outcomes have often been less than optimal. Consequently, discovering new targets to mitigate aging effects is of critical importance. We applied Mendelian randomization (MR) to identify potential pharmacological targets against aging, drawing upon summary statistics from both the Decode and FinnGen cohorts, with further validation in an additional cohort. To address potential reverse causality, bidirectional MR analysis with Steiger filtering was utilized. Additionally, Bayesian co-localization and phenotype scanning were implemented to investigate previous associations between genetic variants and traits. Summary-data-based Mendelian randomization (SMR) analysis was conducted to assess the impact of genetic variants on aging via their effects on protein expression. Additionally, mediation analysis was orchestrated to uncover potential intermediaries in these associations. Finally, we probed the systemic implications of drug-target protein expression across diverse indications by MR-PheWas analysis. Utilizing a Bonferroni-corrected threshold, our MR examination identified 10 protein-aging associations. Within this cohort of proteins, MST1, LCT, GMPR2, PSMB4, ECM1, EFEMP1, and ISLR2 appear to exacerbate aging risks, while MAX, B3GNT8, and USP8 may exert protective influences. None of these proteins displayed reverse causality except EFEMP1. Bayesian co-localization inferred shared variants between aging and proteins such as B3GNT8 (rs11670143), ECM1 (rs61819393), and others listed. Mediator analysis pinpointed 1,5-anhydroglucitol as a partial intermediary in the influence LCT exhibits on telomere length. Circulating proteins play a pivotal role in influencing the aging process, making them promising candidates for therapeutic intervention. The implications of these proteins in aging warrant further investigation in future clinical research.
Insights
This study identifies key proteins influencing aging using Mendelian randomization (MR). Some proteins may accelerate aging, while others offer protection, suggesting novel therapeutic targets for longevity.
Area of Science:
- Genetics and Aging Research
- Pharmacological Target Identification
- Biomarker Discovery
Background:
- Aging is a complex biological process with significant functional decline.
- Current anti-aging interventions have limited efficacy, necessitating new therapeutic targets.
- Identifying genetic factors influencing aging is crucial for developing effective strategies.
Purpose of the Study:
- To identify potential pharmacological targets for mitigating aging using Mendelian randomization (MR).
- To investigate the causal relationships between genetic variants, protein expression, and aging.
- To explore the systemic implications of drug-target protein expression in aging.
Main Methods:
- Applied Mendelian randomization (MR) using summary statistics from large cohorts (Decode, FinnGen).
- Utilized bidirectional MR with Steiger filtering to address reverse causality.
- Performed Bayesian co-localization, phenotype scanning, SMR, mediation, and MR-PheWas analyses.
Main Results:
- Identified 10 significant protein-aging associations.
- MST1, LCT, GMPR2, PSMB4, ECM1, EFEMP1, and ISLR2 were linked to increased aging risk.
- MAX, B3GNT8, and USP8 showed potential protective effects against aging.
- EFEMP1 was the only protein with evidence of reverse causality.
Conclusions:
- Circulating proteins significantly influence the aging process.
- Identified proteins represent promising candidates for novel anti-aging therapeutic interventions.
- Further clinical research is warranted to explore the therapeutic potential of these protein targets.
