Identifying modifiable factors that accelerate or delay aging from genetic variations

Background
With global aging, slowing aging is an urgent priority. While inevitable, aging rate may be modifiable by various environmental factors. This study aims to identify modifiable factors that have causal associations with aging. This can inform strategies to extend healthspan and mitigate the societal burden of aging.
Methods and Design
We evaluated 51 potentially modifiable risk factors for their associations with aging by using a two-sample bidirectional Mendelian randomization (MR) framework from Genome-wide association studies of 12,230 to 766,345 individuals who were predominantly of European descent. MR analyses were primarily conducted using the inverse-variance-weighted method, followed by various sensitivity analyses.
Results
Among 51 potentially risk factors, we identified systolic blood pressure, transferrin saturation, body mass index, osteoarthritis and C reactive protein as key factors that significantly contribute to accelerated aging. Primarily, transferrin saturation exhibits a noteworthy impact on Hannum Age acceleration (β [SE] per 1-SD increase: 0.293 [0.081] year), Horvath Age acceleration (0.327 [0.104] year), GrimAge acceleration (0.273 [0.083] year) and PhenoAge acceleration (0.417 [0.106] year). Meanwhile, educational attainment was identified as an effective factor in slowing the aging process. This study provides unique quantitative insights into modifiable causal risk factors for aging.
Conclusion
The study provides unique quantitative insights into modifiable causal risk factors for aging. Our findings underscore valuable intervention targets capable of slowing biological aging and fostering healthy longevity - an indispensable reference for public health strategies and relevant clinical scenarios.

背景
随着全球人口老龄化进程加剧，延缓衰老已成为当务之急。尽管衰老过程不可避免，但其速率可通过多种环境因素进行干预。本研究旨在识别与衰老存在因果关联的可干预因素，为延长健康寿命、减轻衰老带来的社会负担提供决策依据。

方法与设计
本研究基于纳入12230至766345名以欧洲血统人群为主的全基因组关联研究（Genome-wide Association Study, GWAS）数据，采用双样本双向孟德尔随机化（Mendelian Randomization, MR）框架，对51种潜在可干预衰老风险因素与衰老的关联进行评估。MR分析主要采用逆方差加权法开展，随后辅以多种敏感性分析。

结果
在51种潜在风险因素中，我们识别出收缩压、转铁蛋白饱和度、体重指数（Body Mass Index, BMI）、骨关节炎及C反应蛋白（C-reactive Protein, CRP）为显著促进衰老加速的关键因素。其中，转铁蛋白饱和度对Hannum衰老加速度（Hannum Age acceleration）、Horvath衰老加速度（Horvath Age acceleration）、GrimAge衰老加速度（GrimAge acceleration）及PhenoAge衰老加速度（PhenoAge acceleration）均具有显著影响：每增加1个标准差，对应衰老加速度分别增加0.293（标准误SE=0.081）年、0.327（SE=0.104）年、0.273（SE=0.083）年及0.417（SE=0.106）年。与此同时，受教育程度被证实为可延缓衰老进程的有效因素。本研究为衰老相关可干预因果风险因素提供了独特的定量研究视角。

结论
本研究为衰老相关可干预因果风险因素提供了独特的定量研究视角。研究结果明确了可有效延缓生物学衰老、促进健康长寿的潜在干预靶点，可为公共卫生策略制定及相关临床实践提供不可或缺的参考依据。