Metformin treatment of diverse Caenorhabditis species reveals the importance of genetic background in longevity and healthspan extension outcomes.
Metformin treatment of diverse Caenorhabditis species reveals the importance of genetic background in longevity and healthspan extension outcomes.
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二甲双胍治疗多种细胞炎，揭示了遗传背景在寿命和健康范围扩展结果中的重要性。
DOI：
10.1111/acel.13488
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发表时间：
2022-01
期刊：
影响因子：
7.8
通讯作者：
Driscoll M
中科院分区：
文献类型：
--
作者：
Onken B;Sedore CA;Coleman-Hulbert AL;Hall D;Johnson E;Jones EG;Banse SA;Huynh P;Guo S;Xue J;Chen E;Harinath G;Foulger AC;Chao EA;Hope J;Bhaumik D;Plummer T;Inman D;Morshead M;Guo M;Lithgow GJ;Phillips PC;Driscoll M
二甲双胍是最常用的抗糖尿病药物，据报道具有多种健康益处，包括降低心血管疾病和癌症的风险，改善随着年龄增长的认知功能，延长糖尿病患者的生存期，并且在一些动物模型中，促进年轻的生理和寿命。由于其长寿和健康的影响，二甲双胍现在是第一个抗衰老药物临床试验的重点-靶向衰老与二甲双胍（TAME）项目。当研究二甲双胍对人类健康的影响时，遗传变异可能会影响结果。为了测试二甲双胍对不同遗传背景的影响，我们在三种具有遗传变异性的隐杆线虫物种中测量了二甲双胍治疗对寿命和健康寿命的影响，这些物种的遗传变异性大于小鼠和人类。我们发现二甲双胍增加了三种秀丽隐杆线虫菌株的中位生存，但在C. briggsae和C. tropical菌株中没有。在C. briggsae中，二甲双胍要么对生存没有影响，要么缩短寿命。在热带棘虫中，二甲双胍以剂量依赖性的方式降低中位生存期。我们发现二甲双胍延长了所有秀丽隐杆线虫菌株和两种briggsae菌株的青春活力期，但二甲双胍对热带线虫菌株的运动有负面影响。我们的数据表明，在不同的遗传背景下，二甲双胍可以成为健康衰老的有力促进剂，但遗传变异可以决定二甲双胍对寿命/健康寿命的影响是积极的、中性的还是消极的。这些结果强调了在不同人群中检测二甲双胍的健康益处时对个体进行定制治疗的重要性。我们监测了二甲双胍对九种菌株的影响，这些菌株跨越三种隐杆线虫，其核苷酸多样性大于小鼠和人类之间的差异。我们发现二甲双胍促进不同遗传背景的健康衰老，但遗传背景可以决定二甲双胍是否有积极、中性或消极的影响。数据表明二甲双胍的潜在广泛影响，但也强调个体遗传学将在不同的测试集中发挥作用。
Metformin, the most commonly prescribed anti‐diabetes medication, has multiple reported health benefits, including lowering the risks of cardiovascular disease and cancer, improving cognitive function with age, extending survival in diabetic patients, and, in several animal models, promoting youthful physiology and lifespan. Due to its longevity and health effects, metformin is now the focus of the first proposed clinical trial of an anti‐aging drug—the Targeting Aging with Metformin (TAME) program. Genetic variation will likely influence outcomes when studying metformin health effects in human populations. To test for metformin impact in diverse genetic backgrounds, we measured lifespan and healthspan effects of metformin treatment in three Caenorhabditis species representing genetic variability greater than that between mice and humans. We show that metformin increases median survival in three C. elegans strains, but not in C. briggsae and C. tropicalis strains. In C. briggsae, metformin either has no impact on survival or decreases lifespan. In C. tropicalis, metformin decreases median survival in a dose‐dependent manner. We show that metformin prolongs the period of youthful vigor in all C. elegans strains and in two C. briggsae strains, but that metformin has a negative impact on the locomotion of C. tropicalis strains. Our data demonstrate that metformin can be a robust promoter of healthy aging across different genetic backgrounds, but that genetic variation can determine whether metformin has positive, neutral, or negative lifespan/healthspan impact. These results underscore the importance of tailoring treatment to individuals when testing for metformin health benefits in diverse human populations. We monitored metformin impact in nine strains spanning three Caenorhabditis species that feature a nucleotide diversity greater than that between mouse and humans. We find that metformin promotes healthy aging across diverse genetic backgrounds, but that genetic background can determine whether metformin has a positive, neutral, or negative effect. Data demonstrate the potential broad reach of metformin but also underscore that individual genetics will underlie efficacy over a diverse test set.
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DOI：
10.1073/pnas.1909210116
发表时间：
2019-11-19
影响因子：
11.1
作者：
Laranjeiro, Ricardo;Harinath, Girish;Driscoll, Monica
通讯作者：
Driscoll, Monica
影响因子：
5.8
作者：
Li, Heng
通讯作者：
Li, Heng
影响因子：
8.8
作者：
Gruen, Dominic;Kirchner, Marieluise;Rajewsky, Nikolaus
通讯作者：
Rajewsky, Nikolaus
影响因子：
11.8
作者：
Hill, RC;de Carvalho, CE;Haag, ES
通讯作者：
Haag, ES
影响因子：
3.3
作者：
Lu, Min R.;Lai, Cheng-Kuo;Tsai, Isheng Jason
通讯作者：
Tsai, Isheng Jason