Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia.
Aging Cell. 2024 Jan;23(1):e13862. doi: 10.1111/acel.13862. Epub 2023 May 14.
Sarcopenia, the age-related decline in muscle function, places a considerable burden on health-care systems. While the stereotypic hallmarks of sarcopenia are well characterized, their contribution to muscle wasting remains elusive, which is partly due to the limited availability of animal models. Here, we have performed cellular and molecular characterization of skeletal muscle from the African killifish-an extremely short-lived vertebrate-revealing that while many characteristics deteriorate with increasing age, supporting the use of killifish as a model for sarcopenia research, some features surprisingly reverse to an "early-life" state in the extremely old stages. This suggests that in extremely old animals, there may be mechanisms that prevent further deterioration of skeletal muscle, contributing to an extension of life span. In line with this, we report a reduction in mortality rates in extremely old killifish. To identify mechanisms for this phenomenon, we used a systems metabolomics approach, which revealed that during aging there is a striking depletion of triglycerides, mimicking a state of calorie restriction. This results in the activation of mitohormesis, increasing Sirt1 levels, which improves lipid metabolism and maintains nutrient homeostasis in extremely old animals. Pharmacological induction of Sirt1 in aged animals was sufficient to induce a late life-like metabolic profile, supporting its role in life span extension in vertebrate populations that are naturally long-lived. Collectively, our results demonstrate that killifish are not only a novel model to study the biological processes that govern sarcopenia, but they also provide a unique vertebrate system to dissect the regulation of longevity.
肌肉减少症是与年龄相关的肌肉功能下降，给医疗保健系统带来了相当大的负担。虽然肌肉减少症的典型特征已经得到很好的描述，但它们对肌肉消耗的贡献仍然难以捉摸，部分原因是动物模型的可用性有限。在这里，我们对来自非洲的食蚊鱼（一种极短寿命的脊椎动物）的骨骼肌进行了细胞和分子特征分析，结果表明，虽然随着年龄的增长，许多特征会恶化，但这支持了将食蚊鱼用作肌肉减少症研究模型的观点，一些特征在极老阶段会出人意料地恢复到“早期生命”状态。这表明，在极老的动物中，可能存在防止骨骼肌进一步恶化的机制，从而延长寿命。与此一致的是，我们报告了极老食蚊鱼的死亡率降低。为了确定这种现象的机制，我们使用了系统代谢组学方法，该方法表明，随着衰老，甘油三酯明显耗竭，模拟了热量限制的状态。这导致了 mitohormesis 的激活，增加了 Sirt1 水平，从而改善了脂质代谢，并维持了极老动物的营养稳态。在老年动物中诱导 Sirt1 的药理学方法足以诱导出一种类似于晚年的代谢特征，支持其在自然长寿的脊椎动物种群中延长寿命的作用。总的来说，我们的结果表明，食蚊鱼不仅是研究控制肌肉减少症的生物学过程的新型模型，而且还提供了一个独特的脊椎动物系统来剖析长寿的调节。
