Cardiac PI3K p110α attenuation delays aging and extends lifespan.

IF 4.1 Q2 CELL BIOLOGY Cell Stress Pub Date : 2022-08-08 eCollection Date: 2022-08-01 DOI:10.15698/cst2022.08.270
Mahmoud Abdellatif, Tobias Eisenberg, Alexander Martin Heberle, Kathrin Thedieck, Guido Kroemer, Simon Sedej
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Abstract

Phosphoinositide 3-kinase (PI3K) is a key component of the insulin signaling pathway that controls cellular me-tabolism and growth. Loss-of-function mutations in PI3K signaling and other downstream effectors of the insulin signaling pathway extend the lifespan of various model organisms. However, the pro-longevity effect appears to be sex-specific and young mice with reduced PI3K signaling have increased risk of cardiac disease. Hence, it remains elusive as to whether PI3K inhibition is a valid strategy to delay aging and extend healthspan in humans. We recently demonstrated that reduced PI3K activity in cardiomyocytes delays cardiac growth, causing subnormal contractility and cardiopulmonary functional capacity, as well as increased risk of mortality at young age. In stark contrast, in aged mice, experi-mental attenuation of PI3K signaling reduced the age-dependent decline in cardiac function and extended maximal lifespan, suggesting a biphasic effect of PI3K on cardiac health and survival. The cardiac anti-aging effects of reduced PI3K activity coincided with enhanced oxida-tive phosphorylation and required increased autophagic flux. In humans, explanted failing hearts showed in-creased PI3K signaling, as indicated by increased phos-phorylation of the serine/threonine-protein kinase AKT. Hence, late-life cardiac-specific targeting of PI3K might have a therapeutic potential in cardiac aging and related diseases.

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心脏 PI3K p110α 的衰减可延缓衰老并延长寿命。
磷脂酰肌醇 3-激酶(PI3K)是胰岛素信号通路的一个关键组成部分,它控制着细胞的代谢和生长。PI3K 信号转导和胰岛素信号转导途径的其他下游效应器的功能缺失突变可延长各种模式生物的寿命。然而,这种益寿效应似乎具有性别特异性,PI3K 信号减少的年轻小鼠患心脏病的风险增加。因此,抑制 PI3K 是否是人类延缓衰老和延长健康寿命的有效策略仍是一个未知数。我们最近证实,心肌细胞中 PI3K 活性降低会延缓心脏生长,导致收缩力和心肺功能不正常,并增加年轻时的死亡风险。与此形成鲜明对比的是,在老年小鼠中,通过实验减弱 PI3K 信号传导可减少心脏功能随年龄的下降,并延长最大寿命,这表明 PI3K 对心脏健康和存活具有双相效应。降低 PI3K 活性的心脏抗衰老效应与氧化磷酸化的增强相吻合,并且需要自噬通量的增加。在人体中,切除的衰竭心脏显示出 PI3K 信号的内增,这表现在丝氨酸/苏氨酸蛋白激酶 AKT 的磷酸化增加。因此,晚期心脏特异性靶向 PI3K 可能具有治疗心脏衰老和相关疾病的潜力。
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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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