Cardiac PI3K p110α attenuation delays aging and extends lifespan
Authors:Mahmoud Abdellatif1,2,3,4, Tobias Eisenberg4,5,6, Alexander Martin Heberle7, Kathrin Thedieck7,8,9, Guido Kroemer2,3,10 and Simon Sedej1,4,11
1Department of Cardiology, Medical University of Graz, 8036 Graz, Austria.
2Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris 75006, France.
3Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif 94805, France.
4BioTechMed Graz, 8010 Graz, Austria.
5Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria.
6Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria.
7Institute of Biochemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck 6020, Austria.
8Department of Pediatrics, Section Systems Medicine of Metabolism and Signalingg, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands.
9Department for Neuroscience, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg 26129, Germany.
10Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris 7015, France.
11Institute of Physiology, Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia.
Keywords:
PI3K, IGF1, insulin signaling, cardiomyopathy, heart failure, aging, autophagy, mitochondrial dysfunction.
Corresponding Author(s):
Conflict of interest statement:
G.K. has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sotio, Tollys, Vascage and Vasculox/Tioma. G.K. has been consulting for Reithera. G.K. is on the Board of Directors of the Bristol Myers Squibb Foundation France. G.K. is a scientific cofounder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. G.K. is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. The other authors have nothing to declare. T.E. has equity interests and is an advisor for The Longevity Labs (TLL). T.E. is also an inventor of patents covering the use of spermidine for health benefits. M.A. and S.S. are involved in a patent application dealing with the cardiometabolic effects of caloric restriction mimetics, like spermidine and nicotinamide.
Please cite this article as:
Abdellatif et al. (2022). Cardiac PI3K p110α attenuation delays aging and extends lifespan. Cell Stress: 6(8): 72-75. doi: 10.15698/cst2022.08.270
© 2022 Abdellatif et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
Abstract:
Phosphoinositide 3-kinase (PI3K) is a key component of the insulin signaling pathway that controls cellular metabolism 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, experimental 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 oxidative phosphorylation and required increased autophagic flux. In humans, explanted failing hearts showed increased PI3K signaling, as indicated by increased phosphorylation 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.