Cardiac PI3K P110α Attenuation Delays Aging And Extends Lifespan

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 an increased risk of cardiac disease. Hence, it remains elusive as to whether PI3K inhibition is a valid strategy to delay aging and extend the health span 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 a young age. In stark contrast, in aged mice, experimental attenuation of PI3K signaling reduced the aged-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.

Keywords: PI3K, IGF1, insulin signaling, cardiomyopathy, heart failure, aging, autophagy, mitochondrial dysfunction

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Life expectancy continues to rise worldwide, and so does the prevalence and socioeconomic burden of age-related chronic diseases. Amongst these, cardiovascular disorders remain the leading cause of lost healthy life years and ensuing mortality. Thus, defining the molecular and cellular mechanisms dictating the pace of cardiac aging is required for the development of novel interventions that might improve outcomes in cardiovascular disease, beyond the avoidance of traditional risk factors. The inhibition of the insulin/insulin-like growth factor-1 signaling (IIS) pathway is an evolutionarily conserved mechanism to delay organismal aging. Loss-of-function mutations in key components of the IIS pathway extend the lifespan in various organisms, ranging from yeast to rodents [1, 2]. However, the magnitude of such anti-aging effect appears to depend on the sex and the genetic background of tested animals [3]. Since IIS is required for normal growth and metabolism, further studies – on druggable targets of the IIS pathway and preferably in a cell type-specific fashion – must determine whether inhibiting the IIS pathway is a valid and safe strategy to compress late-life morbidity in humans. In this respect, aged mice with the reduced cardiac activity of phosphoinositide 3-kinase (PI3K), a key downstream effector of the IIS pathway, exhibit preserved cardiac function and reduced expression of senescence markers [4]. By contrast, young mice with cardiomyocyte-specific suppression of PI3K are more prone to dilated and ischemic cardiomyopathy, at least when surgically induced at a young age [5, 6]. To resolve these disparate findings, we performed a comprehensive long-term study, in which we assessed the cardiac health and survival of two transgenic mouse models with increased or reduced cardiac PI3K signaling throughout life [7].

We observed that mice harboring an inactive PI3K p110α isoform specifically in cardiac myocytes (dnPI3K) show delayed cardiac growth, subnormal contractility, and attenuated cardiopulmonary functional capacity, leading to an abnormally increased risk of mortality during early life. In contrast, aged dnPI3K mice displayed an attenuated age-dependent decline in cardiac systolic and diastolic functions, preserved cardiac functional reserve, reduced cardiac remodeling as well as improved myocardial bioenergetics, which was associated with extended survival during late-life stages. Mechanistically, delayed cardiac aging in dnPI3K mice coincided with activated autophagic flux in the heart. Autophagy inhibition using the lysosomotropic agent hydroxychloroquine abolished most of the benefits observed in aged dnPI3K hearts, indicating that functional autophagy has a causal role in the late-life cardioprotective effects of reduced PI3K activity.

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Conversely, increased IIS-PI3K signaling in mice overexpressing the human insulin-like growth factor-1 in cardiac myocytes (IGF1Rtg) led to augmented heart growth, supranormal contractile function, and increased exercise capacity. However, aged IGF1Rtg mice developed signs of accelerated cardiac aging, as indicated by reduced contractility and exacerbated diastolic dysfunction, leading to effort intolerance, compromised cardiopulmonary functional capacity, lung congestion, and shorter lifespan. Aged IGF1Rtg mice also exhibited increased left ventricular fibrosis as well as severe left atrial remodeling, suggesting an age-related shift from physiological hypertrophy toward hypertrophic cardiomyopathy. Premature cardiac aging in IGF1Rtg mice correlated with mitochondrial dysfunction and reduced anti-oxidative potential, likely due to blocked cardiac autophagy. In support of this notion, reduced autophagic flux occurred before the development of these harmful cardiac effects, while reactivating autophagy by the caloric restriction mimetic spermidine prevented the deterioration of oxidative phosphorylation and stress resistance mechanisms, thereby preserving cardiac function and protecting aged IGF1Rtg mice from heart failure [8].

Our findings are likely clinically relevant because we observed cardiac IGF1R overexpression and increased phosphorylation of the serine/threonine-protein kinase AKT in left ventricular samples of patients with non-ischemic dilated cardiomyopathy, denoting activated cardiac IIS-PI3K signaling in heart failure. Downstream to PI3K, we detected an increased mammalian target of rapamycin (MTOR)-dependent inhibitory phosphorylation of unc-51-like autophagy activating kinase 1 (ULK1) [9]. Intriguingly, and unlike failing human hearts, donors with compensated hypertrophy (i.e., preserved function, despite increased remodeling) showed no signs of increased IIS-PI3K signaling as compared to age-matched controls with no history of cardiac disease, suggesting a potential protective role of IIS-PI3K inhibition.

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In sum, age appears to be a key determining factor that defines the role of PI3K signaling in the heart. At a young age, increased activity of the IIS-PI3K axis is required for normal cardiac growth and development. However, later in life reduced PI3K activity confers anti-aging effects, likely through prioritizing cardioprotective quality control mechanisms, such as autophagy, over superfluous cardiac growth (Fig. 1). Such a biphasic relationship between cardiac health and IIS-PI3K signaling activity reconciles previous opposing studies [4, 6], and suggests that partial inhibition of PI3K might be worth considering for the treatment of heart failure and other age-related chronic diseases – albeit at a much lower and safer dosage than that applied in cancer therapy [10, 11]. Alternatively, emerging autophagy inducers and caloric restriction mimetics, like spermidine and nicotinamide adenine dinucleotide (NAD+) precursors [8, 12–14], might offer a readily available, and perhaps safer, strategy for immediate testing in cardiac patients [15].

ACKNOWLEDGMENTS

This work was funded by the Austrian Science Fund (FWF) through grants P27637-B28 and I3301-MINOTAUR to S.S.. M.A. acknowledges support from the Austrian Society of Cardiology (Präsidentenstipendium-ÖKG), Medical University of Graz (Start Fund) and the European Commission (H2020-MSCA-IF, Nr. 101025118). G.K. is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Association “Ruban Rose”; Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); Gustave Roussy Odyssea, the European Union Horizon 2020 Projects Oncobiome and Crimson; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085), Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); the Leducq Foundation; the RHU Torino Lumière; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001. K.T. acknowledges support from the MESI-STRAT project (Grant Agreement 754688), PoLiMeR Innovative Training Network (Marie Skłodowska-Curie Grant Agreement 812616 ), the ARDRE program (Marie Skłodowska-Curie grant agreement No 847681), which all received funding from the European Union Horizon 2020 Research and Innovation Program, and the PARC partnership which has received funding from the European Union's Horizon Europe Research and Innovation Programme under Grant Agreement No 101057014. A.H. is supported by the Tyrolean Science Fund (TWF; grant agreement F.33468/7–2021).

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CONFLICT OF INTEREST

G.K. has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sotio, Tollys, Vascage, 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 co-founder 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.

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