Cardiac PI3K p110α attenuation delays aging and extends lifespan

–

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 insulin/insulin-like growth factor-1 signaling (IIS) pathway is an evolutionary 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 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 IIS pathway is a valid and safe strategy to compress late-life morbidity in humans. In this respect, aged mice with 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]. In order to resolve these disparate findings, we performed a comprehensive long-term study, in which we assessed cardiac health and survival of two transgenic mouse models with increased or reduced cardiac PI3K signaling throughout the course of life [7].
We observed that mice harbouring 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 remodelling as well as improved myocardial bioenergetics, which were associated with extended survival during late-life stages. Mechanistically, delayed cardiac aging in dnPI3K mice coincided with activated autophagic flux in the heart. In fact, 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.
Conversely, increased IIS-PI3K signaling in mice overexpressing the human insulin-like growth factor-1 in cardiac myocytes (IGF1R^tg) led to augmented heart growth, supranormal contractile function and increased exercise capacity. However, aged IGF1R^tg 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 IGF1R^tg mice also exhibited increased left ventricular fibrosis as well as severe left atrial remodelling, suggesting an age-related shift from physiological hypertrophy towards hypertrophic cardiomyopathy. Premature cardiac aging in IGF1R^tg 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 deleterious 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 IGF1R^tg 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 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 remodelling) 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.
In sum, age appears to be a key determining factor that defines the role of PI3K signaling in the heart. At 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][13][14], might offer a readily-available, and perhaps safer, strategy for immediate testing in cardiac patients [15].

–

FIGURE 1. The impact of phosphoinositide 3-kinase (PI3K) signaling in regulating cardiac health and survival during the course of life. PI3K signaling is crucial for cardiac homeostasis during early life as young mice harbouring a dominant-negative mutation in the p110α isoform of PI3K (dnPI3K) exhibited subnormal cardiac performance and increased risk of mortality in early life, but extended cardiac healthspan and longevity later in life (dashed arrow). Accordingly, PI3K activation in mice by cardiomyocyte-specific overexpression of human insulin-like growth factor 1 receptor (IGF1Rtg) induced physiological left ventricular hypertrophy and conferred cardiac functional benefits at young age, but worsened cardiac health at old age, as it accelerated cardiac decline, leading to heart failure and shortened lifespan in IGF1Rtg mice (dotted arrow). Abbreviation: WT, wild type. Mouse cliparts were generated with Biorender.com.

REFERENCES

1. Foukas LC, Bilanges B, Bettedi L, Pearce W, Ali K, Sancho S, Withers DJ, and Vanhaesebroeck B (2013). Long-term p110α PI3K inactivation exerts a beneficial effect on metabolism. EMBO Mol Med 5(4): 563–571. 10.1002/emmm.201201953
2. Milman S, Huffman DM, and Barzilai N (2016). The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research. Cell Metab 23(6): 980–989.. 10.1016/j.cmet.2016.05.014
3. Sell C (2015). Minireview: The Complexities of IGF/Insulin Signalingg in Aging: Why Flies and Worms Are Not Humans. Mol Endocrinol 29(8): 1107–1113. 10.1210/me.2015-1074
4. Inuzuka Y, Okuda J, Kawashima T, Kato T, Niizuma S, Tamaki Y, Iwanaga Y, Yoshida Y, Kosugi R, Watanabe-Maeda K, Machida Y, Tsuji S, Aburatani H, Izumi T, Kita T, and Shioi T (2009). Suppression of phosphoinositide 3-kinase prevents cardiac aging in mice. Circulation 120(17): 1695–1703. 10.1161/CIRCULATIONAHA.109.871137
5. McMullen JR, Shioi T, Zhang L, Tarnavski O, Sherwood MC, Kang PM, and Izumo S (2003). Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc Natl Acad Sci U S A 100(21): 12355–12360. 10.1073/pnas.1934654100
6. Lin RCY, Weeks KL, Gao X-M, Williams RBH, Bernardo BC, Kiriazis H, Matthews VB, Woodcock EA, Bouwman RD, Mollica JP, Speirs HJ, Dawes IW, Daly RJ, Shioi T, Izumo S, Febbraio MA, Du X-J, and McMullen JR (2010). PI3K(p110 alpha) protects against myocardial infarction-induced heart failure: identification of PI3K-regulated miRNA and mRNA. Arterioscler Thromb Vasc Biol 30(4): 724–732. 10.1161/ATVBAHA.109.201988
7. Abdellatif M, Trummer-Herbst V, Heberle AM, Humnig A, Pendl T, Durand S, Cerrato G, Hofer SJ, Islam M, Voglhuber J, Ramos Pittol JM, Kepp O, Hoefler G, Schmidt A, Rainer PP, Scherr D, von Lewinski D, Bisping E, McMullen JR, Diwan A, Eisenberg T, Madeo F, Thedieck K, Kroemer G, and Sedej S (2022). Fine-Tuning Cardiac Insulin-Like Growth Factor 1 Receptor Signalingg to Promote Health and Longevity. Circulation 145(25): 1853–1866. 10.1161/CIRCULATIONAHA.122.059863
8. Abdellatif M, Madeo F, Kroemer G, and Sedej S (2022). Spermidine overrides INSR (insulin receptor)-IGF1R (insulin-like growth factor 1 receptor)-mediated inhibition of autophagy in the aging heart. Autophagy 1–3. 10.1080/15548627.2022.2095835
9. Zimmermann A, Madreiter-Sokolowski C, Stryeck S, and Abdellatif M (2021). Targeting the Mitochondria-Proteostasis Axis to Delay Aging. Front Cell Dev Biol 9: 656201. 10.3389/fcell.2021.656201
10. Nunnery SE, and Mayer IA (2019). Management of toxicity to isoform α-specific PI3K inhibitors. Annals of Oncology 30: x21–x26. 10.1093/annonc/mdz440
11. Sala V, Della Sala A, Ghigo A, and Hirsch E (2021). Roles of phosphatidyl inositol 3 kinase gamma (PI3Kγ) in respiratory diseases. Cell Stress 5(4): 40–51. 10.15698/cst2021.04.246
12. Abdellatif M, Sedej S, and Kroemer G (2021). NAD+ Metabolism in Cardiac Health, Aging, and Disease. Circulation 144(22): 1795–1817. 10.1161/CIRCULATIONAHA.121.056589
13. Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, Harger A, Schipke J, Zimmermann A, Schmidt A, Tong M, Ruckenstuhl C, Dammbrueck C, Gross AS, Herbst V, Magnes C, Trausinger G, Narath S, Meinitzer A, Hu Z, Kirsch A, Eller K, Carmona-Gutierrez D, Büttner S, Pietrocola F, Knittelfelder O, Schrepfer E, Rockenfeller P, Simonini C, Rahn A, Horsch M, Moreth K, Beckers J, Fuchs H, Gailus-Durner V, Neff F, Janik D, Rathkolb B, Rozman J, de Angelis MH, Moustafa T, Haemmerle G, Mayr M, Willeit P, von Frieling-Salewsky M, Pieske B, Scorrano L, Pieber T, Pechlaner R, Willeit J, Sigrist SJ, Linke WA, Mühlfeld C, Sadoshima J, Dengjel J, Kiechl S, Kroemer G, Sedej S, and Madeo F (2016). Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med 22(12): 1428–1438. 10.1038/nm.4222
14. Abdellatif M, Trummer-Herbst V, Koser F, Durand S, Adão R, Vasques-Nóvoa F, Freundt JK, Voglhuber J, Pricolo M-R, Kasa M, Türk C, Aprahamian F, Herrero-Galán E, Hofer SJ, Pendl T, Rech L, Kargl J, Anto-Michel N, Ljubojevic-Holzer S, Schipke J, Brandenberger C, Auer M, Schreiber R, Koyani CN, Heinemann A, Zirlik A, Schmidt A, von Lewinski D, Scherr D, Rainer PP, von Maltzahn J, Mühlfeld C, Krüger M, Frank S, Madeo F, Eisenberg T, Prokesch A, Leite-Moreira AF, Lourenço AP, Alegre-Cebollada J, Kiechl S, Linke WA, Kroemer G, and Sedej S (2021). Nicotinamide for the treatment of heart failure with preserved ejection fraction. Sci Transl Med 13(580): eabd7064. 10.1126/scitranslmed.abd7064
15. Sedej S, and Abdellatif M (2022). Metabolic therapy for managing heart failure with preserved ejection fraction. J Mol Cell Cardiol 168: 68-69. 10.1016/j.yjmcc.2022.04.009