Spermidine overrides INSR (insulin receptor)-IGF1R (insulin-like growth factor 1 receptor)-mediated inhibition of autophagy in the aging heart

Abstract

Although attenuated IGF1R (insulin-like growth factor 1 receptor) signaling has long been viewed to promote longevity in model organisms, adverse effects on the heart have been the subject of major concern. We observed that IGF1R is overexpressed in cardiac tissues from patients with end-stage non-ischemic heart failure, coupled to the activation of the IGF1R downstream effector AKT/protein kinase B and inhibition of ULK1 (unc-51 like autophagy activating kinase 1). Transgenic overexpression of human IGF1R in cardiomyocytes from mice initially induces physiological cardiac hypertrophy and superior function, but later in life confers a negative impact on cardiac health, causing macroautophagy/autophagy inhibition as well as impaired oxidative phosphorylation, thus reducing life expectancy. Treatment with the autophagy inducer and caloric restriction mimetic spermidine ameliorates most of these IGF1R-induced cardiotoxic effects in vivo. Moreover, inhibition of IGF1R signaling by means of a dominant-negative phosphoinositide 3-kinase (PI3K) mutant induces cardioprotective autophagy, restores myocardial bioenergetics and improves late-life survival. Hence, our results demonstrate that IGF1R exerts a dual biphasic impact on cardiac health, and that autophagy mediates the late-life geroprotective effects of IGF1R inhibition in the heart.

Keywords: Heart failure; IGF1R; PI3K; human; insulin signaling; longevity; mitochondrial dysfunction; mouse.

Figure 1.

Autophagy determines the effect of IGF1 (insulin-like growth factor 1) signaling on the aging heart. In mice, cardiomyocyte-specific overexpression of human IGF1R (IGF1 receptor) accelerates cardiac aging, leading to premature heart failure, despite initially inducing physiological cardiac hypertrophy and superior function. Treatment with the autophagy inducer spermidine protects aged IGF1R^tg mice from heart failure, suggesting that reduced autophagic flux underlies the late-life detrimental impact of increased cardiac IGF1R signaling. By contrast, low IGF1R signaling in mice harboring a dominant-negative mutation in the PIK3CA/p110α isoform of phosphoinositide 3-kinase (PI3K) – which is a key downstream effector of IGF1R – decelerates cardiac aging and extends longevity in an autophagy-dependent manner, as indicated by limited cardioprotection upon treatment with the autophagy inhibitor hydroxychloroquine. This figure was created with BioRender.com.