ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2022) 19 4.11 | DOI: 10.1530/ey.19.4.11


Circulation, 2022: Jun 21;145(25):1853-1866 PMID: 35616058

Brief Summary: This translational study evaluated cardiac health and lifespan in two cardiomyocyte-specific transgenic mice with either enhanced or reduced IGF-1 signaling and in human cardiac biopsies from failing and nonfailing hearts. Increased IGF1R expression was related to better cardiac performance in young mice but faster decline of cardiac function with aging. Conversely reduced IGF1R signaling was associated improved lifespan and superior cardiac profile during aging. Human failing hearts showed exaggerated IGF1R signaling. These data unveil a novel role of IGF1R signaling in cardiac health, which acts in a biphasic way according to age and suggest that the use of pharmacological inhibitors of IGF1 could be beneficial in elderly adults at risk of heart failure.

The GH/IGF-1 axis is considered a key regulator of cellular metabolism and aging (1). Previous studies revealed that loss-of-function mutations in the IGF1 receptor (IGF1R) or its downstream effectors promote longevity in various organisms. There is evidence that IGF-1 signaling plays a role in the modulation of lifespan. However, the consequence of diminished IGF1 signaling on health span (i.e., the disease-free period of life), with the exception of cancer, remains largely controversial (2). IGF-1 signaling influences cardiac homeostasis. Reduced cardiomyocyte IGF-1 signaling exerts detrimental effects, whereas its activation is linked to enhanced cardiac contractility and physiological hypertrophy (2, 3). In contrast to this assumption, recent studies have reported a positive effect of reduced IGF-1 signaling on age-related cardiac remodeling, and an improvement of cardiac function obtained with IGF1R monoclonal antibodies in aged female mice. Therefore, modulation of IGF1R signaling might be either beneficial or detrimental on cardiac function depending on the organism age.

To test this hypothesis, the authors generated two cardiomyocyte-specific transgenic mice with either enhanced or reduced IGF-1 signaling. The mice were examined at different life stages by multiple structural and functional analyses. Furthermore, the expression of IGF1R in aged human hearts was investigated using left ventricular (LV) biopsies obtained from explanted failing hearts. Increased IGF1R signaling was associated with a superior cardiac function in young mice but this positive effect declined with aging leading to earlier heart failure and reduced lifespan compared to wild-type animals. On the contrary, mice with reduced IGF1R signaling showed inferior cardiac function in early life but a better cardiac function with aging and prolonged lifespan. Consistently, in humans (mean age 60±2 years), failing hearts showed increased IGF1R expression and signaling. These findings suggest that IGF1R signaling has a double-faced impact on cardiac function according to age, positive in early life and progressively detrimental with age. Aging based pharmacological interventions aimed at modulating IGF1R signaling may be worth testing to improve cardiac function.

References: 1. Aguiar-Oliveira MH, Bartke A. Growth Hormone Deficiency: Health and Longevity. Endocr Rev 2019 Apr 1;40(2):575–601. 2. Gong Z, Kennedy O, Sun H, Wu Y, Williams GA, Klein L, Cardoso L, Matheny RW Jr, Hubbard GB, Ikeno Y, et al. Reductions in serum IGF-1 during aging impair health span. Aging Cell. 2014;13:408–418. 3. Moellendorf S, Kessels C, Peiseler L, Raupach A, Jacoby C, Vogt N, Lindecke A, Koch L, Brüning J, Heger J, et al. IGF-IR signaling attenuates the age-related decline of diastolic cardiac function. Am J Physiol Endocrinol Metab. 2012;303:E213–E222.

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