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Project: MESI-STRAT2
Published year: 20222
Cardiac PI3K p110alpha attenuation delays aging and extends lifespan.

Abstract (Expand)

Phosphoinositide 3-kinase (PI3K) is a key component of the insulin signaling pathway that controls cellular me-tabolism 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, experi-mental 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 oxida-tive phosphorylation and required increased autophagic flux. In humans, explanted failing hearts showed in-creased PI3K signaling, as indicated by increased phos-phorylation 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.

Authors: M. Abdellatif, T. Eisenberg, A. M. Heberle, K. Thedieck, G. Kroemer, S. Sedej

Date Published: 30th Nov 2022

Publication Type: Journal

Fine-Tuning Cardiac Insulin-Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity.

Abstract (Expand)

BACKGROUND: The insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect of attenuated IGF1 … signaling on cardiac aging remains controversial. METHODS: We performed a lifelong study to assess cardiac health and lifespan in 2 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced IGF1 receptor (IGF1R) signaling. Male mice with human IGF1R overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, and treadmill coupled to indirect calorimetry. In vitro assays included cardiac histology, mitochondrial respiration, ATP synthesis, autophagic flux, and targeted metabolome profiling, and immunoblots of key IGF1R downstream targets in mouse and human explanted failing and nonfailing hearts, as well. RESULTS: Young mice with increased IGF1R signaling exhibited superior cardiac function that progressively declined with aging in an accelerated fashion compared with wild-type animals, resulting in heart failure and a reduced lifespan. In contrast, mice with low cardiac IGF1R signaling exhibited inferior cardiac function early in life, but superior cardiac performance during aging, and increased maximum lifespan, as well. Mechanistically, the late-life detrimental effects of IGF1R activation correlated with suppressed autophagic flux and impaired oxidative phosphorylation in the heart. Low IGF1R activity consistently improved myocardial bioenergetics and function of the aging heart in an autophagy-dependent manner. In humans, failing hearts, but not those with compensated hypertrophy, displayed exaggerated IGF1R expression and signaling activity. CONCLUSIONS: Our findings indicate that the relationship between IGF1R signaling and cardiac health is not linear, but rather biphasic. Hence, pharmacological inhibitors of the IGF1 pathway, albeit unsuitable for young individuals, might be worth considering in older adults.

Authors: M. Abdellatif, V. Trummer-Herbst, A. M. Heberle, A. Humnig, T. Pendl, S. Durand, G. Cerrato, S. J. Hofer, M. Islam, J. Voglhuber, J. M. Ramos Pittol, O. Kepp, G. Hoefler, A. Schmidt, P. P. Rainer, D. Scherr, D. von Lewinski, E. Bisping, J. R. McMullen, A. Diwan, T. Eisenberg, F. Madeo, K. Thedieck, G. Kroemer, S. Sedej

Date Published: 21st Jun 2022

Publication Type: Journal

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