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

Mahmoud Abdellatif, Viktoria Trummer-Herbst, Alexander Martin Heberle, Alina Humnig, Tobias Pendl, Sylvère Durand, Giulia Cerrato, Sebastian J. Hofer, Moydul Islam, Julia Voglhuber, José Miguel Ramos Pittol, Oliver Kepp, Gerald Hoefler, Albrecht Schmidt, Peter P. Rainer, Daniel Scherr, Dirk Von Lewinski, Egbert Bisping, Julie R. McMullen, Abhinav DiwanTobias Eisenberg, Frank Madeo, Kathrin Thedieck, Guido Kroemer, Simon Sedej

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1853-1866
Number of pages14
JournalCirculation
Volume145
Issue number25
DOIs
StatePublished - Jun 21 2022

Keywords

  • aging
  • autophagy
  • cardiomyopathies
  • insulin-like growth factor 1
  • mitochondria
  • mouse
  • phosphatidylinositol 3-kinases

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