Growth hormone and aging cardiomyocytes.

Authors

Eckhard U Alt, Reza Izadpanah

Published in

Cardiovascular research. Oct 07, 2026. Epub Oct 07, 2026.

Abstract

The age-related decline in growth hormone (GH) secretion, termed the somatopause, parallels the structural and functional deterioration of the aging heart. How this endocrine withdrawal translates into myocardial failure at the molecular level remains incompletely mapped. GH/insulin-like growth factor 1 (IGF-1) signaling acts via PI3K/Akt/mTOR and Ras/MAPK/c-Myc cascades on four processes central to cardiac aging: Akt-dependent nuclear retention of telomerase reverse transcriptase (TERT), established primarily in non-cardiomyocyte models; PGC-1α-driven mitochondrial biogenesis; suppression of the p53/p16INK4a senescence program; and metabolic-epigenetic regulation of cell-cycle competence via α-ketoglutarate/KDM5 and JMJD3 chromatin gating. In mouse cardiomyocytes, positive transcription elongation factor b (P-TEFb) is rate-limiting for Myc-driven proliferation, plausibly explaining why adult cardiomyocytes retain latent cell-cycle machinery yet rarely divide. A candidate GHRHR-HIF-1α axis, presently supported by preprint evidence, is examined as an emerging hypothesis for cell-type-selective cardioprotection independent of systemic GH. We integrate these strands along a single tractable axis: IGF-1/Akt/TERT/p53/PGC-1α with metabolic-epigenetic modulation. The 2025 Marra trial (NCT03775993; 64 randomized, 45 completers; surrogate and functional endpoints not powered for clinical events) reports that physiological GH restoration improves peak VO2 (+3.1 vs -1.8 mL/kg/min, P<0.01), NYHA class, and quality of life in heart failure with confirmed GH deficiency. A meta-analysis of 25 studies quantifies the U-shaped IGF-1-heart failure relationship, with the HF-versus-control IGF-1 difference derived from six of those studies. Plasma proteomic organ-aging signatures show accelerated cardiac aging is associated with 2.5-fold heart-failure risk. We present a hypothesis-generating framework identifying GH/IGF-1 axis restoration as a candidate determinant of heart-failure progression, warranting event-driven confirmation.

PMID:
42839539
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.

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