Early cardiac aging linked to impaired stress-resistance and transcriptional control of stress response, quality control and mitochondrial pathways.
Exp Gerontol
; 171: 112011, 2023 Jan.
Article
em En
| MEDLINE
| ID: mdl-36347360
ABSTRACT
Phenotypic and transcriptomic evidence of early cardiac aging, and associated mechanisms, were investigated in young to middle-aged male mice (C57Bl/6; ages 8, 16, 32, 48 wks). Left ventricular gene expression (profiled via Illumina MouseWG-6 BeadChips), contractile and coronary function, and stress-resistance were assessed in Langendorff perfused hearts under normoxic conditions and following ischemic insult (20 min global ischemia-45 min reperfusion; I-R). Baseline or normoxic contractile function was unaltered by age, while cardiac and coronary 'reserves' (during ß-adrenoceptor stimulation; 1 µM isoproterenol) declined by 48 wks. Resistance to I-R injury fell from 16 to 32 wks. Age-dependent transcriptional changes In un-stressed hearts were limited to 104 genes (>1.3-fold; 0.05 FDR), supporting up-regulated innate defenses (glutathione and xenobiotic metabolism, chemotaxis, interleukins) and catecholamine secretion; and down-regulated extracellular matrix (ECM), growth factor and survival (PI3K/Akt) signaling. In stressed (post-ischemic) myocardium, â¼15-times as many genes (1528) were age-dependent, grouped into 6 clusters (>1.3-fold change; 0.05 FDR) most changing from 16 wks (45 % up/44 % down), a further 5 % declining from 32 wks. Major age-dependent Biological Processes in I-R hearts reveal declining ATP metabolism, oxidative phosphorylation, cardiac contraction and morphogenesis, phospholipid metabolism and calcineurin signaling; increasing proteolysis and negative control of MAPK; and mixed changes in nuclear transport and angiogenic genes. Pathway analysis supports reductions in autophagy, stress response, ER protein processing, mRNA surveillance and ribosome/translation genes; with later falls in mitochondrial biogenesis, oxidative phosphorylation and proteasome genes in I-R hearts. Summarizing, early cardiac aging is evident from 16 to 32 wks in male mice, characterized by declining cardiovascular reserve and stress-resistance, transcriptomic evidence of constitutive stress and altered catecholamine and survival/growth signaling in healthy hearts; and declining stress response, quality control, mitochondrial energy metabolism and cardiac modeling processes in stressed hearts. These very early changes, potentially key substrate for advanced aging, may inform approaches to healthy aging and cardioprotection in the adult heart.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenômenos Biológicos
/
Traumatismo por Reperfusão Miocárdica
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Exp Gerontol
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Austrália