Abstract
Chronic caloric restriction (CR) and rapamycin inhibit the mechanistic target of rapamycin (mTOR) signaling, thereby regulating metabolism and suppressing protein synthesis. Caloric restriction or rapamycin extends murine lifespan and ameliorates many aging-associated disorders; however, the beneficial effects of shorter treatment on cardiac aging are not as well understood. Using a recently developed deuterated-leucine labeling method, we investigated the effect of short-term (10 weeks) CR or rapamycin on the proteomics turnover and remodeling of the aging mouse heart. Functionally, we observed that short-term CR and rapamycin both reversed the pre-existing age-dependent cardiac hypertrophy and diastolic dysfunction. There was no significant change in the cardiac global proteome (823 proteins) turnover with age, with a median half-life 9.1 days in the 5-month-old hearts and 8.8 days in the 27-month-old hearts. However, proteome half-lives of old hearts significantly increased after short-term CR (30%) or rapamycin (12%). This was accompanied by attenuation of age-dependent protein oxidative damage and ubiquitination. Quantitative proteomics and pathway analysis revealed an age-dependent decreased abundance of proteins involved in mitochondrial function, electron transport chain, citric acid cycle, and fatty acid metabolism as well as increased abundance of proteins involved in glycolysis and oxidative stress response. This age-dependent cardiac proteome remodeling was significantly reversed by short-term CR or rapamycin, demonstrating a concordance with the beneficial effect on cardiac physiology. The metabolic shift induced by rapamycin was confirmed by metabolomic analysis.
Highlights
Caloric restriction (CR) extends lifespan in a wide variety of organisms ranging from yeast to mice and may attenuate several age-relatedAccepted for publication 5 January 2014 diseases including diabetes, cancer, and neurodegenerative disease (Weindruch et al, 1986; Speakman & Mitchell, 2011)
Several nutrient sensing pathways have been implicated in the beneficial effect of caloric restriction on aging process (Kenyon, 2010); interest in the mechanistic target of rapamycin (TOR) has increased following the demonstration that long-term rapamycin (RP) treatment, initiated at 9 or 18 months of age, extends lifespan in murine models (Harrison et al, 2009; Miller et al, 2011)
The mechanisms by which TOR exerts its effects on aging involve the modulation of protein synthesis (Steffen et al, 2008), ribosomal biogenesis, and autophagy through Mechanistic target of rapamycin (mTOR) complex 1 and downstream targets ribosomal S6 kinase (S6K) and the translational repressor 4E-BP1 (Guertin & Sabatini, 2007; Sengupta et al, 2010)
Summary
Caloric restriction (CR) extends lifespan in a wide variety of organisms ranging from yeast to mice and may attenuate several age-relatedAccepted for publication 5 January 2014 diseases including diabetes, cancer, and neurodegenerative disease (Weindruch et al, 1986; Speakman & Mitchell, 2011). Long-term caloric restriction has been shown to ameliorate age-associated cardiac hypertrophy and diastolic dysfunction (Taffet et al, 1997; Niemann et al, 2010; Shinmura et al, 2011) as well as cardiomyopathy in rodents and in monkeys (Maeda et al, 1985; Colman et al, 2009). Several nutrient sensing pathways have been implicated in the beneficial effect of caloric restriction on aging process (Kenyon, 2010); interest in the mechanistic target of rapamycin (TOR) has increased following the demonstration that long-term rapamycin (RP) treatment, initiated at 9 or 18 months of age, extends lifespan in murine models (Harrison et al, 2009; Miller et al, 2011). 4E-BP has been shown to act downstream of TOR to modulate cardiac functional aging in Drosophila (Wessells et al, 2009)
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