Altered proteome turnover and remodeling by short‐term caloric restriction or rapamycin rejuvenate the aging heart

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.

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

“…The specific targets of histone deacetylases that are altered in skeletal muscle during aging are not known. In some tissues, there are few changes in the total proteome during aging (Walther & Mann, 2010; Dai et al ., 2014). Thus, post‐translational modifications are one of the major modes of regulation that might contribute to reduced function during aging.…”

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

“…We conclude that aging does not result in a generalized increase in mTOR signaling in C57BL/6J.Nia mice, a strain in which dietary rapamycin significantly extends lifespan and rejuvenates the aging heart (Dai et al ., 2014; Fok et al ., 2014). We do observe age‐associated increases in mTOR signaling in specific tissues of C57BL/6J.Nia mice, and the beneficial effects of rapamycin on longevity in this strain may be due in part to the blunting of age‐associated increases in mTOR signaling in specific tissues such as adipose and HSCs (Chen et al ., 2009).…”

Systems biology approaches to study the molecular effects of caloric restriction and polyphenols on aging processes

“…The benefits of CR on slowing or preventing age-related dysfunctions are the result of its influence on the many systemic effectors previously mentioned as being affected in aging. This is demonstrated by several studies which showed that CR (1) negatively regulates the insulin-like growth factor (IGF-1)/insulin receptor substrate (IRS)/PI3k-Atk pathways, (2) activates SIRT family members, (3) activates AMPK (through decreased ATP/AMP ratio), (4) inhibits the mTOR pathway, (5) improves fatty acid metabolism (via CPT-1 and SREBP-1), (6) decreases the release of ROS and pro-inflammatory compounds and (7) modulates the expression of genes implicated in neuroprotection (Lee et al 2000;Rubinsztein et al 2011;Speakman and Mitchell 2011;Dai et al 2014). …”