Date Published: August 11, 2017
Publisher: John Wiley and Sons Inc.
Author(s): Yunlu Sheng, Shan Lv, Min Huang, Yifan Lv, Jing Yu, Juan Liu, Tingting Tang, Hanmei Qi, Wenjuan Di, Guoxian Ding.
Calorie restriction (CR) increases average and maximum lifespan and exhibits an apparent beneficial impact on age‐related diseases. Several studies have shown that CR initiated either in middle or old age could improve ischemic tolerance and rejuvenate the aging heart; however, the data are not uniform when initiated in young. The accurate time to initiate CR providing maximum benefits for cardiac remodeling and function during aging remains unclear. Thus, whether a similar degree of CR initiated in mice of different ages could exert a similar effect on myocardial protection was investigated in this study. C57BL/6 mice were subjected to a calorically restricted diet (40% less than the ad libitum diet) for 3 months initiated in 3, 12, and 19 months. It was found that CR significantly reversed the aging phenotypes of middle‐aged and old mice including cardiac remodeling (cardiomyocyte hypertrophy and cardiac fibrosis), inflammation, mitochondrial damage, telomere shortening, as well as senescence‐associated markers but accelerated in young mice. Furthermore, whole‐genome microarray demonstrated that the AMP‐activated protein kinase (AMPK)–Forkhead box subgroup ‘O’ (FOXO) pathway might be a major contributor to contrasting regulation by CR initiated in different ages; thus, increased autophagy was seen in middle‐aged and old mice but decreased in young mice. Together, the findings demonstrated promising myocardial protection by 40% CR should be initiated in middle or old age that may have vital implications for the practical nutritional regimen.
CR is defined as a 20–50% reduction in calorie intake than ad libitum (AL) level without malnutrition. Over the last several decades, CR has been known to prolong average and maximum lifespan in a wide variety of organisms (Finkel, 2015). In addition, hitherto, CR is the most successful intervention for delaying aging progression or the development of age‐related chronic diseases (Speakman & Mitchell, 2011). Cardiac aging is a complex pathophysiological process accompanied by a number of biological events including cardiac remodeling and dysfunction (Boengler et al., 2009). Although CR was found to be highly effective in lowering blood pressure, decreasing systemic inflammation, and improving cardiac diastolic parameters (Fontana et al., 2004; Fontana, 2008), almost all previous reports were focused on pathological states such as obesity and myocardial ischemia. Whether the anti‐aging effects of CR also extend to cardiac functions in physiological conditions is currently unknown.
In the present study, we demonstrated age‐related cardiac changes including cardiomyocyte hypertrophy and cardiac fibrosis in 6‐, 15‐, and 22‐month‐old mice, which were in agreement with the previous remodeling of the aged heart (Boyle et al., 2011). CR is currently the only known intervention that significantly prolongs the maximal lifespan and retards the onset of age‐associated diseases. However, prior studies of CR were mostly concentrated in middle‐aged and elderly mice and the pathological states such as postmyocardial infarction models when CR initiated in 2‐ to 9‐month‐old mice (Peart et al., 2012; Dai et al., 2014; Noyan et al., 2015). The most significant finding of our study was that the age‐associated cardiomyocyte hypertrophy and cardiac fibrosis were attenuated by CR in middle‐aged and old mice, whereas both were exacerbated in young healthy mice.
This research study was supported by the grants from the National Natural Science Foundation of China (91649122) to Guoxian Ding, the grants from the National Natural Science Foundation of China (81100236) to Shan Lv, and also by the National Natural Science Foundation of China (81501201), the Natural Science Foundation of Jiangsu Province of China (BK20151032) to Min Huang.
GD, YS, and SL designed the experiments, conducted the study, wrote, and revised the manuscript. Protein assays, RT‐qPCR, and histopathological analysis were performed by YS and SL. Echocardiography and telomere length measurements were performed by MH and TT. Electron microscopy analysis was performed by JL. Microarray analysis was performed by YL, JY, HQ, and WD. GD is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.