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Calorie restriction (CR) is the most widely studied intervention protecting from the adverse effects of aging. Almost all prior studies have examined the effects of CR initiated in young animals. Studies examining the effects of CR on development of aging cardiomyopathy found only partial prevention. The major goal of this study was to determine whether CR initiated after aging cardiomyopathy developed could reverse the cardiomyopathy. Aging cardiomyopathy in 2-year-old mice was characterized by reduced left ventricular (LV) function, cardiac hypertrophy, and increased cardiac apoptosis and fibrosis. When short-term (2 months) CR was initiated after aging cardiomyopathy developed in 20-month-old mice, the decrease in cardiac function, and increases in LV weight, myocardial fibrosis and apoptosis were reversed, such that the aging hearts in these mice were indistinguishable from those of young mice or mice where CR was initiated in young mice. If apoptosis was the mechanism for protecting against aging cardiomyopathy, then total myocyte numbers should have reverted to normal with CR, but did not. However, the alterations in cytoskeletal proteins, which contribute to aging cardiomyopathy, were no longer observed with CR. This is the first study to demonstrate complete prevention of aging cardiomyopathy by CR and, more importantly, that instituting this intervention even later in life can rapidly correct aging cardiomyopathy, which could have important therapeutic implications.

We studied gender-specific changes in aging cardiomyopathy in a primate model, Macaca fascicularis, free of the major human diseases, complicating the interpretation of data specific to aging in humans. Left ventricular (LV) weight/body weight decreased, p<0.05, in old males but did not change in old females. However, despite the decrease in LV weight, mean myocyte cross-sectional area in the old males increased by 51%. This increase in myocyte size was not uniform in old males, i.e., it was manifest in only 20-30% of all the myocytes from old males. In old males there was a 4-fold increase in frequency of myocyte apoptosis without any increase in proliferation-capable myocytes assessed by Ki-67 expression. Apoptosis was unchanged in old female monkey hearts, whereas the frequency of myocytes expressing Ki-67 declined 90%. These results, opposite to findings from rodent studies, indicate distinct differences in which male and female monkeys maintain functional heart mass during aging. The old male hearts demonstrated increased apoptosis, which more than offset the myocyte hypertrophy. Interestingly, the hypertrophy was not uniform and there was no significant increase in myocyte proliferation.