Abstract 40: Investigation into Heart Aging

Abstract

Background: Aging is a well-known contributing factor for heart failure, which is the leading cause of death world-wide. However, the underlying mechanisms of heart aging are less clear. Methods and Results: We found that the overall heart size, heart weight, and cardiomyocyte size were increased in aged mice (24 months). Cardiac fibrosis was also found in old mice. Therefore, aging induced cardiac hypertrophy and remodeling. Concomitantly, heart function declined significantly in aged mice, as evidenced by decreases in fraction shorting, ejection fraction, left ventricular stroke volume, and cardiac output. Renal and circulating Klotho levels were dramatically decreased, suggesting that there may be association between a decrease in Klotho and heart failure in aged mice. Using Klotho mutant homozygous (KL-/-) mice, we found that Klotho deficiency caused cardiac hypertrophy and heart failure. Interestingly, treatment with secreted Klotho prevented cardiac hypertrophy, remodeling and heart failure in aged mice and KL (-/-) mice. Secreted Klotho treatment attenuated excessive cardiac oxidative stress and apoptosis in old mice and KL (-/-) mice. In this study, all KL (-/-) mice were fed with low-phosphate diet which maintained serum phosphate at the normal level, suggesting that the cardioprotective effects of secreted Klotho were independent of phosphate metabolism. Mechanistically, Klotho deficiency suppressed glutathione reductase (GR) expression and activity in the heart through downregulation of a transcription factor Nrf2. Furthermore, heart-specific overexpression of GR prevented aging- and Klotho deficiency-induced heart failure, excessive cardiac oxidative stress and apoptosis in old mice and KL (-/-) mice. Conclusions: Klotho deficiency plays an important role in aging-related heart failure. Secreted Klotho protects against heart aging via activation of glutathione reductase which attenuates cardiac oxidative stress, apoptosis and fibrosis.