Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart

Abstract

Abstract-Silent information regulator (Sir)2, a class III histone deacetylase, mediates lifespan extension in model organisms and prevents apoptosis in mammalian cells. However, beneficial functions of Sir2 remain to be shown in mammals in vivo at the organ level, such as in the heart. We addressed this issue by using transgenic mice with heart-specific overexpression of Sirt1, a mammalian homolog of Sir2. Sirt1 was significantly upregulated (4-to 8-fold) in response to pressure overload and oxidative stress in nontransgenic adult mouse hearts. Low (2.5-fold) to moderate (7.5-fold) overexpression of Sirt1 in transgenic mouse hearts attenuated age-dependent increases in cardiac hypertrophy, apoptosis/fibrosis, cardiac dysfunction, and expression of senescence markers. In contrast, a high level (12.5-fold) of Sirt1 increased apoptosis and hypertrophy and decreased cardiac function, thereby stimulating the development of cardiomyopathy. Moderate overexpression of Sirt1 protected the heart from oxidative stress induced by paraquat, with increased expression of antioxidants, such as catalase, through forkhead box O (FoxO)-dependent mechanisms, whereas high levels of Sirt1 increased oxidative stress in the heart at baseline. Thus, mild to moderate expression of Sirt1 retards aging of the heart, whereas a high dose of Sirt1 induces cardiomyopathy. Furthermore, although high levels of Sirt1 increase oxidative stress, moderate expression of Sirt1 induces resistance to oxidative stress and apoptosis. These results suggest that Sirt1 could retard aging and confer stress resistance to the heart in vivo, but these beneficial effects can be observed only at low to moderate doses (up to 7.5-fold) of Sirt1. (Circ Res. 2007;100:1512-1521.)

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

“…Silent information regulator T1 (SIRT1) plays an important role in the regulation of aging and longevity in mammals (Alcendor et al., 2007; Satoh et al., 2013; Wang, Chen, Lv & Liu, 2013). There exist cross‐talks between SIRT1‐ and AMP‐activated protein kinase (AMPK)/eNOS, which are involved in the control of the senescence program (Wang, Liang & Vanhoutte, 2011).…”

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…In the heart, a moderate increase in SIRT1 may serve to enhance the tolerance to oxidative stress, as originally reported by Alcendor et al. (2007). On the other hand, SIRT1 activation can inhibit NF‐ κ B signaling either directly by deacetylating the RelA/p65 subunit (Yeung et al.…”

“…2016) changes in free NAD + , (Alcendor et al. 2007) levels of the inhibitor molecule nicotinamide (product inhibition), (Alrob et al. 2014) flux through the nicotinamide salvage pathway, (Anderson et al.…”

Blockade of senescence‐associated micro RNA ‐195 in aged skeletal muscle cells facilitates reprogramming to produce induced pluripotent stem cells.

“…For example, moderate expression of SIRT1 attenuates the age‐dependent incidence of cardiac hypertrophy and dysfunction by inducing cardiac resistance to oxidative stress in mice. However, high levels of SIRT1 have been found to increase heart dysfunction (Alcendor et al ., 2007). In this regard, our previous data showed that depletion of miR‐195 in the heart restored cardiac diastolic function in old mice (Okada et al ., unpublished data) by putative mechanisms that are guided by SIRT1 when expression levels are restored to similar levels as found in young cells.…”