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Circulation Research. 2007;100:1512-1521
Published online before print April 19, 2007, doi: 10.1161/01.RES.0000267723.65696.4a
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(Circulation Research. 2007;100:1512.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart

Ralph R. Alcendor, Shumin Gao, Peiyong Zhai, Daniela Zablocki, Eric Holle, Xianzhong Yu, Bin Tian, Thomas Wagner, Stephen F. Vatner, Junichi Sadoshima

From the Cardiovascular Research Institute (R.R.A., S.G., P.Z., D.Z., S.F.V., J.S.), Department of Cell Biology and Molecular Medicine; Department of Biochemistry and Molecular Biology (B.T.), University of Medicine & Dentistry of New Jersey, New Jersey Medical School, Newark; and Oncology Research Institute (E.H., X.Y., T.W.), Greenville, SC.

Correspondence to Junichi Sadoshima, MD PhD, Cardiovascular Research Institute, UMDNJ, 185 S Orange Ave, MSB G609, Newark, NJ 07103. E-mail sadoshju{at}umdnj.edu


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
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.


Key Words: Sirt1 • aging • longevity factor • oxidative stress


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Extrinsic and intrinsic factors cooperate in determining the rate of aging and the aging phenotype. Because aging reduces the function of organs and increases the risk of diseases, elucidating the mechanisms controlling aging has significant clinical implications.1 Increasing lines of evidence suggest that evolutionarily conserved molecular mechanisms are involved in the regulation of lifespan in animals.2 For example, caloric restriction prolongs the lifespan of organisms, from yeast to primates,3 possibly through silent information regulator 2 (Sir2)-dependent mechanisms.4,5 Genetic alterations causing metabolic effects similar to caloric restriction, including mutation/deletion of Cyr1/Sch9, also cause lifespan extension in yeast.6–8 Similarly, inhibition of insulin-like growth factor (IGF)-I signaling, including Daf-2 mutation in Caenorhabditis elegans, causes lifespan extension9 mediated by a loss of suppression of Daf-16 or forkhead box O (FoxO) transcription factors, which regulate antioxidant expression and DNA damage repair (GADD45).7,10,11 In mammals, Ames and Snell dwarf mice lacking GH/IGF-I signaling and IGF-I receptor heterozygous knockout mice have longer lifespans,12 and systemic overexpression of klotho, a hormone known to inhibit insulin/IGF-I signaling, extends lifespan in mice.13 Another important mechanism controlling aging is oxidative stress.1 Overexpression of antioxidant molecules, including mitochondrial catalase and thioredoxin,14,15 induces lifespan extension. Mice deficient in either mclk1 or p66shc, both of which are involved in mitochondrial electron transfer, have longer lifespans.16,17 Importantly, these longevity factors also confer stress resistance to the organism,18 the accumulation of which leads to longer lifespan.

Yeast Sir2, an NAD+-dependent protein deacetylase and a founding member of the sirtuin family,19 functions in a wide array of cellular processes, including gene silencing, longevity, muscle differentiation, and DNA damage repair (reviewed elsewhere20). Stimulation of Sir2 by overexpression or sirtuin-activating compounds, such as resveratrol, is sufficient to induce prolonged lifespan in yeast, Caenorhabditis elegans, Drosophila melanogaster,21,22 and mice.23 Sirt1, a mammalian ortholog of Sir2, provides protection against apoptosis and plays an essential role in mediating survival of cardiac myocytes and neurons under stress in vitro.24–26 Sirt1-deficient mice rarely survive postnatally and exhibit developmental abnormalities in several organs, including the heart.27,28 Pancreatic ß-cell–specific overexpression of Sirt1 enhances ATP production, thereby enhancing insulin secretion in response to glucose in transgenic mice, suggesting that Sirt1 potentially improves glucose metabolism.29 Judging from the generally cell-protective function of Sir2 in model organisms, Sirt1 may prevent aging and play a protective role in mammalian cells in vivo. Importantly, however, it remains to be shown, without relying on pharmacological interventions, that specific activation of Sirt1 confers antiaging and stress-resistance benefits to mammalian cells in vivo. In fact, recent evidence suggests that nonreplicating yeast cells without Sir2 exhibit greater stress resistance in extremely long-lived yeast mutants,30 suggesting that Sir2 could make cells more prone to stress under some conditions. Furthermore, overexpression of the Sir2 family proteins does not extend replicative lifespan in normal human fibroblasts or prostate epithelial cells31 but rather promotes replicative senescence in response to chronic cellular stress via a p19ARF-dependent mechanism in mouse embryonic fibroblasts.32 These reports suggest that the molecular mechanism mediating lifespan extension in lower organisms may not work as expected in higher organisms. Thus, it is important to examine whether Sir2 is able to retard in vivo aging of mammalian organs, such as the heart, the major component of which is terminally differentiated cardiac myocytes.

To elucidate the in vivo function of Sirt1 in the heart, we have recently generated transgenic mice with cardiac specific overexpression of Sirt1 (Tg-Sirt1). The central hypothesis in this study was that Sirt1 mediates antiaging and cell-protective effects in the heart in vivo.


*    Materials and Methods
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 up arrowAbstract
 up arrowIntroduction
 *Materials and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
For an expanded Materials and Methods section, refer to the online data supplement at http://circres.ahajournals.org. Tg-Sirt1 mice were generated on an FVB background using the {alpha}-myosin heavy chain ({alpha}-MHC) promoter. All experiments involving animals were approved by the Institutional Animal Care and Use Committee at the New Jersey Medical School. ATP content and citrate synthase activity were measured using assay kits from Sigma. DNA microarray analyses were conducted using a GeneChip Mouse Genome 430 2.0 probe array (Affymetrix). Data are reported as mean±SEM. Statistical analyses between groups were done by 1-way ANOVA, and when probability values were significant, differences among group means were evaluated using t test with Bonferroni’s correction. A probability value of <0.05 was considered significant.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 *Results
down arrowDiscussion
 down arrowReferences
 
Sirt1 Is Upregulated in Response to Stress in the Heart
We have shown that expression of Sirt1 is upregulated in the dog heart during heart failure.24 We examined whether Sirt1 is upregulated in response to stresses. In mice, the level of Sirt1 in the heart was significantly upregulated after 2 and 4 weeks of pressure overload (5.5- and 8.8-fold) and by paraquat injection (4.3-fold), which induces oxidative stress33 in the heart (Figure 1A). Expression of Sirt1 in the heart was also significantly greater (2.9-fold) in old (20.8 years) than in young (6.1 years) monkeys (Figure 1B).


Figure 1
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  		Figure 1. The effect of stress (A) and aging (B) on expression of Sirt1 in the heart. Heart homogenates were prepared from mice subjected to transverse aortic constriction (TAC) for 2 or 4 weeks or paraquat (PQ) injection for 2 weeks (A), or from young and old monkeys (B), and subjected to immunoblot analyses with anti-Sirt1 and anti-actin or anti–glyceraldehyde-3-phosphate dehydrogenase (GAPDH) antibodies. Results are representative of 3 to 5 experiments. In the bar graph, expression of Sirt1 normalized by actin without stress (A) or GAPDH (B) in young monkeys was expressed as 1. *P<0.05 vs control.

Basal Characterization of Tg-Sirt1
To examine the function of Sirt1 in the adult heart in vivo and to elucidate the role of Sirt1 upregulation during stress and aging, we generated Tg-Sirt1 using the {alpha}-MHC promoter. We generated 3 lines (lines 39, 40, and 53) of Tg-Sirt1 with different levels of Sirt1 in the heart (2.5-, 7.5-, and 12.5-fold increase more than nontransgenic [NTg] mice, respectively) (Figure 2A). Immunoblot analyses using homogenates from multiple organs confirmed that Sirt1 is overexpressed in a heart-specific manner (Figure 2B). Initial characterization of cardiac phenotype was conducted using mice aged 6 months old. Postmortem analyses showed that Tg-Sirt1 lines 39 and 40 had normal heart size, whereas the Tg-Sirt1 line 53 showed an enlarged left atrium and left ventricle (LV) (Figure 2C). The LV enlargement in line 53 was confirmed by echocardiographic measurement of the LV end-diastolic dimension (LVEDD) (supplemental Table I). Baseline LV weight (LVW)/body weight and LVW/tibial length (LVW/TL) ratios, indices of cardiac hypertrophy, in Tg-Sirt1 lines 39 and 40 were normal, whereas those in the Tg-Sirt1 line 53 were significantly greater than those in NTg (supplemental Table II). There was no significant change in the level of hypertrophy-associated ("fetal type") gene expression in Tg-Sirt1 line 39 or 40. In contrast, expression of ß-MHC, atrial natriuretic factor, and {alpha}-skeletal actin was significantly upregulated, whereas that of {alpha}-MHC was significantly downregulated in Tg-Sirt1 line 53 (Figure 2D). These results indicate that high levels of Sirt1 overexpression induce cardiac hypertrophy in vivo.


Figure 2
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  		Figure 2. Baseline characterization of Tg-Sirt1 mice at 6 months of age (lines 39, 40 and 53). A, Representative immunoblots of heart homogenates with anti-Sirt1 and anti-actin antibodies. Note that endogenous Sirt1 in NTg mice was easily detected after longer exposure of the x-ray film. B, Tissue homogenates were prepared from multiple organs in Tg-Sirt1. Immunoblots with anti-Sirt1 and anti-GAPDH are shown. Sk muscle indicates skeletal muscle; LV, left ventricle. C, Gross morphology of the hearts. D, mRNA expression of ß-MHC, atrial natriuretic factor (ANF) {alpha}-MHC, and {alpha}-skeletal actin (ASA). Expression of fetal type gene normalized by that of GAPDH in NTg was expressed as 1. Each column represents the mean from 5 mice.

To assess whether increased expression of Sirt1 alters baseline cardiac function, we performed echocardiographic analyses. Cardiac chamber size and cardiac function were normal in Tg-Sirt1 lines 39 and 40 (supplemental Table I). In Tg-Sirt1 line 53, however, the LV was significantly dilated and both LV ejection fraction (LVEF) and percentage fractional shortening were significantly reduced compared with those in NTg. Hemodynamic measurements indicated that LV end-diastolic pressure was significantly elevated, whereas the rates of contraction (dP/dt) and relaxation (–dP/dt) were significantly reduced in Tg-Sirt1 line 53 (supplemental Table III). The lung weight/body weight ratio was normal in Tg-Sirt1 lines 39 and 40, but significantly elevated, suggesting lung congestion, in line 53 (supplemental Table II). These results suggest that 2.5- to 7.5-fold overexpression of Sirt1 does not affect baseline cardiac chamber size or cardiac function, whereas 12.5-fold overexpression of Sirt1 induces LV chamber dilation, hypertrophy, and dysfunction, thereby mimicking cardiomyopathy.

Histological analyses of LV myocardial sections indicated that there was no significant fibrosis in Tg-Sirt1 line 39 or 40 at 6 months of age (Figure 3A and 3B). Tg-Sirt1 line 53 mice, however, showed a significantly increased level of LV fibrosis compared with NTg (Figure 3A and 3B). TUNEL analyses at 6 months of age showed that the frequency of TUNEL-positive nuclei was significantly lower in Tg-Sirt1 lines 39 and 40, whereas it was significantly elevated in Tg-Sirt1 line 53, compared with NTg, suggesting that myocardial apoptosis is suppressed by mild to modest overexpression of Sirt1 but is enhanced by a high level of Sirt1 overexpression (Figure 3C).


Figure 3
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  		Figure 3. Basal histological findings in Tg-Sirt1 mouse hearts at 6 months of age. A, Hematoxylin/eosin staining. B, Picric acid Sirius red (PASR) staining. The bar graph represents the extent of PASR-positive area (n=3 in each group). C, Representative TUNEL staining (top), 2',6'-diamidino-2-phenylindole (DAPI) staining (middle), and merged image (bottom). Percentage of apoptosis was determined by the number of TUNEL-positive myocytes divided by that of DAPI-positive nuclei in 6 separate fields (n=4 to 5).

Mild to Moderate Overexpression of Sirt1 Retards Age-Dependent Changes in the Heart
Because Sirt1 is overexpressed in a heart-specific manner in Tg-Sirt1, overexpression of Sirt1 may not be sufficient to extend the lifespan of the animals. Nonetheless, we followed up the lifespan of Tg-Sirt1 mice for more than 600 days. Kaplan–Meier analysis indicated that there was no significant difference in mortality in line 39 or 40 compared with NTg mice. Tg-Sirt1 line 53 mice die significantly earlier than NTg and rarely survived more than 250 days (Figure I in the online data supplement).

Increases in hypertrophy, interstitial fibrosis, and apoptosis are commonly observed as age-dependent changes in the heart.34–36 To examine whether Sirt1 overexpression affects the progression of aging in the heart, we conducted histopathological analyses by using all 3 lines of Tg-Sirt1 at mean ages of 2 to 3, 6 to 7, and 18 months. Cardiac myocyte size and LVW/TL in Tg-Sirt1 line 53 were significantly greater than those in NTg at 2 to 3 months, and both parameters in line 53 were even greater at 6 to 7 months. Tg-Sirt1 lines 39 and 40 showed smaller increases in cell size and LVW/TL by age, and their cell size at 18 months was significantly smaller than that of NTg (Figure 4A and supplemental Figure II). Similar results were obtained regarding age-dependent increases in fibrosis and myocyte apoptosis (Figure 4B and 4C and supplemental Figure II). The same trend was also observed in age-dependent decreases in cardiac function. LVEDD and LV end systolic dimension (LVESD) in Tg-Sirt1 line 53 were significantly greater than those in NTg at 6 to 7 months. LVEDD and LVESD in NTg were greater at 18 months than at 2 to 3 and 6 to 7 months, whereas LVEDD and LVESD in Tg-Sirt1 lines 39 and 40 were significantly smaller than those in NTg at 18 months (Figure 5A and 5B). Tg-Sirt1 line 53 mice showed significantly lower LVEF and percentage fractional shortening than NTg starting from 2 to 3 months. NTg mice showed significantly lower LVEF and percentage fractional shortening at 18 months than at 2 to 3 and 6 to 7 months, whereas lines 39 and 40 mice exhibited significantly greater LVEF and percentage fractional shortening than NTg at 18 months (Figure 5C and 5D). Taken together, although high levels of Sirt1 expression stimulate the development of cardiomyopathy, mild to moderate expression of Sirt1 retards aging-induced histological changes and LV dysfunction in the heart.


Figure 4
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  		Figure 4. LV myocardial sections were obtained from NTg and Tg-Sirt1 (lines 39, 40, and 53) at mean ages of 2 to 3, 6 to 7, and 18 months old. A, Cardiac myocyte cross sectional areas (n=5 in each group). B, The extent of interstitial fibrosis determined by PASR-positive area (n=5 in each group). C, Percentage of apoptosis as determined by the number of TUNEL-positive myocytes divided by the number of DAPI-positive nuclei in 6 separate fields (n=9 in each group). In each graph, the mean value of NTg at 2 to 3 months old was expressed as 1.


Figure 5
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  		Figure 5. Echocardiographic measurements were conducted in NTg and Tg-Sirt1 (lines 39, 40 and 53) at mean ages of 2 to 3, 6 to 7, and 18 months old. A, LVEDD. B, LVESD. C, LVEF. D, Percentage fractional shortening (%FS); n=9 in each group.

Moderate Overexpression of Sirt1 Stimulates Cell-Protective Molecules and Inhibits Expression of Aging Markers
Expression of the INK4/ARF family proteins, inducers of cellular senescence, increases with advancing age in many organs in rodents, including the heart.37 Protein levels of p15INK4b and p19ARF were significantly lower in Tg-Sirt1 lines 39 and 40, but not in line 53, than in NTg at 2 to 3 and 8 to 12 months of age (Figure 6A and 6B). A similar result was obtained regarding expression of p53, another regulator of senescence (Figure 6C). Expression of Bcl-2 and Bcl-xL, both antiapoptotic molecules, was elevated in Tg-Sirt1 lines 39, 40, and 53, with the greatest expression found in line 40 (Figure 6D and data not shown).


Figure 6
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  		Figure 6. Expression of aging markers and cell-protective molecules. A through C, Expression levels of senescence markers, including p15 (A), p19 (B), and p53 (C) in Tg-Sirt1 and NTg hearts (n=4 to 6). D, Expression of Bcl-2 at 2 to 3 months old (n=5). In each graph, the mean value of NTg at 2 to 3 months old was expressed as 1.

To identify potential targets of Sirt1 that might mediate its antiaging effects, DNA microarray analyses were conducted. (The data have been deposited in the Gene Expression Omnibus [GEO] database, www.ncbi.nlm.nih.gov/geo; accession no. GSE7407.) Preliminary results indicated that some cell-protective molecules and potential regulators of aging are upregulated in Tg-Sirt1 line 40 mice. These include heat shock protein (Hsp)40, Hsp70, Hsp90, telomere reverse transcriptase, telomere repeat binding factor2, Klotho, and Werner syndrome protein (supplemental Figure III).

Tg-Sirt1 Line 53 Mice Have Lower Cardiac ATP Content
Because Tg-Sirt1 line 53 exhibited reduced cardiac function at baseline, we examined potential mechanisms. Although the cardiac ATP content in Tg-Sirt1 line 40 was not significantly different from NTg, Tg-Sirt1 line 53 exhibited significantly lower cardiac ATP content than NTg at 2 to 3 months of age (Figure 7A). The ratio of phospho–5'-AMP-activated protein kinase (AMPK)/total AMPK was significantly elevated in Tg-Sirt1 line 53, but not in line 40, compared with NTg (Figure 7A), consistent with the notion that heart cells are under energy starvation in Tg-Sirt1 line 53. Tg-Sirt1 line 40 exhibited significantly higher, whereas line 53 showed significantly lower, citrate synthase activity than NTg, suggesting that mitochondrial function is depressed by high levels of Sirt1 (Figure 7B). Electron microscopic analyses indicated that the number of mitochondria is significantly smaller in Tg-Sirt1 line 53 than in NTg mice (Figure 7C), suggesting that mitochondrial biogenesis is reduced in Tg-Sirt1 line 53. Peroxisome proliferator-activated receptor {gamma} coactivator (PGC)-1{alpha} is a transcriptional cofactor that plays an important role in mediating mitochondrial biogenesis. Interestingly, mRNA expression of PGC-1{alpha} was dose-dependently reduced by Sirt1 overexpression, where Tg-Sirt1 line 53 mice exhibited {approx}50% reduction in PGC-1{alpha} expression in the heart (Figure 7D).


Figure 7
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  		Figure 7. All experiments were conducted using NTg and Tg-Sirt1 at 2 to 3 months of age. A (left), Relative cardiac ATP content in lines 40 and 53 mice (n=4 to 5). A (right), Immunoblot analyses of phospho-AMPK/total AMPK (n=6). B, Relative citrate synthase activity in the hearts from lines 40 and 53 (n=4 to 5). C, Electron microscopic analyses of cardiac mitochondria in line 53 mice (n=3 each). The number of mitochondria was determined from 8 sections. D, mRNA expression of PGC-1{alpha} in line 39, 40, and 53 mouse hearts (n=4). In each graph, the mean value of NTg was expressed as 1.

Tg-Sirt1 Mice Are Protected Against Oxidative Stress
Because Tg-Sirt1 line 40 exhibited reduced levels of baseline apoptosis and aging markers, we further examined whether modest overexpression of Sirt1 is protective against stress. To this end, we treated mice with paraquat33 for 14 days. Paraquat treatment significantly reduced LV contraction in NTg controls but not in Tg-Sirt1 line 40 (supplemental Table IV and Figure IV). Furthermore, the extent of cardiac myocyte apoptosis after paraquat treatment was significantly greater in NTg than in Tg-Sirt1 (Figure 8A). Paraquat treatment significantly increased the extent of oxidative stress in NTg mouse hearts as determined by 8-hydroxy-deoxyguanosine (8-OHdG) staining and malondialdehyde content, established markers of oxidative stress. However, the paraquat-induced increases in oxidative stress were abolished in Tg-Sirt1 line 40 (Figure 8B). These results suggest that increased oxidative stress and myocardial damage induced by paraquat were significantly attenuated by moderate Sirt1 overexpression. In addition, paraquat-induced increases in expression of catalase, an antioxidant, were greater in Tg-Sirt1 line 40 than in NTg hearts (Figure 8C). On the other hand, the tissue level of oxidative stress was significantly enhanced in Tg-Sirt1 line 53, even at baseline (Figure 8D), suggesting that high levels of Sirt1 overexpression rather enhance oxidative stress.


Figure 8
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  		Figure 8. Tg-Sirt1 and NTg mice from line 40 were treated with intraperitoneal injection of 10 mg/kg of paraquat (PQ) for 2 weeks. A, Representative TUNEL staining (left panels), DAPI staining (middle panels), and merged (right panels) images. Percentage of apoptosis as determined by the number of TUNEL-positive myocytes divided by the number of DAPI-positive nuclei in 6 separate fields (n=4 to 5). B, 8-OHdG staining of heart sections from Tg-Sirt1 line 40 mice, with or without PQ treatment. Similar results were obtained from 4 other pairs. Malondialdehyde (MDA) content in untreated and PQ-treated hearts (n=5). C, Relative protein expression of catalase and actin in Tg-Sirt1 and NTg hearts after PQ treatment (n=5). D, 8-OHdG staining of heart sections in line 53 at baseline. The results are representative of 4 hearts. Cont indicates control.

We examined the mechanism by which Sirt1 upregulates catalase by using cultured cardiac myocytes. In particular, we examined the role of FoxO in mediating the catalase upregulation, because Sirt1 stimulates resistance to oxidative stress through FoxO in fibroblasts.38 Overexpression of either Sirt1 or constitutively active FoxO1a in cultured cardiac myocytes stimulated expression of catalase, whereas upregulation of catalase was inhibited in the presence of dominant negative FoxO1a (supplemental Figure V). These results suggest that FoxO1a plays an important role in mediating Sirt1-induced upregulation of catalase, which may in part mediate suppression of myocardial damage caused by oxidative stress in Tg-Sirt1 line 40.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
Aging hearts exhibit unique histological and biochemical features.35,36 Increases in apoptosis and necrosis, proliferation of myocyte nuclei, increased myocyte volume, and connective tissue accumulation are frequently observed in the myocardium of old animals.34 Aging also affects the level of expression of INK4/ARF family senescence factors.37 Induction of cell-protective mechanisms, such as antioxidants and heat shock proteins, in response to pathologic insults is attenuated in aging hearts.39 As a result, aging cardiac myocytes cannot be transcriptionally reprogrammed in response to increased workload.36,39 Optimal therapeutic interventions to antagonize aging should prevent cell death and accumulation of senescent myocytes,36 eventually leading to decreases in the occurrence of adult heart diseases.

Although mechanisms inducing extension of lifespan may slow down aging of the whole organism, whether or not each longevity factor can prevent the aging process of organs and cells in mammals remains to be tested. Heart-specific expression of a molecule known to induce lifespan extension (dPTEN or dFoxO) prevents the age-dependent decline of the heart function in Drosophila,40 indicating that the longevity factors may function autonomously to prevent aging of individual organs. Overexpression of catalase targeted to mitochondria retarded aging-induced cardiac damage in mice.15 Our results suggest that Sirt1 prevents aging of the heart when 2.5- to 7.5-fold overexpressed in the heart. Although these results are consistent with the notion that stimulation of a longevity mechanism could prevent aging of the heart, more studies are needed to determine whether this is the property of the longevity mechanism in general or merely a molecule-specific effect. For example, considering the apparent cardioprotective effects of the IGF-I–Akt axis, at in the least short term,41 whether or not inhibiting IGF-I signaling, which extends the lifespan of mice,12,13 prevents aging and aging-related diseases in the mammalian heart without impairing cardiac function remains to be tested. IGF-I may produce only a tradeoff between current benefits and later costs in senescence, like the relationship between inotropic agents and their exacerbation of heart failure long term.42 We have shown that cardiac specific overexpression of mammalian sterile 20 like kinase1 (Mst1) in transgenic mice induces dilated cardiomyopathy.43 Interestingly, a homolog of Mst1 induces lifespan extension in Caenorhabditis elegans through phosphorylation/activation of DAF-16.44 Although this example may represent a difference in the mechanism mediating longevity/stress resistance between lower organisms and mammals, careful reevaluation of the effect of longevity factors on aging/stress resistance of the heart, with particular emphasis on dosages and its long-term effects, seems essential. The antiaging and stress-resistance effects of Sirt1 could be mediated not only by well-established mechanisms of longevity, such as FoxO family transcription factors, but also by nonspecific upregulation of cytoprotective pathways. Further investigation is required to identify downstream targets of Sirt1 in cardiac myocytes.

Treatment with mice on a high-calorie diet with resveratrol improves health and survival, which is assumed to be mediated by stimulation of Sirt1.23 Whether or not stimulation of Sirt1 is sufficient to extend the lifespan of mammals remains to be tested. Our results suggest that heart-specific overexpression is not sufficient to induce lifespan extension in mice.

Sir2 increases replicative lifespan, but actually inhibits chronological lifespan under extreme stresses in yeast.30 Increasing lines of evidence suggest that the heart may be a regenerative organ whose aging could be defined by the capacity for self-renewal in cardiac stem cells.45 In this regard, Sirt1 may protect the heart from aging even if it selectively affects the replicative lifespan of mammalian cells.

Importantly, a very high level of Sirt1 is not protective for the heart. Tg-Sirt1 line 53, with 12.5-fold overexpression of Sirt1, spontaneously developed heart failure, accompanied by hypertrophy, increases in apoptosis and fibrosis, and oxidative stress. ATP content, citrate synthase activity, and mitochondrial biogenesis were all reduced in line 53, suggesting that high levels of Sirt1 induce mitochondrial dysfunction, which may in turn cause increases in oxidative stress. Interestingly, Sirt1 significantly reduced protein expression of PGC-1{alpha}, a master regulator of mitochondrial biogenesis and fatty acid oxidation. Downregulation of PGC-1{alpha} could be the result rather than the cause of heart failure. Thus, the causative role of PGC-1{alpha} downregulation in mediating mitochondrial dysfunction in Tg-Sirt1 line 53 mice remains to be elucidated. High levels of Sirt1 may also consume NAD+, thereby causing depletion of NAD+.46 Such dose-dependent adverse effects have been documented in poly ADP-ribose polymerase-1 (PARP-1), another NAD+-dependent enzyme implicated in DNA repair, where high doses of PARP-1 could lead to NAD+ depletion.47 Because NAD+ is required for mitochondrial respiration, depletion of NAD+ could lead to deficiency in ATP and, consequently, cellular dysfunction and eventual cell death.26

Expression of Sirt1 is upregulated 3- to 9-fold in response to stresses24,48 (see also Figure 1). Similarly, Sirt1 was upregulated 2.9-fold in old monkey hearts. Such modest upregulation of Sirt1 is likely to be a compensatory mechanism and is expected to retard aging and inhibit apoptosis without causing mitochondrial dysfunction or NAD+ depletion. It would be important to keep the extent of Sirt1 overexpression modest, however, if upregulation of Sirt1 is to be considered as a therapeutic option.

Resistance to intrinsic and extrinsic stressors is strongly correlated with lifespan in many species.49 This positive correlation between stress resistance and longevity is also observed in mice with genetic mutations,12,17 as well as in animals pretreated with sublethal doses of stress, a phenomenon known as hormesis.49 According to the hormesis hypothesis, the longevity factors could be upregulated in response to a low grade of stress and confer stress resistance to the organism.49 Expression of Sirt1 was upregulated in failing hearts24 as well as in animals subjected to caloric restriction.48 Here we demonstrated that Tg-Sirt1 exhibited resistance to oxidative stress. We have previously shown that expression of thioredoxin 1, an antioxidant, is upregulated in response to pressure overload and acts as an antihypertrophic factor, as well as a stimulator of mitochondrial function.50 Thioredoxin1 is among the few antioxidants that prolong the lifespan of mice when overexpressed systemically.14 This raises a possibility that stimulation of the known longevity mechanisms could be a new modality of heart failure treatment, by increasing resistance of the heart to pathologic insults.

In summary, 2.5- to 7.5-fold overexpression of Sirt1 has antiaging and stress-resistance effects, whereas higher levels of Sirt1 induces cardiomyopathy, possibly through induction of mitochondrial dysfunction in the heart in vivo. Although stimulation of Sirt1 may be considered as an antiaging therapy for the heart, careful evaluation regarding the dosage seems essential to best use the therapeutic potential of Sirt1.


*    Acknowledgments
 
Sources of Funding

This work was supported by US Public Health Service grants HL 59139, HL67724, HL69020, AG023039, and AG28787 and by American Heart Association Grant 0340123N.

Disclosures

None.


*    Footnotes
 
Original received October 31, 2006; resubmission received March 8, 2007; revised resubmission received April 4, 2007; accepted April 10, 2007.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

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