This Article Abstract Full Text (PDF) Services Download to citation manager Citing Articles Citing Articles via HighWire PubMed PubMed Citation

Peroxisome Proliferator-Activated Receptor Coactivator 1 in Caloric Restriction and Other Models of Longevity

¹ United States Environmental Protection Agency, Research Triangle Park, North Carolina.
² Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks.

Address correspondence to J. Christopher Corton, PhD, Division of Environmental Carcinogenesis, NHEERL, US-EPA, MD B105-01, Research Triangle Park, NC 27711. E-mail: corton.chris{at}epa.gov

	Abstract

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

 
Dietary restriction of calories (caloric restriction [CR]) increases longevity in phylogenetically diverse species. CR retards or prevents age-dependent deterioration of tissues and an array of spontaneous and chemically induced diseases associated with obesity including cardiovascular disease, diabetes, and cancer. An understanding of the molecular mechanisms that underlie the beneficial effects of CR will help identify novel dietary, pharmacological, and lifestyle strategies for slowing the rate of aging and preventing these diseases as well as identify factors which modulate chemical toxicity. Here, we review the involvement of transcriptional coactivator proteins, peroxisome proliferator-activated receptor (PPAR) coactivator 1 (PGC-1) and ß, and regulated nuclear receptors (NR) in mediating the phenotypic changes found in models of longevity which include rodent CR models and mouse mutants in which insulin and/or insulin-like growth factor-I signaling is attenuated. PGC-1 is transcriptionally or posttranslationally regulated in mammals by: 1) forkhead box "other" (FoxO) transcription factors through an insulin/insulin-like growth factor-I -dependent pathway, 2) glucagon-stimulated cellular AMP (cAMP) response element binding protein, 3) stress-activated kinase signaling through p38 mitogen-activated protein kinase, and 4) the deacetylase and longevity factor sirtuin 1 (SIRT1). PGC-1 and PGC-1ß regulate the ligand-dependent and -independent activation of a large number of NR including PPAR and constitutive activated receptor (CAR). These NR regulate genes involved in nutrient and xenobiotic transport and metabolism as well as resistance to stress. CR reverses age-dependent decreases in PGC-1, PPAR, and regulated genes. Strategies that target one or multiple PGC-1-regulated NR could be used to mimic the beneficial health effects found in models of longevity.

In animals the development of an efficient energy storage and utilization machinery has allowed survival during times of food shortages through appropriate management of available energy. However, these abilities are ill-suited to the lifestyles of modern society, as evidenced by the fact that obesity has reached epidemic proportions in most industrialized nations. More than 60% of U.S. adults are now overweight or obese, predisposing millions of Americans to chronic diseases including cardiovascular disease (CVD), diabetes mellitus, and certain forms of cancer (5,6). Although high consumption of calorie-rich foods and sedentary lifestyles are considered the major risk factors for the high incidence of obesity, genetic and socioeconomic factors also play a significant role (5).

Laboratory animals fed an ad libitum diet can be considered models for sedentary humans who are at risk for obesity and associated diseases. CR counteracts the trend for laboratory rodents and primates to progressively add body fat during aging. In rodent models, CR decreases the incidence of many diseases associated with obesity (7). Recent studies of CR in rhesus monkeys (8,9) have produced physiological effects that parallel those observed in rodents including reduction of established risk factors for diabetes and CVD. However, the effects of CR on monkey mortality and morbidity require further study. Although there are indications that biomarkers of CR associated with increased longevity are more frequently observed in long-lived humans (10), and there are abundant epidemiological data linking excessive caloric intake to many chronic diseases, evidence is lacking whether CR can retard aging processes in humans (11).

CR has been used to describe a wide variety of protocols but is generally defined as a reduction in the number of calories consumed to a level less than that eaten by ad libitum fed animals without any observable malnutrition. Malnutrition is important to monitor, because it can cause secondary effects predisposing animals to a number of diseases including cancer. Two paradigms have proven effective in increasing life span and disease resistance in rodents. In the more common paradigm, animals are provided a daily food allotment that is typically 30%–40% less than the ad libitum consumption of a control population; this feeding regimen leads to initial decreases and then usually stabilization of body weight. In the second paradigm, used in only a limited number of studies, animals are subjected to fasting every other day (EOD) (e.g., 12–15) or once a week (16,17). EOD fasting results in lower body weights although there is one mouse strain that loses little or no weight (13). Animals on the EOD regimen live longer than do animals on an ad libitum diet (12,13). Animals on either of the fasting protocols share some of the beneficial effects of CR (14–17). It should be noted that many of the phenotypic effects of CR cannot be adequately attributed to the CR itself or to the fasting before killing that some protocols follow.

Recent studies have shed new light on the molecular basis for CR effects. Here, we review the involvement of transcriptional coactivator proteins collectively called peroxisome proliferator-activated receptor (PPAR) coactivator-1 (PGC-1) in the phenotypic effects found in CR as well as other models of longevity. PGC-1 is negatively regulated by a well conserved insulin/insulin-like growth factor (IGF-I)-dependent pathway involved in longevity and stress resistance. We examined the: 1) role of insulin/IGF-I signaling in longevity, 2) regulation of PGC-1 expression and activity by fasting or CR-induced changes in insulin/IGF-I signaling, 3) regulation of nuclear receptor (NR) activity by PGC-1, 4) roles of PGC-1-regulated NR in CR effects, 5) role of PGC-1 in other models of longevity, and 6) reversal of age-dependent decreases in PGC-1 and regulated genes by CR.

	PGC-1 FAMILY MEMBERS INVOLVED IN RESPONSES TO CR

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

 
Animals have evolved highly regulated systems to maintain nutrient levels within tight limits, even during times of food deprivation. Blood glucose levels are determined by glucose uptake in peripheral tissues and the hormonal modulation of glucose production. Glucose production is controlled by both transcriptional and posttranslational mechanisms. During short-term fasting, exercise, or times of stress, glucose is released from glycogen stores by posttranslational activation of glycogenolysis enzymes. When glycogen stores are depleted, metabolic gene expression programs including those involved in gluconeogenesis are activated to maintain appropriate glucose levels. Furthermore, triglycerides are released from fat stores in adipocytes by the action of lipases and are carried to the liver and other organs to be used for fatty acid oxidation.

PGC-1 family members have emerged as central regulators of the adaptive responses to caloric deprivation. The first member of the family to be characterized was PGC-1, a protein that interacts with the NR PPAR, and acts as a master regulator of brown fat differentiation during cold adaptation (18). PGC-1 also carries out essential roles in white fat differentiation, mitochondrial biogenesis, and muscle fiber-type switching (19). PGC-1 and related family member PGC-1ß (also called PGC-1 estrogen receptor coactivator [PERC]) coordinately regulate genes involved in gluconeogenesis and fatty acid ß-oxidation in a number of organs during fasting (19–24). An additional structurally related family member has been preliminarily characterized called PGC-1-related coactivator [PRC; (25)] that may also be involved in mitochondrial biogenesis (26). PGC-1 family members, like other coactivators, modulate transcription by providing bridging interactions between DNA binding transcription factors and the transcriptional machinery in the putative absence of any direct interaction with DNA themselves. Ligand-dependent and -independent activation of NR by PGC-1 family members results in increases in transcription initiation of target genes.

The PGC-1 family members share homology within specific regions of their primary protein sequence relevant to their functions as coactivators (19). Their N termini contain an acidic transcriptional activation domain important for interaction with NR. Within this region are embedded at least three LXXLL motifs (where L is leucine and X is any amino acid) which provide a protein interface in an -helical region essential for interactions between NR and coactivators. The sequences flanking the LXXLL motif provide a role in determining NR selectivity. The C termini of PGC-1 family members contain an RNA-binding domain and an arginine–serine-rich domain, both of which are likely important for interaction with messenger RNA (mRNA) processing complexes (27). These structural domains in the N and C termini have been conserved in rodents and humans (19) suggesting that underlying mechanisms of transcriptional regulation by PGC-1 family members during times of nutritional deprivation may be conserved.

Two mouse lines in which the PGC-1 gene was disrupted have been recently reported (23,24). Both lines exhibit cold intolerance, decreases in hepatocyte respiration rates, and neurological lesions. The lines also possess a number of interesting differences including the level of basal and fasting-induced expression of gluconeogenesis genes, and a fasting-induced hepatic steatotic phenotype which may be due to reductions in fatty acid oxidation rate and activation of triglyceride synthesis. These mice will be useful models for understanding the role of PGC-1 in fasting and CR.

	ROLE OF INSULIN/IGF-I SIGNALING IN LONGEVITY

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

 
Insulin and IGF-I play contributory roles in diseases of aging, whereas CR counteracts their effects. An insulin-regulated pathway is important in determining longevity in diverse species (Figure 1). In mammals, insulin and IGF-I bind to their respective receptors triggering a cascade of events including activation of phosphatidylinositol 3-kinase (PI3K) and serine–threonine protein kinases (Akt-1/Akt-2/protein kinase B [PKB]). In the worm Caenorhabditis elegans, this pathway determines responses to longevity and environmental stress (28). Mutations in C. elegans which inactivate the insulin/IGF-I pathway, including Daf-2, the receptor for insulin/IGF-I or the PI3K ortholog Age-1, result in increased longevity as well as increased thermotolerance and antioxidant defenses. These effects require reversal of negative regulation of the stress resistance factor, Daf-16 (29–33). Daf-16 encodes a transcription factor containing a "winged helix" or "forkhead" DNA binding domain. (These factors are now called forkhead box [Fox] factors.) Overexpression of Daf-16 in worms (33) or an ortholog in flies (34) extends life span. Daf-16 regulates the expression of a large number of genes involved in xenobiotic metabolism and stress resistance, many of which when individually inactivated or overexpressed in C. elegans have incremental effects on longevity (30–32).

View larger version (53K): [in this window] [in a new window]   Figure 1. Regulation of peroxisome proliferator-activated receptor (PPAR) coactivator 1 (PGC-1) by insulin. Insulin and insulin-like growth factor-I (IGF-I) bind to their respective receptors triggering a cascade of events including activation of phosphatidylinositol 3-kinase (PI3K), p66Shc, and serine-threonine protein kinases (Akt-1/Akt-2/protein kinase B [PKB]). Mutations in Caenorhabditis elegans which inactivate the insulin/IGF-I pathway including Daf-2, the receptor for insulin/IGF-I, the PI3K ortholog (Age-1), or Akt result in increased longevity. These effects require reversal of negative regulation of the stress resistance factor, Daf-16. In times of nutrient availability, binding of insulin or insulin-like molecules to their respective receptors leads to activation of PI3K and Akt, inactivation of Daf-16 in C. elegans and forkhead box "other" (FoxOs) in mammals by phosphorylation and subsequent transport of these factors out of the nucleus. FoxOs regulate the activity and expression of the transcriptional coactivator, PGC-1. PGC-1 family members control the activity of a large number of nuclear receptors. FoxO and PGC-1 activity is also negatively regulated by cellular AMP (cAMP) response element binding protein binding protein (CBP), through acetylation during conditions of oxidative stress. The deacetylase sirtuin 1 (SIRT1), positively regulated by FoxO1 and p53, negatively regulates the effects of CBP by deacetylating FoxO family members and PGC-1. FoxO is also phosphorylated by the Jun N-terminal kinase (JNK)-1 under conditions of environmental stress resulting in nuclear localization and activation of PGC-1

IGF-I, like insulin, stimulates PI3K and Akt/PKB and inhibits the function of FoxO1 (45–52), FoxO3, and FoxO4 (53) through phosphorylation and nuclear export (Figure 1). Phosphorylation and inactivation of FoxO factors by IGF-I and insulin probably occur through different mechanisms, as the sites of phosphorylation are not the same (48,54). Although there is presently no evidence that IGF-I regulates PGC-1, IGF-I does inhibit the expression of gluconeogenesis genes (55–57) by a mechanism similar to that of insulin albeit through different membrane receptors (57).

Mutations in mammalian genes which downregulate insulin/IGF-I signaling increase longevity. Genes which determine growth hormone (GH) secretion (Ghrhr, Pit1, Prop1) or signaling (Ghr) are partially or completely inactivated in dwarf mice and result in decreased insulin and IGF-I levels and increased longevity (58,59) (discussed in greater detail below). Mice nullizygous for p66Shc exhibit increased ability to respond to oxidative stress (60) and, along with IGF-I receptor heterozygote mice that lack wild-type activation of p66Shc (61), live longer than do wild-type mice. Adipocyte-specific deletion of the insulin receptor gene also increases longevity (62). In another model of longevity, transgenic mice containing the murine uroplasminogen activator under the control of the A-crystallin gene promoter (MUPA mice) have lower serum IGF-I levels possibly because the mice eat less (63).

CR in rodents also has dramatic effects on insulin signaling. CR uncouples insulin/IGF-I signaling to FoxO factors by markedly reducing plasma IGF-I and insulin levels over the life span of rats (64,65). These decreases in circulating insulin and IGF-I levels are associated with decreased Akt phosphorylation in liver (39), decreased PI3K expression in muscle (66), and increases in the expression of FoxO family members by fasting (37,38) or CR (39,40). In addition, a diet low in the amino acid methionine led to decreases in insulin and IGF-I and increases in life span without altering food intake (67). However, given that the mice lost weight on this diet, further studies are necessary to determine if the diet alters absorption, excretion, and physical activity.

There is evidence that long-lived humans such as centenarians have decreased insulin signaling. In the Baltimore Longitudinal Study of Aging, a decreased insulin level is one predictor of longer life in males (10). Long-lived humans (i.e., >85 years) have lower IGF-I plasma levels, and these levels are affected by polymorphisms in IGF-I receptor and phosphatidyl inositol 3-kinase (PI3K) genes (68). Women with one copy of a variant of the GH gene were 20% less likely to die at any given age than were women with other variants of GH (69). Obesity can lead to insulin resistance, higher circulating levels of insulin/IGF-I, and increased incidence of an array of diseases that may have as their basis uncontrolled insulin signaling (5,70). Overall, the studies reviewed in this section demonstrate that downregulation of insulin/IGF-I signaling results in increases in the activity of Daf-16 and FoxO factors consistently found in diverse models of longevity.

	SIRTUIN 1 AND JUN N-TERMINAL KINASE SIGNALING TO FOXO

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

 
FoxO factors may be a key link to other mechanisms that affect longevity. Like Daf-16 in C. elegans, mammalian FoxO family members carry out functions that determine cell survival during times of stress including regulation of apoptosis, cell-cycle checkpoint control, and oxidative stress resistance (35,71). Activation of FoxO3 or FoxO4 leads to increases in cell-cycle G1 arrest (72,73) and increases in apoptosis (73,74) presumably as a way to eliminate cells damaged by oxidative stress. In addition to negative regulation by insulin signaling, FoxO factors are regulated by the cAMP response element binding protein (CREB) binding protein (CBP) or a related protein called p300. The activity of CBP and p300 can enhance trans-activation of DNA binding transcription factors through histone acetylation and dissolution of chromatin structure which facilitates assembly of transcription complexes on regulated promoters. Overexpression of CBP (75) or p300 (76) enhances the ability of FoxO factors to trans-activate gene expression through this mechanism. However, CBP also exhibits negative effects on FoxO factors through direct acetylation of FoxO proteins (72–76) triggered on exposure of cells to hydrogen peroxide (72,74) or other treatments that induce oxidative stress including ultraviolet light (74) and heat (75).

The sirtuin 1 (SIRT1) protein can reverse the negative regulation of FoxO family members by CBP. SIRT1 is a mammalian SIR2 family member of conserved NAD⁺-dependent deacetylases that have roles in gene silencing, DNA repair, and aging (77,78), and is activated by polyphenolic compounds including resveratrol (found in red wine) which increase longevity in C. elegans and D. melanogaster in a SIR2-dependent manner (79). In D. melanogaster, SIRT2 is also required for CR to increase longevity (80). Like PGC-1, SIRT1 levels are increased during CR in rat liver and are negatively regulated by insulin and IGF-I (81). Additionally, the related family member SIRT3, a mitochondrial protein, exhibited increased expression in white and brown fat upon CR (82). SIRT1 gene expression is under positive control by FoxO3 and p53 (83). Interestingly, SIRT1 at least, partially reverses the acetylation of FoxO1, FoxO3a, and FoxO4 caused by CBP or p300 (72–76). Deacetylation is coincident with direct interactions between SIRT1 and FoxO family members (72–76), enhanced in response to acetylation during oxidative stress (72,73). SIRT1 has divergent effects on FoxO-regulated gene expression including positive regulation of cell-cycle arrest or stress genes p27, GADD45, or MnSOD (72,73,75), and negative regulation of PEPCK involved in gluconeogenesis and the proapoptotic regulator, Bim (74). These important findings provide a logical framework by which CR, through increased expression and activity of SIRT1, can protect cells during oxidative stress by enhancing G1 arrest and decreasing apoptosis, allowing time for FoxO-regulated genes to repair the damage.

FoxOs are regulated by c-Jun N-terminal kinase 1 (JNK-1), which serves as a molecular sensor for various stressors. In C. elegans, JNK-1 directly interacts with and phosphorylates Daf-16 and in response to heat stress, JNK-1 promotes the translocation of Daf-16 into the nucleus. Overexpression of JNK-1 in C. elegans leads to increases in life span and increased survival after heat stress (84). In D. melanogaster, mild activation of JNK leads to increased stress tolerance and longevity (85) dependent on an intact dFoxO (86). JNK-1 activity antagonizes insulin-like signaling to dFoxO leading to nuclear translocation. Expression of activated JNK-1 in insulin-producing cells in the D. melanogaster brain is sufficient for life-span extension (86). Oxidative stress can also induce JNK-1-dependent phosphorylation and nuclear translocation of mammalian FoxO4, even in the presence of serum growth factors which allow for a basal level of PKB activity (87). Thus, when PKB activity is relatively low (as opposed to insulin-stimulated PKB activity), the JNK-1 signaling pathway acts opposite to and dominates PKB. At higher concentrations of hydrogen peroxide following treatment with insulin, PKB activation increases to dominate JNK-1 activity (87). A further understanding of this interplay of signaling will help to determine the relative contribution of PKB and JNK-1 in modulating the ability of FoxO to regulate different sets of cell survival genes under different environmental conditions.

	REGULATION OF PGC-1 GENE EXPRESSION

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

 
PGC-1 is tightly regulated by environmental stimuli and hormones that respond to altered glucose levels. Insulin negatively regulates gluconeogenesis and fatty acid ß-oxidation in mammals through effects on the PGC-1 promoter as well as FoxO interactions with PGC-1 itself (see below). When insulin levels are low, PGC-1 and PGC-1ß genes are induced by fasting in rodents (19,88–90). PGC-1 was also induced in the livers of mice (91) and rats (92) after longer term CR. A 5-day severe CR induced PGC-1 mRNA expression in skeletal muscle of obese but not lean humans (93). A 10-week hypocaloric diet in obese persons resulted in 7 kg loss of weight and increases in PGC-1 in subcutaneous fat (94). In reporter gene assays, insulin as well as ectopic expression of an activated form of Akt suppressed PGC-1 promoter activity. FoxO1 induced PGC-1 expression through insulin-responsive sequences in the PGC-1 promoter (95) (Figure 2). Inhibition of FoxO1 activity by Akt can account for the inhibitory effect of insulin on PGC-1 promoter activity. Consistent with this, inactivation of the insulin receptor in mouse liver increased the expression of PGC-1 (96), and chronic activation of Akt in mouse heart led to decreased expression of PGC-1 (97).

View larger version (34K): [in this window] [in a new window]   Figure 2. Transcriptional regulation of the peroxisome proliferator-activated receptor (PPAR) coactivator (PGC)-1 gene by forkhead box "other" (FoxO), cellular AMP (cAMP) response element binding protein (CREB) and myocyte enhancer factor (MEF) 2. FoxO1 increases the expression of the PGC-1 gene through recognition of insulin response elements (IRS). CREB is positively regulated by protein kinase A (PKA) through increased cAMP levels generated by glucagon stimulation of adenylate cyclase in the liver. CREB is also activated by calmodulin-dependent protein kinase IV (CaMKIV) which is itself activated by increases in calcium. Activated CREB increases the expression of the PGC-1 gene through a cAMP response element (CRE) in the PGC-1 promoter. CaMKIV also activates MEF2 which binds to and activates the PGC-1 promoter at an MEF2 binding element (MBE). Increases in the AMP levels activate AMP protein kinase (AMPK). There is only limited evidence (dashed line) that increases in AMP levels increase PGC-1 levels due to increases in CaMKIV activity (see text). The locations of the transcription factor binding sites are not to scale. The locations of the binding sites in the human PGC-1 promoter are –1308 to –1293 (MEF2), –976 to –970, –586 to –580, and –354 to –348 (IRS1, IRS2, and IRS3, respectively), and –132 to –125 (CRE) (95,99)

Conditions that induce mitochondrial biogenesis also increase PGC-1 promoter activity. Nitric oxide produced by endothelial nitric oxide synthase controls mitochondrial biogenesis possibly through increased expression of PGC-1 as well as other transcription factors. This process is mediated by cyclic guanosine 3',5'-phosphate, resulting from activation of "soluble" guanylate cyclase (98). The mechanisms by which PGC-1 expression is increased by cyclic guanosine 3',5'-phosphate have not been identified. Exercise leads to elevated intracellular calcium levels resulting in the activation of calcium/calmodulin-dependent protein kinase IV (CaMKIV) and calcineurin in skeletal muscle. Activated CaMKIV phosphorylates CREB, which increases transcription at CREB-responsive elements in the PGC-1 promoter. CaMKIV and calcineurin increase the transcriptional activity of myocyte enhancer factor 2 (MEF2), which in combination with another transcription factor, Nuclear Factor of Activated T-cells (NFAT), binds to at least one MEF2 binding site in the PGC-1 promoter (99). Exercise also increases PGC-1 gene expression through p38 mitogen-activated protein kinase (MAPK) pathway in skeletal muscle (100). It is worthwhile to note that long-term CR abrogates the age-dependent decline in skeletal muscle aerobic function by preventing the decline of mitochondrial oxidative capacity (101) which may have at its basis increases in PGC-1 expression and activity.

Caloric deprivation switches off adenosine triphosphate (ATP)-consuming processes such as biosynthetic pathways, while switching on catabolic processes that generate ATP including fatty acid uptake and oxidation (102). These processes are controlled in part by 5'-AMP-activated protein kinase (AMPK), through increased cellular AMP concentrations that accompany a fall in the cellular ATP/AMP ratio. Overexpression of the AMPK subunit AMPK2 was shown to extend life span in C. elegans (103). Basal level expression of PGC-1 in skeletal muscle was decreased in mice deficient in the AMPK2 subunit (104). Exposure of mice to ß-guanidinopropionic acid, a creatine analog which activates AMPK, led to increases in expression of PGC-1 possibly due to increases in CaMKIV (105). However, evidence exists for adaptive responses to fasting and CR being AMPK-independent (106).

	POSTTRANSLATIONAL REGULATION OF PGC-1 ACTIVITY

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

 
PGC-1 is regulated by three types of posttranslational modifications. Activated under conditions of stress, p38 MAPK phosphorylates PGC-1 at three sites within a region involved in repression of transcriptional activation. Phosphorylation results in increased activation of genes involved in ß-oxidation of fatty acids (107,108). Overexpression of an N-terminal region of PGC-1 containing the NR interaction domain overcomes repression of target gene expression (109). This N-terminal region contains a binding site for p160 myb binding protein, a repressor of PGC-1 activation of mitochondrial genes (110). Thus, the negative regulation of PGC-1 by p160 myb-binding protein is relieved by p38 MAPK phosphorylation of the PGC-1 N terminus. This mechanism provides a logical link between conditions of stress requiring higher metabolic demands and the increased expression of genes involved in energy generation.

PGC-1 activity is potentiated by arginine methylation by a protein arginine methyltransferase (PMRT1), another NR coactivator. Methylation by PRMT1 of two or three of the arginine residues found within the C-terminal glutamic acid-rich region of PGC-1 plays an important role in the coactivator function of PGC-1 and ability to activate genes involved in mitochondrial biogenesis (111). Further work is needed to determine when PMRT1 is activated, how arginine methylation changes the transcriptional activation properties of PGC-1, and the relative role of this modification in PGC-1 function.

PGC-1 activity is dependent on the acetylation state of the protein (Figure 1). PGC-1 is acetylated in vivo, and acetylation is augmented by p300 (112). SIRT1 can form a complex with PGC-1 facilitating deacetylation. The interactions between SIRT1 and PGC-1 are distinct from those of SIRT1 with p53 and FoxO3A (112). Interaction with SIRT1 and deacetylation of PGC-1 result in increases in the expression of gluconeogenesis genes, suppression of glycolytic genes, and increases in hepatic glucose output. Interestingly, SIRT1 does not regulate the effects of PGC-1 on mitochondrial gene expression (113).

	REGULATION OF NR ACTIVITY BY PGC-1 FAMILY MEMBERS

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

 
NR are critical modulators of developmental and physiological processes, and are targets of drugs as well as chemicals of environmental significance. NR are divided into classes based on their properties as regulatable DNA binding transcription factors. Class I NR including estrogen and glucocorticoid receptors bind as homodimers to response elements and shuttle between the cytoplasm and nucleus depending on availability of ligand. Most of the NR regulated by PGC-1 and PGC-1ß that play known or putative roles in response to nutrient deprivation are class II NR, i.e., they heterodimerize with family members of another NR called retinoid X receptors (RXR). These heterodimers bind to NR DNA response elements found in the promoters of regulated genes consisting of two direct repeats (DR) of TGACCT separated by 1 to 5 nucleotides (DR-1 to DR-5). Class III NR include estrogen receptor-related (ERR) family members that bind as monomers to an extended direct repeat with a consensus sequence TGACCTTGA. Hepatocyte nuclear factor 4 (HNF-4) is a class IV NR which binds as a homodimer to a DR-1 element. For most NR, ligand binding brings about a conformational change within the ligand binding domain resulting in exposure of a protein interface recognized by coactivator proteins including PGC-1. Assembly of transcriptional complexes on regulated genes subsequently follows.

PGC-1 family members mediate effects on gene expression through both ligand-dependent and -independent activation of NR. Differences between PGC-1 family members exist in the spectrum of NR with which they interact and activate. PGC-1 interacts with a large number of NR including constitutive activated receptor (CAR), ERR, farnesoid X receptor (FXR), glucocorticoid receptor, HNF-4, liver X receptor (LXR), PPAR, PPAR, pregnane X receptor (PXR), vitamin D receptor, and RXR (19,21,114,115) (Table 1). PGC-1ß interacts with or activates ERR family members (21,115), PPAR, thyroid hormone receptor ß (20,116), PPAR, and ER (22). NR require one of the N-terminal LXXLL motifs of PGC-1 for ligand-dependent interaction including ER (117), LXR (118), PPAR (20,109,119), FXR (120), RXR (121), and glucocorticoid receptor (122). The LXXLL motif in PGC-1 is also important for ligand-independent interactions with NR including HNF-4 (89) and CAR (123). FXR (124), PPAR (19), LXR (118), ERR, and ERR (125,126) interact with a region of PGC-1 distinct from other NR. In contrast, PRC activates a number of non-NR transcription factors (Nrf-1, Nrf-2) involved in mitochondrial biogenesis (26). PGC-1 and ß exhibit differences in side-by-side NR activation. HNF-4 is preferentially activated by PGC-1 whereas PPAR is preferentially activated by PGC-1ß. These differences may explain the targeted activation of gluconeogenesis genes by PGC-1 (but not PGC-1ß) through HNF-4 and the activation of fatty acid ß-oxidation and mitochondrial energy production genes by both PGC-1 and PGC-1ß through PPAR (116).

View this table: [in this window] [in a new window]   Table 1. NRs Regulated by PGC-1 or PGC-1ß.

	RECIPROCAL REGULATION OF FOXO1 AND NR

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

View larger version (14K): [in this window] [in a new window]   Figure 3. Protein interactions between peroxisome proliferator-activated receptor (PPAR) coactivator (PGC)-1, forkhead box "other" (FoxO1), and nuclear receptors (NR). PGC-1 increases the activity of NR through coordinated bridging interactions between the activation helix in the ligand binding domain of NR and the transcriptional machinery. PGC-1 can also interact with and activate the ability of FoxO1 to increase transcription of gluconeogenesis genes. The NR constitutive activated receptor (CAR), PPAR, and pregnane X receptor (PXR) negatively regulate the activity of FoxO1, whereas FoxO1 can either increase (CAR, PXR) or decrease (hepatocyte nuclear factor 4 [HNF-4], PPAR) NR activation

	ROLE OF PGC-1-REGULATED NR IN CR

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

PPAR
PPAR has well characterized roles in fasting and emerging roles in CR. PPAR, like other PPAR subtypes, is activated by a large, structurally diverse group of amphipathic chemicals. Most notably, PPAR is activated by peroxisome proliferators (PP) including hypolipidemic agents that increase the number and size of peroxisome organelles in mouse and rat liver (131). PPAR is also activated by a large number of compounds that are either found endogenously within the cell (e.g., fatty acids) or that are dietary components (e.g., pristanic acid, phytanic acid, and resveratrol) (132–134). In addition, the naturally occurring lipid oleylethanolamide (OEA) is a PPAR agonist and requires PPAR for regulation of satiety and body weight (135). PPAR agonists elicit a predictable course of adaptive responses in the liver, including peroxisome proliferation, induction of lipid-metabolizing genes, hepatomegaly, and eventually liver cancer (131). Studies in wild-type and PPAR-null mice demonstrated that the phenotypic effects of PP exposure in the liver require a functional PPAR (131,136).

PPAR plays a key role in carbon source utilization during fasting. PPAR was upregulated in liver, duodenum, jejunum, colon, thymus (137), and pancreas (138) by fasting and downregulated in pancreatic ß-cells by glucose (139). In contrast, PPAR was downregulated in the rat gastrocnemius muscle after a 48-hour fast, even though a large number of genes involved in fatty acid ß-oxidation, known to be regulated by PPAR, were simultaneously increased in expression (140). During fasting, PPAR-null mice exhibit defects in the ability to regulate genes involved in fatty acid ß- and -oxidation and ketogenesis in liver, kidney, and heart in parallel with an inability to maintain proper levels of blood glucose or ketone bodies (141–147). Although fasted PPAR-null mice can still mobilize and transport triglycerides from fat stores to the liver, fasting results in severe micro- and macrovesicular steatosis because of impairment of fatty acid ß- and -oxidation (142,143). The induction by fasting of pyruvate dehydrogenase kinase 4 (PDK4), a key gene controlling carbon source utilization was found to be PPAR-dependent in a number of tissues (148) but PPAR-independent in mouse muscles (149). In humans, the Leu162Val polymorphism of PPAR was associated with a decreased level of fasting serum triglyceride in glucose-tolerant white persons (150).

PPAR also plays roles in long-term CR. The expression of the PPAR gene but not protein was increased in the livers of CR mice (151). Examination of the transcript profiles in the livers of wild-type and PPAR-null mice revealed that 20% of all gene expression changes were PPAR-dependent after a 4-week 65% CR (91). Despite the fact that PPAR regulates fatty acid ß-oxidation genes in the liver after fasting and PP exposure, genes involved in fatty acid ß-oxidation were induced by CR through a PPAR-independent mechanism. However, the induction of fatty acid -hydroxylases Cyp4a10 and Cyp4a14 by CR was PPAR-dependent (91).

In addition to roles in lipid metabolism, PPAR likely carries out other unexpected functions during CR. PPAR was partially or completely required for CR to downregulate acute phase genes (C4bp, C9, Mbl1, Orm1, Saa4) responsive to inflammatory cytokines (91), possibly through the ability of PPAR to negatively regulate transcription factors important in inflammatory responses (131). The downregulation by CR of the epidermal growth factor receptor (Egfr), a key gene involved in carcinogenesis, required PPAR, whereas downregulation of GHR was PPAR-independent. Thus, PPAR is required for regulation of a subset of CR-responsive genes in the liver involved in fatty acid metabolism, inflammation, and cell growth. Further experiments are required to determine if these changes in gene expression are functionally relevant to suppression of inflammation and cancer found in CR animals.

CR protects the liver from a wide range of environmental stressors, many of which induce damage through inflammatory mediators (152,153). Like CR, PPAR regulates responses to diverse forms of stress. Wild-type mice preexposed to PPAR agonists exhibit decreased cellular damage, increased tissue repair, and decreased mortality after exposure to a number of physical and chemical stressors in liver (154–158). Additionally, hepatocytes from PPAR-null mice exhibit decreased resistance to oxidative stress induced by chemical exposure (159). PPAR was required for CR to protect the liver from damage induced by the hepatotoxicant thioacetamide. PPAR-null mice fed a CR diet were as sensitive to hepatotoxicity as were wild-type or PPAR-null mice on an ad libitum diet. The mechanism of CR protection likely includes enhanced repair of damage as compensatory cell proliferation was increased earlier and to a greater extent in wild-type CR mice compared to PPAR-null CR mice in the absence of major differences in the amount of tissue damage (91). The molecular basis for the PPAR-dependent increased cell proliferation in CR mice is not known, but it is possible that PPAR is required for energy production needed for tissue repair or optimal expression of repair genes (154,157). Given that PGC-1 expression is increased with CR (91,92), PGC-1 through regulation of PPAR may be required for CR to protect the liver from chemical-induced stress. Support for this hypothesis comes from studies showing that the livers of diabetic mice in which PGC-1 is induced (19) are protected from toxicity induced by acetaminophen, carbon tetrachloride and bromobenzene due to robust tissue repair (160,161). Moreover, like CR, the protection observed in diabetic mice treated with acetaminophen required PPAR (157). Taken together, these data indicate the importance of PGC-1-mediated regulation of PPAR in CR-induced hepatoprotection. Future experiments should test directly the role of PGC-1 in CR stress resistance.

CAR
A number of enzyme classes work in concert to dispose of toxic endogenous or xenobiotic compounds including carcinogens, drugs, and toxins. The NR CAR regulates phase I, phase II, and phase III pathways of oxidative metabolism, conjugation, and transport of xenobiotics (162). CAR exhibits constitutive activity as an NR but in the presence of exogenous compounds, CAR can be further activated by two mechanisms. Phenobarbital induces activation of CAR through increases in CAR phosphorylation. Other activators bind to CAR directly including the planar hydrocarbon 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene. Both processes lead to increased interaction of CAR with binding sites in the promoters of regulated genes. CAR expression was induced in the livers of mice fasted for 24 or 48 hours (163).

Decreases in thyroid hormone levels may be associated with changes in metabolic rate upon CR (164). CAR controls the expression of genes involved in thyroid hormone metabolism induced upon fasting. Expression of Cyp2b10 and members of the uridine 5'-diphosphate-glucosyltransferase and sulfotransferase families (phase I and II genes) are induced in parallel with decreases in T3 and T4 levels by fasting in wild-type but not CAR-null mice (165). CAR-null mice on a 40% CR diet had a higher basal metabolic rate and lost more body weight than did wild-type mice (165). These results demonstrate that CAR controls the expression of xenobiotic metabolism genes that regulate thyroid hormone levels during CR. It is worth noting the parallel between the increased expression of xenobiotic metabolism genes by CR through CAR and in the long-lived C. elegans daf-2 mutant (compared to wild-type animals). In the daf-2 mutant, constitutively active Daf-16 increases the expression of drug detoxification genes including cytochrome P450 family members, short-chain dehydrogenases/reductases, uridine 5'-diphosphate-glucosyltransferases, and glutathione-S-transferases (166) suggesting a general role for these genes in stress resistance and possibly longevity in multiple species.

	ROLE OF PGC-1 AND REGULATED NR IN DWARF MICE WITH INCREASED LONGEVITY

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

 
Dwarf mice have defects in GH action and share a number of beneficial phenotypic characteristics with rodents on CR diets. Mutations that lead to the dwarf phenotype are found in transcription factors that determine development of the anterior pituitary (Pit1, Prop1), as well as the GH releasing hormone receptor (Ghrhr) and the GH receptor (Ghr). GH elicits many of its effects through regulation of IGF-I in the liver, and dwarf mice have very low circulating levels of IGF-I. In addition, dwarf mice exhibit decreased levels of insulin and increased insulin sensitivity (167). These shared decreases in insulin and IGF-I may be the basis for beneficial phenotypic effects in common with CR and dwarf mutations. Like CR animals, dwarf mice are protected from spontaneous and chemically induced cancer (168–171), age-dependent declines in cognitive function (172), and age-related declines in immune function and collagen cross-linking (173). Fibroblasts from Snell (Pit1), Ames, and GHR-null dwarf mice exhibited increased resistance to diverse physical and chemical stressors in vitro compared to wild-type fibroblasts (174,175).

Evidence that insulin/IGF-I-regulated pathways are disrupted in dwarf mice comes from a number of studies. Snell mouse livers exhibited decreased insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1), IRS-2, PI3K, and Akt (176,177). Ames (Prop1) mice also had decreases in insulin-stimulated signaling including decreases in PI3K activity and Akt phosphorylation (167). Similar changes in the direction and sometimes magnitude of changes were observed in insulin/IGF-I signaling after CR in wild-type mice and in ad libitum dwarf GHR-null mice including decreases in insulin and IGF-I levels and Akt phosphorylation, with parallel increases in FoxO1 mRNA, CREB phosphorylation, and PGC-1 protein levels (39). Importantly, CR brought about additive changes in GHR-null mice in most of these facets of insulin signaling indicating that similar mechanisms are behind the changes in insulin signaling. However, there were differences in the two models including increases in Akt2 mRNA, FoxO1 protein, AMPK phosphorylation, and PGC-1 mRNA expression in dwarf mice only. In contrast, CR uniquely increased expression of SIRT1. These studies provide strong evidence that insulin/IGF-I-regulated signaling is decreased resulting in activation of FoxO1 and PGC-1, in both CR wild-type mice and ad libitum dwarf mice.

Dwarf mutations and CR result in overlaps in expression of liver genes, some of which are regulated by PGC-1. The effect of the GHR-null or Snell dwarf mutations and CR led to a partial overlap in the transcript profiles (178). A more recent study in which a greater number of genes were queried also showed that the Ames mutation and CR affect overlapping sets of genes and suggest that the additive effects of the dwarf mutation and CR on life span arise from their additive effects on the level of expression of some genes and from their independent effects on other genes (40). The Ames mutation and, to a lesser extent, CR had effects on a number of gene categories that are under control of PGC-1 including increases in fatty acid ß-oxidation and xenobiotic metabolism. Many of these same genes were also regulated to greater levels in young and old Snell dwarf mice (179) or by a 4-week CR in wild-type mice (91). In Ames, Snell, and Little mice, CAR (NR1I3, I4) and target genes Cyp2b9, Cyp2b10, Sult-N, and Sult1a1, as well as PXR (NR1I2) and target gene Cyp3a11 (179,180) exhibited increased expression indicating that these PGC-1-regulated NR may also be activated under these conditions.

Many genes under control of PPAR were constitutively regulated in dwarf mice. In Snell dwarf mice these included those involved in ß- and -oxidation of fatty acids (Acox1, Cyp4a10, Cyp4a14) and those involved in stress responses (the chaperonin, Tcp1) and CVD (fibrinogen, Fib). The levels of some of these gene products were also altered in other dwarf mouse models including Ames, Little (Ghrhr mutant mice), and GHR-null mice (181). The constitutive increases in PPAR-regulated genes may be partly due to increased expression of PPAR mRNA and protein observed in the livers of control Snell dwarf mice (181). However, PPAR gene and protein levels were not altered in Ames dwarf mice compared to phenotypically normal controls (151).

The molecular basis for some of these gene expression changes in dwarf mice may be the antagonistic relationship between GH signaling and PPAR-regulated gene expression. STAT5b, a GH-inducible transcription factor, inhibited the ability of PPAR to activate PPAR-dependent reporter gene transcription by endogenous or xenobiotic PP in vitro (182,183), and a transcript profiling study in the livers of GH-treated rats revealed a subset of PPAR-regulated genes that were downregulated including CYP4A3 as well as PPAR itself (184). Mice with defects in GH-responsive STAT5b transcription factor exhibited constitutive increases in PPAR-regulated gene expression (185). Given the role of PPAR in mediating the transcriptional responses of CR (91), PGC-1-regulated PPAR may be one common pathway operational in dwarf mouse mutants and CR mice.

	PGC-1 AND REGULATED NR IN EXERCISE AND HIBERNATION

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

 
A number of other models of longevity and/or health have features in common with CR and dwarf mice including altered expression of PGC-1 and PPAR. Exercise improves overall health and offsets the risk of age-related disease (186). The effect of exercise in rodents is primarily on median but not maximum life span, suggesting that although beneficial in terms of slowing age-dependent diseases, exercise may not retard aging at the molecular level (187). Exercise offsets many age-related gene expression changes observed in the hearts of sedentary mice, indicating that adaptive physiological mechanisms induced by exercise can retard many effects of aging on the transcriptional profile in heart muscle (188). PGC-1 (19,189,190) and PRC (190) but not PGC-1ß (90) are induced during exercise. PGC-1 promotes muscle fiber-type switching from fast-twitch fibers which rely only on glucose as an energy source (glycolytic; type IIa and IIb) to slow-twitch which rely on glucose and fatty acids (oxidative; type I) (191). PGC-1 expression was positively regulated in muscle by CaMKIV operating through CREB (99) (Figure 2). PPAR levels are also increased in the muscles of men undergoing endurance training (192). Many genes involved in fatty acid oxidation, mitochondrial biogenesis, and mitochondrial oxidative phosphorylation are regulated by PGC-1 in muscle (see below).

Hibernation can extend life span in at least one mammal (193). In hibernating 13-lined ground squirrels, Akt phosphorylation and kinase activity were significantly reduced (194) and PGC-1, PPAR, and regulated genes were coordinately increased during hibernation (195–197). Thus, an increase in PGC-1 activation of PPAR is a common feature in a number of models of mammalian longevity.

	REVERSAL OF AGE-DEPENDENT CHANGES BY CR

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

 
If PGC-1-dependent regulation of NR is involved in beneficial effects of CR, it would follow that CR prevents any age-dependent decline in PGC-1-regulated pathway expression. Systematically comparing gene expression patterns in C. elegans and D. melanogaster using genome-wide comparative analysis of transcript profile data showed that aging repressed genes in gene ontology (GO) categories for mitochondrial membrane and mitochondrial inner membrane including components of the mitochondrial respiratory chain and the ATP synthase complex (198), which are under positive control by PGC-1 in mammals (199,200). A subset of these genes involved in energy metabolism including mitochondrial electron transport, oxidative phosphorylation, and gluconeogenesis regulated by PGC-1 are downregulated in the muscles of aging mice (201,202) or rhesus monkeys (203) and are partially or completely reversed by CR in mice but not monkeys. In humans, genes involved in mitochondrial functions including electron transport, ATP synthesis, and protein synthesis are also downregulated in muscle from older (67–75 years) men (204). Consistent with these findings, aging reduced PGC-1 and PGC-1ß mRNA levels in human muscle (205) and PGC-1 in the livers of male but not female rats (206). Endothelial cells that overexpress PGC-1 show decreased accumulation of ROS, increased mitochondrial membrane potential, and decreases in apoptotic cell death under both basal and oxidative stress conditions. Decreased expression of PGC-1 by small inhibitory RNA decreased expression of mitochondrial detoxification proteins revealing linkage of mitochondrial activation and oxidative stress protective systems (207). When additional genome-wide transcript profile experiments are performed in aging mammals, it will be interesting to determine the extent of cross-species conservation of these age-dependent declines in PGC-1-regulated genes.

PPAR plays multiple roles in the aging process. Older animals exhibit decreases in the expression of PPAR or regulated genes in T lymphocytes (208), liver (209–211), kidney (212), and heart (213,214). The activity of PPAR as well as other type II NR may also decrease indirectly through age-dependent decreases in liver RXR (215), heart RXR (216), and brain RXR (217). Aging in experimental animals is associated with increases in oxidative stress, and PPAR plays a role in reducing endogenous oxidative stress in the liver, as lipid peroxide levels were increased in 12-month-old PPAR-null mice compared to wild-type mice (218). PPAR may also influence aging through regulation of damage and repair processes after exposure to endogenous or environmental stressors as discussed above. PPAR-null mice exhibited age-dependent defects in heart (219,220), liver, and kidney consistent with decreases in longevity compared to wild-type mice (220). Furthermore, many age-dependent decreases in PPAR or PPAR-regulated genes in the mouse heart (214), rat kidney (212), or rat liver (221) were reversed by CR. Taken together, these studies indicate that PPAR plays an important role in suppression of endogenous and chemical-induced damage and that reversal of age-dependent decreases in expression of PPAR during aging may be linked to increased longevity.

Summary
We have reviewed data that explore the hypothesis that insulin and/or IGF-I are major factors in determining the responses to CR through regulation of PGC-1 and regulated NR. This hypothesis is supported by the following: 1) decreases in insulin/IGF-I signaling are mechanistically linked to increased longevity in phylogenetically diverse species; 2) CR decreases insulin and IGF-I signaling resulting in increases in PGC-1 expression and activity mediated in part by activation of FoxO activity; and 3) PGC-1 and PGC-1ß activate many NR, at least two of which (CAR and PPAR) have unequivocally been shown to play roles in responses to CR. The relevance of other NR regulated by PGC-1 in CR effects must still be ascertained. This hypothesis provides opportunities for integration of a large number of disparate findings in the CR field.

	Acknowledgments

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

 
The preparation of this review has been funded wholly by the U.S. Environmental Protection Agency. It has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

We thank Dr. Bob MacPhail for reviewing the manuscript.

	Footnotes

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

 
Decision Editor: James R. Smith, PhD

Received January 28, 2005

Accepted August 2, 2005

	References

Top Abstract PGC-1 Family Members Involved... Role of Insulin/IGF-I Signaling... Sirtuin 1 and Jun... Regulation of PGC-1{alpha} Gene... Posttranslational Regulation of... Regulation of NR Activity... Reciprocal Regulation of FoxO1... Role of PGC-1-Regulated NR... Role of PGC-1 and... PGC-1 and Regulated NR... Reversal of Age-Dependent... References

 

1. NWeindruch R, Walford RL., In: Thomas E, ed. The Retardation of Aging and Disease by Dietary Restriction. Springfield, IL: C. C. Thomas; 1988:31–71.
2. Frame LT, Hart RW, Leakey JE. Caloric restriction as a mechanism mediating resistance to environmental disease. Environ Health Perspect. 1998;106:Suppl 1: 313-324.[Medline]
3. Wanagat J, Allison DB, Weindruch R. Caloric intake and aging: mechanisms in rodents and a study in nonhuman primates. Toxicol Sci. 1999;52:(2 Suppl): 35-40.[Abstract]
4. Yu BP, Chung HY. Stress resistance by caloric restriction for longevity. Ann N Y Acad Sci. 2001;928:39-47.[Medline]
5. Kopelman PG. Obesity as a medical problem. Nature. 2000;404:635-643.[Medline]
6. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625-1638.[Abstract/Free Full Text]
7. Das M, Gabriely I, Barzilai N. Caloric restriction, body fat and ageing in experimental models. Obes Rev. 2004;5:13-19.[Medline]
8. Cefalu WT, Wang ZQ, Bell-Farrow AD, Collins J, Morgan T, Wagner JD. Caloric restriction and cardiovascular aging in cynomolgus monkeys (Macaca fascicularis): metabolic, physiologic, and atherosclerotic measures from a 4-year intervention trial. J Gerontol Biol Sci Med Sci. 2004;59A:1007-1014.[Medline]
9. Roth GS, Mattison JA, Ottinger MA, Chachich ME, Lane MA, Ingram DK. Aging in rhesus monkeys: relevance to human health interventions. Science. 2004;305:1423-1426.[Abstract/Free Full Text]
10. Roth GS, Lane MA, Ingram DK, et al. Biomarkers of caloric restriction may predict longevity in humans. Science. 2002;297:811.[Free Full Text]
11. Heilbronn LK, Ravussin E. Calorie restriction and aging: review of the literature and implications for studies in humans. Am J Clin Nutr. 2003;78:361-369.[Abstract/Free Full Text]
12. Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider NL. Effects of intermittent feeding upon growth, activity, and lifespan in rats allowed voluntary exercise. Exp Aging Res. 1983;9:203-209.[Medline]
13. Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider N. Effects of intermittent feeding upon body weight and lifespan in inbred mice: interaction of genotype and age. Mech Ageing Dev. 1990;55:69-87.[Medline]
14. Nakamura H, Kouda K, Tokunaga R, Takeuchi H. Suppressive effects on delayed type hypersensitivity by fasting and dietary restriction in ICR mice. Toxicol Lett. 2004;146:259-267.[Medline]
15. Mattson MP, Wan R. Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. J Nutr Biochem. 2005;16:129-137.[Medline]
16. Donati A, Cavallini G, Carresi C, Gori Z, Parentini I, Bergamini E. Anti-aging effects of anti-lipolytic drugs. Exp Gerontol. 2004;39:1061-1067.[Medline]
17. Rocha NS, Barbisan LF, de Oliveira ML, de Camargo JL. Effects of fasting and intermittent fasting on rat hepatocarcinogenesis induced by diethylnitrosamine. Teratog Carcinog Mutagen. 2002;22:129-138.[Medline]
18. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998;92:829-839.[Medline]
19. Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev. 2003;24:78-90.[Abstract/Free Full Text]
20. Lin J, Puigserver P, Donovan J, Tarr P, Spiegelman BM. Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor. J Biol Chem. 2002;277:1645-1648.[Abstract/Free Full Text]
21. Kamei Y, Ohizumi H, Fujitani Y, et al. PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc Natl Acad Sci U S A. 2003;100:12378-12383.[Abstract/Free Full Text]
22. Kressler D, Schreiber SN, Knutti D, Kralli A. The PGC-1-related protein PERC is a selective coactivator of estrogen receptor alpha. J Biol Chem. 2002;277:13918-13925.[Abstract/Free Full Text]
23. Lin J, Wu PH, Tarr PT, et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell. 2004;119:121-135.[Medline]
24. Leone TC, Lehman JJ, Finck BN, et al. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol. 2005;3:e101.[Medline]
25. Andersson U, Scarpulla RC. Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells. Mol Cell Biol. 2001;21:3738-3749.[Abstract/Free Full Text]
26. Gleyzer N, Vercauteren K, Scarpulla RC. Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol Cell Biol. 2005;25:1354-1366.[Abstract/Free Full Text]
27. Monsalve M, Wu Z, Adelmant G, Puigserver P, Fan M, Spiegelman BM. Direct coupling of transcription and mRNA processing through the thermogenic coactivator PGC-1. Mol Cell. 2000;6:307-316.[Medline]
28. Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature. 2000;408:255-262.[Medline]
29. Libina N, Berman JR, Kenyon C. Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell. 2003;115:489-502.[Medline]
30. McElwee J, Bubb K, Thomas JH. Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell. 2003;2:111-121.[Medline]
31. Murphy CT, McCarroll SA, Bargmann CI, et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature. 2003;424:277-283.[Medline]
32. Lee SS, Kennedy S, Tolonen AC, Ruvkun G. DAF-16 target genes that control C. elegans life-span and metabolism. Science. 2003;300:644-647.[Abstract/Free Full Text]
33. Henderson ST, Johnson TE. daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol. 2001;11:1975-1980.[Medline]
34. Giannakou ME, Goss M, Junger MA, Hafen E, Leevers SJ, Partridge L. Long-lived Drosophila with overexpressed dFOXO in adult fat body. Science. 2004;305:361.[Abstract/Free Full Text]
35. Coffer P. OutFOXing the grim reaper: novel mechanisms regulating longevity by forkhead transcription factors. Sci STKE. 2003;2003:PE39.[Medline]
36. Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MF, Smidt MP. FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem. 2003;278:35959-35967.[Abstract/Free Full Text]
37. Imae M, Fu Z, Yoshida A, Noguchi T, Kato H. Nutritional and hormonal factors control the gene expression of FoxOs, the mammalian homologues of DAF-16. J Mol Endocrinol. 2003;30:253-262.[Abstract]
38. Furuyama T, Kitayama K, Yamashita H, Mori N. Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. Biochem J. 2003;375:365-371.[Medline]
39. Al-Regaiey KA, Masternak MM, Bonkowski M, Sun L, Bartke A. Long-lived growth hormone receptor knockout mice: interaction of reduced IGF-1/insulin signaling and caloric restriction. Endocrinology. 2005;146:851-860.[Abstract/Free Full Text]
40. Tsuchiya T, Dhahbi JM, Cui X, Mote PL, Bartke A, Spindler SR. Additive regulation of hepatic gene expression by dwarfism and caloric restriction. Physiol Genomics. 2004;17:307-315.[Abstract/Free Full Text]
41. Van Der Heide LP, Hoekman MF, Smidt MP. The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation. Biochem J. 2004;380:297-309.[Medline]
42. Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell. 2004;117:421-426.[Medline]
43. Nemoto S, Finkel T. Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science. 2002;295:2450-2452.[Abstract/Free Full Text]
44. You H, Jang Y, You-Ten AI, et al. p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1. Proc Natl Acad Sci U S A. 2004;101:14057-14062.[Abstract/Free Full Text]
45. Rena G, Guo S, Cichy SC, Unterman TG, Cohen P. Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem. 1999;274:17179-17183.[Abstract/Free Full Text]
46. Rena G, Prescott AR, Guo S, Cohen P, Unterman TG. Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting. Biochem J. 2001;354:605-612.[Medline]
47. Richards JS, Sharma SC, Falender AE, Lo YH. Expression of FKHR, FKHRL1, and AFX genes in the rodent ovary: evidence for regulation by IGF-I, estrogen, and the gonadotropins. Mol Endocrinol. 2002;16:580-599.[Abstract/Free Full Text]
48. Nakae J, Barr V, Accili D. Differential regulation of gene expression by insulin and IGF-1 receptors correlates with phosphorylation of a single amino acid residue in the forkhead transcription factor FKHR. EMBO J. 2000;19:989-996.[Medline]
49. Tseng YH, Ueki K, Kriauciunas KM, Kahn CR. Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. J Biol Chem. 2002;277:31601-31611.[Abstract/Free Full Text]
50. Liu W, Chin-Chance C, Lee EJ, Lowe WL, Jr. Activation of phosphatidylinositol 3-kinase contributes to insulin-like growth factor I-mediated inhibition of pancreatic beta-cell death. Endocrinology. 2002;143:3802-3812.[Abstract/Free Full Text]
51. Collins BJ, Deak M, Arthur JS, Armit LJ, Alessi DR. In vivo role of the PIF-binding docking site of PDK1 defined by knock-in mutation. EMBO J. 2003;22:4202-4211.[Medline]
52. Xu J, Liao K. Protein kinase B/AKT 1 plays a pivotal role in insulin-like growth factor-1 receptor signaling induced 3T3-L1 adipocyte differentiation. J Biol Chem. 2004;279:35914-35922.[Abstract/Free Full Text]
53. Zheng WH, Kar S, Quirion R. Insulin-like growth factor-1-induced phosphorylation of transcription factor FKHRL1 is mediated by phosphatidylinositol 3-kinase/Akt kinase and role of this pathway in insulin-like growth factor-1-induced survival of cultured hippocampal neurons. Mol Pharmacol. 2002;62:225-233.[Abstract/Free Full Text]
54. Woods YL, Rena G. Effect of multiple phosphorylation events on the transcription factors FKHR, FKHRL1 and AFX. Biochem Soc Trans. 2002;30:391-397.[Medline]
55. Feng B, Li J, Kliegman RM. Differential effects of insulin-like growth factor-1 on neonatal canine gene expression. Biochem Mol Med. 1996;59:154-160.[Medline]
56. Feng BC, Li J, Kliegman RM. Insulin resistance and the transcription of the glucose-6-phosphatase gene in newborn dogs. Biochem Mol Med. 1997;60:134-141.[Medline]
57. Di Cola G, Cool MH, Accili D. Hypoglycemic effect of insulin-like growth factor-1 in mice lacking insulin receptors. J Clin Invest. 1997;99:2538-2544.[Medline]
58. Liang H, Masoro EJ, Nelson JF, Strong R, McMahan CA, Richardson A. Genetic mouse models of extended lifespan. Exp Gerontol. 2003;38:1353-1364.[Medline]
59. Longo VD, Finch CE. Evolutionary medicine: from dwarf model systems to healthy centenarians? Science. 2003;299:1342-1346.[Abstract/Free Full Text]
60. Migliaccio E, Giorgio M, Mele S, et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature. 1999;402:309-313.[Medline]
61. Holzenberger M, Dupont J, Ducos B, et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature. 2003;421:182-187.[Medline]
62. Bluher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003;299:572-574.[Abstract/Free Full Text]
63. Miskin R, Tirosh O, Pardo M, et al. alphaMUPA mice: a transgenic model for longevity induced by caloric restriction. Mech Ageing Dev. 2005;126:255-261.[Medline]
64. Masoro EJ. Caloric restriction and aging: an update. Exp Gerontol. 2000;35:299-305.[Medline]
65. Sonntag WE, Lynch CD, Cefalu WT, et al. Pleiotropic effects of growth hormone and insulin-like growth factor (IGF)-1 on biological aging: inferences from moderate caloric-restricted animals. J Gerontol Biol Sci. 1999;54A:B521-B538.[Abstract]
66. Argentino DP, Dominici FP, Munoz MC, Al-Regaiey K, Bartke A, Turyn D. Effects of long-term caloric restriction on glucose homeostasis and on the first steps of the insulin signaling system in skeletal muscle of normal and Ames dwarf (Prop1(df)/Prop1(df)) mice. Exp Gerontol. 2005;40:27-35.[Medline]
67. Miller RA, Buehner G, Chang Y, Harper JM, Sigler R, Smith-Wheelock M. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell. 2005;4:119-125.[Medline]
68. Franceschi C, Olivieri F, Marchegiani F, et al. Genes involved in immune response/inflammation, IGF1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians. Mech Ageing Dev. 2005;126:351-361.[Medline]
69. van Heemst D, Beekman M, Mooijaart SP, et al. Reduced insulin/IGF-1 signaling and human longevity. Aging Cell. 2005;4:79-85.[Medline]
70. Conway B, Rene A. Obesity as a disease: no lightweight matter. Obes Rev. 2004;5:145-151.[Medline]
71. Furukawa-Hibi Y, Yoshida-Araki K, Ohta T, Ikeda K, Motoyama N. FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress. J Biol Chem. 2002;277:26729-26732.[Abstract/Free Full Text]
72. Brunet A, Sweeney LB, Sturgill JF, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004;303:2011-2015.[Abstract/Free Full Text]
73. van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, Burgering BM. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem. 2004;279:28873-28879.[Abstract/Free Full Text]
74. Motta MC, Divecha N, Lemieux M, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004;116:551-563.[Medline]
75. Daitoku H, Hatta M, Matsuzaki H, et al. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A. 2004;101:10042-10047.[Abstract/Free Full Text]
76. Fukuoka M, Daitoku H, Hatta M, Matsuzaki H, Umemura S, Fukamizu A. Negative regulation of forkhead transcription factor AFX (Foxo4) by CBP-induced acetylation. Int J Mol Med. 2003;12:503-508.[Medline]
77. North BJ, Verdin E. Sirtuins: Sir2-related NAD-dependent protein deacetylases. Genome Biol. 2004;5:224.[Medline]
78. Blander G, Guarente L. The Sir2 family of protein deacetylases. Annu Rev Biochem. 2004;73:417-435.[Medline]
79. Wood JG, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004;430:686-689.[Medline]
80. Rogina B, Helfand SL. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A. 2004;101:15998-16003.[Abstract/Free Full Text]
81. Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004;305:390-392.[Abstract/Free Full Text]
82. Shi T, Wang F, Stieren E, Tong Q. SIRT3, a mitochondrial Sirtuin deacetylase, regulates mitochondrial function and thermogenesis in Brown adipocytes. J Biol Chem. 2005;280:13560-13567.[Abstract/Free Full Text]
83. Nemoto S, Fergusson MM, Finkel T. Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science. 2004;306:2105-2108.[Abstract/Free Full Text]
84. Oh SW, Mukhopadhyay A, Svrzikapa N, Jiang F, Davis RJ, Tissenbaum HA. JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc Natl Acad Sci U S A. 2005;102:4494-4499.[Abstract/Free Full Text]
85. Wang MC, Bohmann D, Jasper H. JNK signaling confers tolerance to oxidative stress and extends lifespan in Drosophila. Dev Cell. 2003;5:811-816.[Medline]
86. Wang MC, Bohmann D, Jasper H. JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell. 2005;121:115-125.[Medline]
87. Essers MA, Weijzen S, de Vries-Smits AM, et al. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J. 2004;23:4802-4812.[Medline]
88. Herzig S, Long F, Jhala US, et al. CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature. 2001;413:179-183.[Medline]
89. Yoon JC, Puigserver P, Chen G, et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature. 2001;413:131-138.[Medline]
90. Meirhaeghe A, Crowley V, Lenaghan C, et al. Characterization of the human, mouse and rat PGC1 beta (peroxisome-proliferator-activated receptor-gamma co-activator 1 beta) gene in vitro and in vivo. Biochem J. 2003;373:155-165.[Medline]
91. Corton JC, Apte U, Anderson SP, et al. Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors. J Biol Chem. 2004;279:46204-46212.[Abstract/Free Full Text]
92. Zhu M, de Cabo R, Lane MA, Ingram DK. Caloric restriction modulates early events in insulin signaling in liver and skeletal muscle of rat. Ann N Y Acad Sci. 2004;19:448-452.
93. Larrouy D, Vidal H, Andreelli F, Laville M, Langin D. Cloning and mRNA tissue distribution of human PPARgamma coactivator-1. Int J Obes Relat Metab Disord. 1999;23:1327-1332.[Medline]
94. Viguerie N, Vidal H, Arner P, et al. Adipose tissue gene expression in obese subjects during low-fat and high-fat hypocaloric diets. Diabetologia. 2005;48:123-131.[Medline]
95. Daitoku H, Yamagata K, Matsuzaki H, Hatta M, Fukamizu A. Regulation of PGC-1 promoter activity by protein kinase B and the forkhead transcription factor FKHR. Diabetes. 2003;52:642-649.[Abstract/Free Full Text]
96. Michael MD, Kulkarni RN, Postic C, et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell. 2000;6:87-97.[Medline]
97. Cook SA, Matsui T, Li L, Rosenzweig A. Transcriptional effects of chronic Akt activation in the heart. J Biol Chem. 2002;277:22528-22533.[Abstract/Free Full Text]
98. Nisoli E, Clementi E, Paolucci C, et al. Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science. 2003;299:896-899.[Abstract/Free Full Text]
99. Handschin C, Rhee J, Lin J, Tarr PT, Spiegelman BM. An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle. Proc Natl Acad Sci U S A. 2003;100:7111-7116.[Abstract/Free Full Text]
100. Akimoto T, Pohnert SC, Li P, et al. Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. J Biol Chem. 2005;280:19587-19593.[Abstract/Free Full Text]
101. Hepple RT, Baker DJ, Kaczor JJ, Krause DJ. Long-term caloric restriction abrogates the age-related decline in skeletal muscle aerobic function. FASEB J. 2005;19:1320-1322.[Abstract/Free Full Text]
102. Hardie DG. AMP-activated protein kinase: a master switch in glucose and lipid metabolism. Rev Endocr Metab Disord. 2004;5:119-125.[Medline]
103. Apfeld J, O'Connor G, McDonagh T, DiStefano PS, Curtis R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev. 2004;18:3004-3009.[Abstract/Free Full Text]
104. Jorgensen SB, Wojtaszewski JF, Viollet B, et al. Effects of alpha-AMPK knockout on exercise-induced gene activation in mouse skeletal muscle. FASEB J. 2005;19:1146-1148.[Abstract/Free Full Text]
105. Zong H, Ren JM, Young LH, et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A. 2002;99:15983-15987.[Abstract/Free Full Text]
106. Gonzalez AA, Kumar R, Mulligan JD, Davis AJ, Weindruch R, Saupe KW. Metabolic adaptations to fasting and chronic caloric restriction in heart, muscle, and liver do not include changes in AMPK activity. Am J Physiol Endocrinol Metab. 2004;287:E1032-E1037.[Abstract/Free Full Text]
107. Puigserver P, Rhee J, Lin J, et al. Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. Mol Cell. 2001;8:971-982.[Medline]
108. Barger PM, Browning AC, Garner AN, Kelly DP. p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: a potential role in the cardiac metabolic stress response. J Biol Chem. 2001;276:44495-44501.[Abstract/Free Full Text]
109. Oberkofler H, Esterbauer H, Linnemayr V, Strosberg AD, Krempler F, Patsch W. Peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1 recruitment regulates PPAR subtype specificity. J Biol Chem. 2002;277:16750-16757.[Abstract/Free Full Text]
110. Fan M, Rhee J, St-Pierre J, et al. Suppression of mitochondrial respiration through recruitment of p160 myb binding protein to PGC-1alpha: modulation by p38 MAPK. Genes Dev. 2004;18:278-289.[Abstract/Free Full Text]
111. Teyssier C, Ma H, Emter R, Kralli A, Stallcup MR. Activation of nuclear receptor coactivator PGC-1{alpha} by arginine methylation. Genes Dev. 2005;19:1466-1473.[Abstract/Free Full Text]
112. Nemoto S, Fergusson MM, Finkel T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J Biol Chem. 2005;280:16456-16460.[Abstract/Free Full Text]
113. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005;434:113-118.[Medline]
114. Savkur RS, Bramlett KS, Stayrook KR, Nagpal S, Burris TP. Coactivation of the human vitamin D receptor by the peroxisome proliferator-activated receptor {gamma} coactivator-1 {alpha} (PGC-1{alpha}). Mol Pharmacol. 2005;68:511-517.[Abstract/Free Full Text]
115. Hentschke M, Susens U, Borgmeyer U. PGC-1 and PERC, coactivators of the estrogen receptor-related receptor gamma. Biochem Biophys Res Commun. 2002;299:872-879.[Medline]
116. Lin J, Tarr PT, Yang R, et al. PGC-1beta in the regulation of hepatic glucose and energy metabolism. J Biol Chem. 2003;78:30843-30848.
117. Tcherepanova I, Puigserver P, Norris JD, Spiegelman BM, McDonnell DP. Modulation of estrogen receptor-alpha transcriptional activity by the coactivator PGC-1. J Biol Chem. 2000;275:16302-16308.[Abstract/Free Full Text]
118. Oberkofler H, Schraml E, Krempler F, Patsch W. Potentiation of liver X receptor transcriptional activity by peroxisome-proliferator-activated receptor gamma co-activator 1 alpha. Biochem J. 2003;371:89-96.[Medline]
119. Vega RB, Huss JM, Kelly DP. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol. 2000;20:1868-1876.[Abstract/Free Full Text]
120. Savkur RS, Thomas JS, Bramlett KS, Gao Y, Michael LF, Burris TP. Ligand-dependent coactivation of the human bile acid receptor FXR by the peroxisome proliferator-activated receptor {gamma} coactivator-1{alpha}. J Pharmacol Exp Ther. 2005;312:170-178.[Abstract/Free Full Text]
121. Delerive P, Wu Y, Burris TP, Chin WW, Suen CS. PGC-1 functions as a transcriptional coactivator for the retinoid X receptors. J Biol Chem. 2002;277:3913-3917.[Abstract/Free Full Text]
122. Knutti D, Kaul A, Kralli A. A tissue-specific coactivator of steroid receptors, identified in a functional genetic screen. Mol Cell Biol. 2000;20:2411-2422.[Abstract/Free Full Text]
123. Shiraki T, Sakai N, Kanaya E, Jingami H. Activation of orphan nuclear constitutive androstane receptor requires subnuclear targeting by peroxisome proliferator-activated receptor gamma coactivator-1 alpha. A possible link between xenobiotic response and nutritional state. J Biol Chem. 2003;278:11344-11350.[Abstract/Free Full Text]
124. Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev. 2004;18:157-169.[Abstract/Free Full Text]
125. Huss JM, Kopp RP, Kelly DP. Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha. J Biol Chem. 2002;277:40265-40274.[Abstract/Free Full Text]
126. Schreiber SN, Knutti D, Brogli K, Uhlmann T, Kralli A. The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha). J Biol Chem. 2003;278:9013-9018.[Abstract/Free Full Text]
127. Puigserver P, Rhee J, Donovan JG, et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature. 2003;423:550-555.[Medline]
128. Hirota K, Daitoku H, Matsuzaki H, et al. Hepatocyte nuclear factor-4 is a novel downstream target of insulin via FKHR as a signal-regulated transcriptional inhibitor. J Biol Chem. 2003;278:13056-13060.[Abstract/Free Full Text]
129. Dowell P, Otto TC, Adi S, Lane MD. Convergence of peroxisome proliferator-activated receptor gamma and Foxo1 signaling pathways. J Biol Chem. 2003;278:45485-45491.[Abstract/Free Full Text]
130. Kodama S, Koike C, Negishi M, Yamamoto Y. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol Cell Biol. 2004;24:7931-7940.[Abstract/Free Full Text]
131. Corton JC, Anderson SP, Stauber A. Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators. Annu Rev Pharmacol Toxicol. 2000;40:491-518.[Medline]
132. Corton JC, Lapinskas PJ, Gonzalez FJ. Central role of PPARalpha in the mechanism of action of hepatocarcinogenic peroxisome proliferators. Mutat Res. 2000;448:139-151.[Medline]
133. Klaunig JE, Babich MA, Baetcke KP, et al. PPARalpha agonist-induced rodent tumors: modes of action and human relevance. Crit Rev Toxicol. 2003;33:655-780.[Medline]
134. Inoue H, Jiang XF, Katayama T, Osada S, Umesono K, Namura S. Brain protection by resveratrol and fenofibrate against stroke requires peroxisome proliferator-activated receptor alpha in mice. Neurosci Lett. 2003;352:203-206.[Medline]
135. Fu J, Gaetani S, Oveisi F, et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature. 2003;425:90-93.[Medline]
136. Lee SS, Pineau T, Drago J, et al. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol. 1995;15:3012-3022.[Abstract]
137. Escher P, Braissant O, Basu-Modak S, Michalik L, Wahli W, Desvergne B. Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding. Endocrinology. 2001;142:4195-4202.[Abstract/Free Full Text]
138. Gremlich S, Nolan C, Roduit R, et al. Pancreatic islet adaptation to fasting is dependent on peroxisome proliferator-activated receptor alpha transcriptional up-regulation of fatty acid oxidation. Endocrinology. 2005;146:375-382.[Abstract/Free Full Text]
139. Roduit R, Morin J, Masse F, et al. Glucose down-regulates the expression of the peroxisome proliferator-activated receptor-alpha gene in the pancreatic beta -cell. J Biol Chem. 2000;275:35799-35806.[Abstract/Free Full Text]
140. de Lange P, Ragni M, Silvestri E, et al. Combined cDNA array/RT-PCR analysis of gene expression profile in rat gastrocnemius muscle: relation to its adaptive function in energy metabolism during fasting. FASEB J. 2004;18:350-352.[Abstract/Free Full Text]
141. Kroetz DL, Yook P, Costet P, Bianchi P, Pineau T. Peroxisome proliferator-activated receptor alpha controls the hepatic CYP4A induction adaptive response to starvation and diabetes. J Biol Chem. 1998;273:31581-31589.[Abstract/Free Full Text]
142. Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest. 1999;103:1489-1498.[Medline]
143. Leone TC, Weinheimer CJ, Kelly DP. A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci U S A. 1999;96:7473-7478.[Abstract/Free Full Text]
144. Sugden MC, Bulmer K, Gibbons GF, Holness MJ. Role of peroxisome proliferator-activated receptor-alpha in the mechanism underlying changes in renal pyruvate dehydrogenase kinase isoform 4 protein expression in starvation and after refeeding. Arch Biochem Biophys. 2001;395:246-252.[Medline]
145. Young ME, Patil S, Ying J, et al. Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor (alpha) in the adult rodent heart. FASEB J. 2001;15:833-845.[Abstract/Free Full Text]
146. Kamijo Y, Hora K, Tanaka N, et al. Identification of functions of peroxisome proliferator-activated receptor alpha in proximal tubules. J Am Soc Nephrol. 2002;13:1691-1702.[Abstract/Free Full Text]
147. Kok T, Wolters H, Bloks VW, et al. Induction of hepatic ABC transporter expression is part of the PPARalpha-mediated fasting response in the mouse. Gastroenterology. 2003;124:160-171.[Medline]
148. Wu P, Peters JM, Harris RA. Adaptive increase in pyruvate dehydrogenase kinase 4 during starvation is mediated by peroxisome proliferator-activated receptor alpha. Biochem Biophys Res Commun. 2001;287:391-396.[Medline]
149. Holness MJ, Bulmer K, Gibbons GF, Sugden MC. Up-regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) protein expression in oxidative skeletal muscle does not require the obligatory participation of peroxisome-proliferator-activated receptor alpha (PPARalpha). Biochem J. 2002;366:839-846.[Medline]
150. Nielsen EM, Hansen L, Echwald SM, et al. Evidence for an association between the Leu162Val polymorphism of the PPARalpha gene and decreased fasting serum triglyceride levels in glucose tolerant subjects. Pharmacogenetics. 2003;13:417-423.[Medline]
151. Masternak MM, Al-Regaiey K, Bonkowski MS, et al. Divergent effects of caloric restriction on gene expression in normal and long-lived mice. J Gerontol Biol Sci Med Sci. 2004;59A:784-788.[Medline]
152. Kim HJ, Jung KJ, Yu BP, Cho CG, Choi JS, Chung HY. Modulation of redox-sensitive transcription factors by calorie restriction during aging. Mech Ageing Dev. 2002;123:1589-1595.[Medline]
153. Bokov A, Chaudhuri A, Richardson A. The role of oxidative damage and stress in aging. Mech Ageing Dev. 2004;125:811-826.[Medline]
154. Anderson SP, Yoon L, Richard EB, Dunn CS, Cattley RC, Corton JC. Delayed liver regeneration in peroxisome proliferator-activated receptor-alpha-null mice. Hepatology. 2002;36:544-554.[Medline]
155. Chen C, Hennig GE, Whiteley HE, Corton JC, Manautou JE. Peroxisome proliferator-activated receptor alpha-null mice lack resistance to acetaminophen hepatotoxicity following clofibrate exposure. Toxicol Sci. 2000;57:338-344.[Abstract/Free Full Text]
156. Mehendale HM. PPAR-alpha: a key to the mechanism of hepatoprotection by clofibrate. Toxicol Sci. 2000;57:187-190.[Abstract/Free Full Text]
157. Shankar K, Vaidya VS, Corton JC, et al. Activation of PPAR-alpha in streptozotocin-induced diabetes is essential for resistance against acetaminophen toxicity. FASEB J. 2003;17:1748-1750.[Abstract/Free Full Text]
158. Wheeler MD, Smutney OM, Check JF, Rusyn I, Schulte-Hermann R, Thurman RG. Impaired Ras membrane association and activation in PPARalpha knockout mice after partial hepatectomy. Am J Physiol Gastrointest Liver Physiol. 2003;284:G302-G312.[Abstract/Free Full Text]
159. Anderson SP, Howroyd P, Liu J, et al. The transcriptional response to a peroxisome proliferator-activated receptor alpha agonist includes increased expression of proteome maintenance genes. J Biol Chem. 2004;279:52390-52398.[Abstract/Free Full Text]
160. Shankar K, Vaidya VS, Apte UM, et al. Type 1 diabetic mice are protected from acetaminophen hepatotoxicity. Toxicol Sci. 2003;73:220-234.[Abstract/Free Full Text]
161. Shankar K, Vaidya VS, Wang T, Bucci TJ, Mehendale HM. Streptozotocin-induced diabetic mice are resistant to lethal effects of thioacetamide hepatotoxicity. Toxicol Appl Pharmacol. 2003;188:122-134.[Medline]
162. Ueda A, Hamadeh HK, Webb HK, et al. Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol Pharmacol. 2002;61:1-6.[Abstract/Free Full Text]
163. Bauer M, Hamm AC, Bonaus M, et al. Starvation response in mouse liver shows strong correlation with life-span-prolonging processes. Physiol Genomics. 2004;17:230-244.[Abstract/Free Full Text]
164. Weindruch R, Sohal RS. Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. N Engl J Med. 1997;337:986-994.[Free Full Text]
165. Maglich JM, Watson J, McMillen PJ, Goodwin B, Willson TM, Moore JT. The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction. J Biol Chem. 2004;279:19832-19838.[Abstract/Free Full Text]
166. McElwee JJ, Schuster E, Blanc E, Thomas JH, Gems D. Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance. J Biol Chem. 2004;279:44533-44543.[Abstract/Free Full Text]
167. Dominici FP, Argentino DP, Bartke A, Turyn D. The dwarf mutation decreases high dose insulin responses in skeletal muscle, the opposite of effects in liver. Mech Ageing Dev. 2003;124:819-827.[Medline]
168. Bielschowsky F, Bielschowsky M. Carcinogenesis in the pituitary dwarf mouse. The response to methylcholanthrene injected subcutaneously. Br J Cancer. 1959;13:302-305.[Medline]
169. Rennels EG, Anigstein DM, Anigstein L. A cumulative study of the growth of sarcoma 180 in anterior pituitary dwarf mice. Tex Rep Biol Med. 1965;23:776-781.[Medline]
170. Ikeno Y, Bronson RT, Hubbard GB, Lee S, Bartke A. Delayed occurrence of fatal neoplastic diseases in Ames dwarf mice: correlation to extended longevity. J Gerontol Biol Sci Med Sci. 2003;58A:291-296.[Medline]
171. Bugni JM, Poole TM, Drinkwater NR. The little mutation suppresses DEN-induced hepatocarcinogenesis in mice and abrogates genetic and hormonal modulation of susceptibility. Carcinogenesis. 2001;22:1853-1862.[Abstract/Free Full Text]
172. Kinney BA, Meliska CJ, Steger RW, Bartke A. Evidence that Ames dwarf mice age differently from their normal siblings in behavioral and learning and memory parameters. Horm Behav. 2001;39:277-284.[Medline]
173. Flurkey K, Papaconstantinou J, Miller RA, Harrison DE. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci U S A. 2001;98:6736-6741.[Abstract/Free Full Text]
174. Murakami S, Salmon A, Miller RA. Multiplex stress resistance in cells from long-lived dwarf mice. FASEB J. 2003;17:1565-1566.[Abstract/Free Full Text]
175. Salmon AB, Murakami S, Bartke A, Kopchick J, Yasumura K, Miller RA. Fibroblast cell lines from young adult mice of long-lived mutant strains are resistant to multiple forms of stress. Am J Physiol Endocrinol Metab. 2005;289:E23-E29.[Abstract/Free Full Text]
176. Hsieh CC, DeFord JH, Flurkey K, Harrison DE, Papaconstantinou J. Effects of the Pit1 mutation on the insulin signaling pathway: implications on the longevity of the long-lived Snell dwarf mouse. Mech Ageing Dev. 2002;123:1245-1255.[Medline]
177. Hsieh CC, Papaconstantinou J. Akt/PKB and p38 MAPK signaling, translational initiation and longevity in Snell dwarf mouse livers. Mech Ageing Dev. 2004;125:785-798.[Medline]
178. Miller RA, Chang Y, Galecki AT, Al-Regaiey K, Kopchick JJ, Bartke A. Gene expression patterns in calorically restricted mice: partial overlap with long-lived mutant mice. Mol Endocrinol. 2002;16:2657-2666.[Abstract/Free Full Text]
179. Boylston WH, Gerstner A, DeFord JH, et al. Papaconstantinou J. Altered cholesterologenic and lipogenic transcriptional profile in livers of aging Snell dwarf (Pit1dw/dwJ) mice. Aging Cell. 2004;3:283-296.[Medline]
180. Amador-Noguez D, Yagi K, Venable S, Darlington G. Gene expression profile of long-lived Ames dwarf mice and Little mice. Aging Cell. 2004;3:423-441.[Medline]
181. Stauber AJ, Brown-Borg H, Liu J, et al. Constitutive expression of peroxisome proliferator-activated receptor {alpha}-regulated genes in dwarf mice. Mol Pharmacol. 2005;67:681-694.[Abstract/Free Full Text]
182. Zhou YC, Waxman DJ. Cross-talk between janus kinase-signal transducer and activator of transcription (JAK-STAT) and peroxisome proliferator-activated receptor-alpha (PPARalpha) signaling pathways. Growth hormone inhibition of PPARalpha transcriptional activity mediated by stat5b. J Biol Chem. 1999;274:2672-2681.[Abstract/Free Full Text]
183. Zhou YC, Waxman DJ. STAT5b down-regulates peroxisome proliferator-activated receptor alpha transcription by inhibition of ligand-independent activation function region-1 trans-activation domain. J Biol Chem. 1999;274:29874-29882.[Abstract/Free Full Text]
184. Tollet-Egnell P, Flores-Morales A, Stahlberg N, Malek RL, Lee N, Norstedt G. Gene expression profile of the aging process in rat liver: normalizing effects of growth hormone replacement. Mol Endocrinol. 2001;15:308-318.[Abstract/Free Full Text]
185. Zhou YC, Davey HW, McLachlan MJ, Xie T, Waxman DJ. Elevated basal expression of liver peroxisomal beta-oxidation enzymes and CYP4A microsomal fatty acid omega-hydroxylase in STAT5b(-/-) mice: cross-talk in vivo between peroxisome proliferator-activated receptor and signal transducer and activator of transcription signaling pathways. Toxicol Appl Pharmacol. 2002;182:1-10.[Medline]
186. Astrand PO. Physical activity and fitness. Am J Clin Nutr. 1992;55:1231S-1236S.[Abstract/Free Full Text]
187. McCarter RJ. Age-related changes in skeletal muscle function. Aging (Milano). 1990;2:27-38.[Medline]
188. Bronikowski AM, Carter PA, Morgan TJ, et al. Lifelong voluntary exercise in the mouse prevents age-related alterations in gene expression in the heart. Physiol Genomics. 2003;12:129-138.[Abstract/Free Full Text]
189. Norrbom J, Sundberg CJ, Ameln H, Kraus WE, Jansson E, Gustafsson T. PGC-1alpha mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle. J Appl Physiol. 2004;96:189-194.[Abstract/Free Full Text]
190. Russell AP, Hesselink MK, Lo SK, Schrauwen P. Regulation of metabolic transcriptional co-activators and transcription factors with acute exercise. FASEB J. 2005;19:986-988.[Abstract/Free Full Text]
191. Lin J, Wu H, Tarr PT, et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature. 2002;418:797-801.[Medline]
192. Russell AP, Feilchenfeldt J, Schreiber S, et al. Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes. 2003;52:2874-2881.[Abstract/Free Full Text]
193. Lyman CP, O'Brien RC, Greene GC, Papafrangos ED. Hibernation and longevity in the Turkish hamster Mesocricetus brandti. Science. 1981;212:668-670.[Abstract/Free Full Text]
194. Cai D, McCarron RM, Yu EZ, Li Y, Hallenbeck J. Akt phosphorylation and kinase activity are down-regulated during hibernation in the 13-lined ground squirrel. Brain Res. 2004;1014:14-21.[Medline]
195. Storey KB. Mammalian hibernation. Transcriptional and translational controls. Adv Exp Med Biol. 2003;543:21-38.[Medline]
196. Andrews MT. Genes controlling the metabolic switch in hibernating mammals. Biochem Soc Trans. 2004;32:1021-1024.[Medline]
197. Glueck SB, Heldmaier G. Settling down for a long winter's nap: focus on "coordinate expression of the PDK4 gene: a means of regulating fuel selection in a hibernating mammal". Physiol Genomics. 2002;8:3-4.[Free Full Text]
198. McCarroll SA, Murphy CT, Zou S, et al. Comparing genomic expression patterns across species identifies shared transcriptional profile in aging. Nat Genet. 2004;36:197-204.[Medline]
199. Patti ME, Butte AJ, Crunkhorn S, et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A. 2003;100:8466-8471.[Abstract/Free Full Text]
200. Mootha VK, Lindgren CM, Eriksson KF, et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34:267-273.[Medline]
201. Lee CK, Klopp RG, Weindruch R, Prolla TA. Gene expression profile of aging and its retardation by caloric restriction. Science. 1999;285:1390-1393.[Abstract/Free Full Text]
202. Weindruch R, Kayo T, Lee CK, Prolla TA. Gene expression profiling of aging using DNA microarrays. Mech Ageing Dev. 2002;123:177-193.[Medline]
203. Kayo T, Allison DB, Weindruch R, Prolla TA. Influences of aging and caloric restriction on the transcriptional profile of skeletal muscle from rhesus monkeys. Proc Natl Acad Sci U S A. 2001;98:5093-5098.[Abstract/Free Full Text]
204. Welle S, Brooks AI, Delehanty JM, Needler N, Thornton CA. Gene expression profile of aging in human muscle. Physiol Genomics. 2003;14:149-159.[Abstract/Free Full Text]
205. Ling C, Poulsen P, Carlsson E, et al. Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins. J Clin Invest. 2004;114:1518-1526.[Medline]
206. Sanguino E, Roglans N, Alegret M, Sanchez RM, Vazquez-Carrera M, Laguna JC. Atorvastatin reverses age-related reduction in rat hepatic PPARalpha and HNF-4. Br J Pharmacol. 2005;145:853-861.[Medline]
207. Valle I, Alvarez-Barrientos A, Arza E, Lamas S, Monsalve M. PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc Res. 2005;66:562-573.[Abstract/Free Full Text]
208. Jones DC, Manning BM, Daynes RA. A role for the peroxisome proliferator-activated receptor alpha in T-cell physiology and ageing immunobiology. Proc Nutr Soc. 2002;61:363-369.[Medline]
209. Perichon R, Bourre JM. Liver peroxisomal fatty acid oxidizing system during aging in control and clofibrate-treated mice. Biochem Mol Biol Int. 1995;37:475-480.[Medline]
210. Perichon R, Bourre JM. Aging-related decrease in liver peroxisomal fatty acid oxidation in control and clofibrate-treated mice. A biochemical study and mechanistic approach. Mech Ageing Dev. 1996;87:115-126.[Medline]
211. Youssef J, Badr M. Biology of senescent liver peroxisomes: role in hepatocellular aging and disease. Environ Health Perspect. 1999;107:791-797.[Medline]
212. Sung B, Park S, Yu BP, Chung HY. Modulation of PPAR in aging, inflammation, and calorie restriction. J Gerontol Biol Sci Med Sci. 2004;59A:997-1006.[Medline]
213. Iemitsu M, Miyauchi T, Maeda S, et al. Aging-induced decrease in the PPAR-alpha level in hearts is improved by exercise training. Am J Physiol Heart Circ Physiol. 2002;283:H1750-H1760.[Abstract/Free Full Text]
214. Lee CK, Allison DB, Brand J, Weindruch R, Prolla TA. Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts. Proc Natl Acad Sci U S A. 2002;99:14988-14993.[Abstract/Free Full Text]
215. Chao C, Youssef J, Rezaiekhaleigh M, Birnbaum LS, Badr M. Senescence-associated decline in hepatic peroxisomal enzyme activities corresponds with diminished levels of retinoid X receptor alpha, but not peroxisome proliferator-activated receptor alpha. Mech Ageing Dev. 2002;123:1469-1476.[Medline]
216. Long X, Boluyt MO, O'Neill L, et al. Myocardial retinoid X receptor, thyroid hormone receptor, and myosin heavy chain gene expression in the rat during adult aging. J Gerontol Biol Sci Med Sci. 1999;54A:B23-B27.[Abstract]
217. Enderlin V, Pallet V, Alfos S, et al. Age-related decreases in mRNA for brain nuclear receptors and target genes are reversed by retinoic acid treatment. Neurosci Lett. 1997;229:125-129.[Medline]
218. Poynter ME, Daynes RA. Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging. J Biol Chem. 1998;273:32833-32841.[Abstract/Free Full Text]
219. Watanabe K, Fujii H, Takahashi T, et al. Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor alpha associated with age-dependent cardiac toxicity. J Biol Chem. 2000;275:22293-22299.[Abstract/Free Full Text]
220. Howroyd P, Swanson C, Dunn C, Cattley RC, Corton JC. Decreased longevity and enhancement of age-dependent lesions in mice lacking the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Toxicol Pathol. 2004;32:591-599.[Medline]
221. Teillet L, Ribiere P, Gouraud S, Bakala H, Corman B. Cellular signaling, AGE accumulation and gene expression in hepatocytes of lean aging rats fed ad libitum or food-restricted. Mech Ageing Dev. 2002;123:427-439.[Medline]

This article has been cited by other articles:

				G. G. Lavery, E. A. Walker, N. Turan, D. Rogoff, J. W. Ryder, J. M. Shelton, J. A. Richardson, F. Falciani, P. C. White, P. M. Stewart, et al. Deletion of Hexose-6-phosphate Dehydrogenase Activates the Unfolded Protein Response Pathway and Induces Skeletal Myopathy J. Biol. Chem., March 28, 2008; 283(13): 8453 - 8461. [Abstract] [Full Text] [PDF]

				D. Li, Q. Kang, and D.-M. Wang Constitutive Coactivator of Peroxisome Proliferator-Activated Receptor (PPAR{gamma}), a Novel Coactivator of PPAR{gamma} that Promotes Adipogenesis Mol. Endocrinol., October 1, 2007; 21(10): 2320 - 2333. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Services Download to citation manager Citing Articles Citing Articles via HighWire PubMed PubMed Citation