The mTOR signaling pathway in cardiac aging
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, ... Abstract
The mammalian target of rapamycin (mTOR) is one of the most important signaling pathways that regulate nutrient sensing, cell growth, metabolism, and aging. The mTOR pathway, particularly mTOR complex 1 (mTORC1), has been shown to control aging, lifespan, and healthspan through the regulation of protein synthesis, autophagy, mitochondrial function, and metabolic health. The mTOR pathway also plays critical roles in the heart, from cardiac development, growth and maturation, and maintenance of cardiac homeostasis. Hyperactivation of mTORC1 signaling is well documented in aging and many age-related pathologies, including age-related cardiac dysfunction and heart failure. Suppression of mTORC1 by calorie restriction or rapamycin not only extends lifespan but also restores youthful phenotypes in the heart. In this article, we review model organisms of cardiac aging and highlight recent advances in the impact of the mTORC1 pathway on organismal and cardiac aging, particularly in Drosophila and mice. We focus on the downstream signaling pathways S6 kinase and 4EBP1, which regulates protein synthesis, as well as ULK1 and its related pathway that regulates autophagy. The interaction with mTOR complex 2 (mTORC2) and its potential role in cardiac aging are also discussed.
Keywords
INTRODUCTION
The target of rapamycin (TOR) was originally identified in yeast as the cellular target of the immunosuppressant and anticancer drug known as rapamycin[1]. In mammals, two mTOR complexes with distinct structures and functions are found - the mTOR complex 1 (mTORC1) and the mTOR complex 2 (mTORC2). The mTORC1 consists of mTOR, Raptor (regulatory-associated protein of mTOR), and mammalian LST8 homolog (mLst8). The mTORC1 activity is modulated by several additional components, including DEPTOR, the DEP domain containing mTOR interacting protein, and the PRAS40. The mTORC2 contains mTOR, the rapamycin-insensitive companion of mTOR (Rictor), mLST8, and the mammalian stress-activated protein kinase-interacting 1 (mSin1). Further, the additional components of mTORC2 include DEPTOR and the protein observed with Rictor 1 and 2 (also known as Protor1/2)[2,3] (see review[4] for detail).
The mTORC1 activity is finely tuned by several environmental cues, including the levels of intracellular nutrients and energy, growth factors as well as other cellular stresses [Figure 1]. The current review will focus on downstream pathways regulated by mTOR and will briefly discuss the upstream regulators of mTOR [Figure 1].
Figure 1. mTORC1 and mTORC2 signaling in the regulation of protein synthesis, lipid and glucose metabolism, mitochondrial function, autophagy, and cytoskeleton organization.
UPSTREAM REGULATORS OF mTOR
mTORC1 is activated by nutrients, growth factors and mitogen-dependent signaling. Many of these signals inhibit the Tuberous Sclerosis Complex (TSC, a key negative regulator of mTORC1), which then activate the small GTPase Rheb[5]. Conversely, mTORC1 is inactivated by nutrient deprivation. On the one hand, upon depletion in cellular energy, adenosine monophosphate (AMP)-activated protein kinase (AMPK) is activated to block mTORC1 activities via the phosphorylation of either TSC2 or Raptor[6,7]. On the other hand, glucose deprivation inhibits mTORC1 via Rag GTPases in an AMPK-independent manner[8,9]. These are consistent with the essential role of mTORC1 in nutrient sensing and growth promotion[10] [Figure 1].
Amino acids are major nutrients activating mTORC1. During aging, mTORC1 is activated by food intake, particularly amino acid availability. Breakdown of dietary proteins from food intake increases serum amino acid levels. Amino acid stimulates the Rag GTPases to facilitate the binding to Raptor and activation of mTORC1[11,12]. GATOR1 and GATOR2 complexes have been reported as amino acid sensors and upstream activators of mTORC1[13]. Branched-chain amino acids (BCAA, including isoleucine, leucine and valine) are potent activators of mTORC1 that increase protein synthesis, as well as regulate lipid and glucose metabolisms. In addition, a high concentration of BCAA induces mitochondrial dysfunction and ROS, promotes the activation of NF-κB, and increases the expression of cytokines and adhesion molecules in peripheral blood mononuclear cells[14]. The effect of BCAA in increasing oxidative stress and inflammation is mediated through the activation of mTORC1[14]. This links many signaling pathways that have been implicated in the aging process, including ROS, inflammation and mTOR.
Besides nutrient sensing, mTORC1 is involved in the regulation of hypoxia and DNA damage responses. For example, mTORC1 is inhibited by AMPK and REDD1 under hypoxia[15], while DNA damage inhibits mTORC1 through p53 activation[16]. Interestingly, resistance exercise inhibits mTORC1 via AMPK and Sestrins[17]. Sestrins are a family of evolutionarily conserved exercise-inducible proteins that mediate the metabolic benefits of exercise through mTORC1 inhibition and mTORC2 activation[18,19]. Molecular and genetic evidence suggests that Sestrins are induced by the FOXO transcription factor, while Sestrins inhibit mTORC1 via activation of AMPK and TSC2[20,21]. The upstream regulators of mTOR signaling are discussed in further detail in the previous review[10].
mTORC2 can also be activated by growth factor pathways, in particular insulin/PI3K signaling [Figure 1]. Upon the activation of PI3K signaling, PtdIns(3,4,5)P3 binds to the pleckstrin homology (PH) domain of mTORC2 subunit SIN1, which releases the autoinhibition on the mTOR kinase domain and triggers mTORC2 activation[22]. The mTORC2 activity can also be influenced by mTORC1. Two phosphoproteomic studies identify that mTORC1 phosphorylates and activates Grb10 to negatively control insulin/IGF-1 signaling, the upstream effector of mTORC2[23]. In addition, mTORC1 target S6K1 inhibits mTORC2 through the phosphorylation of insulin receptor substrate 1 (IRS1)[24,25]
DOWNSTREAM SIGNALING PATHWAYS
Regulation of protein synthesis through S6 Kinase and 4EBP1
Overall, mTORC1 activation increases the expression of genes related to growth and metabolism[26]. However, it decreases the expression of genes involved in stress adaptation[27]. To support growth, mTORC1 plays a major role in controlling protein synthesis. mTORC1 activation promotes protein translation through both S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding proteins (4E-BP)[26] [Figure 1]. S6K1 upregulates genes for ribosomal proteins, ribosome biogenesis factors, and tRNAs, leading to ribosome biogenesis[28-31] and promoting protein synthesis. Ribosomal protein S6 is the substrate of S6K1 that has been used as a marker of mTORC1 activity[32]. When phosphorylated and activated by mTORC1, S6K1 phosphorylates programmed cell death protein 4 (PDCD4), which is then targeted for degradation[33]. The PDCD4 functions to inhibit protein translation by blocking eIF4A helicase that controls ribosome biogenesis. The ability of mTORC1 to phosphorylate and activate S6K1 is modulated by the alterations of intracellular ATP levels[34]. S6K1 regulates cell size, growth, and metabolism[35]. The latter is modulated by adenosine monophosphate (AMP)-activated protein kinase (AMPK)[36]. This interaction between mTOR and AMPK links the major nutrient pathway and energy sensor signaling pathways within the cells.
The mTORC1 also targets 4E-BP1 through phosphorylation and releases the latter from eiF4E, thereby de-repressing the cap-dependent initiation of translation[37]. The eukaryotic initiation factor - 4F (eIF4F) complex - regulates the association between mRNA cap-binding protein - eIF4E - and scaffold protein - eIF4G, thus mediating growth-dependent protein synthesis[38]. Consequently, this process leads to mRNA circularization and an increased translation rate[38].
Inhibition of autophagy
Autophagy is an essential cellular homeostasis process responsible for the degradation and recycling of damaged macromolecules and organelles[39]. This essential cellular process is also modulated by mTOR. Autophagy is activated or inhibited in response to a variety of upstream signaling, such as nutrient signaling (mTOR, insulin, AMPK), Ras/PKA pathway, ER stress, hypoxia, oxidative stress and pathogen infection[40]. Autophagic activity declines in aged tissues[41], including the hypothalamus[42], liver[43], skeletal muscle[44], and heart[45,46]. Studies in model organisms demonstrate a direct link between autophagy and longevity control since genetic disruption of autophagy genes blocks the lifespan extension by insulin-like signaling mutants, dietary restriction, and rapamycin treatment[47-49]. Furthermore, suppression of autophagy can lead to cardiomyopathy[46], while activation of autophagy by disruption of beclin1 significantly increases lifespan and diminishes age-related cardiac hypertrophy and fibrosis[50].
Autophagic activity can be enhanced by fasting or rapamycin, both of which are mediated by mTORC1 inhibition[51,52]. Mechanistically, mTORC1 inhibits autophagy by the phosphorylation of Unc-51 Like Autophagy Activating Kinase 1 (ULK1), ATG13[53], and transcription factor EB (TFEB)[54,55] [Figure 1]. Inhibition of mTOR by rapamycin (RP) treatment results in the dephosphorylation of ULK1, which then initiates autophagosome formation[53]. In addition, the mTORC1 also phosphorylates TFEB, a master transcriptional regulator of autophagy and lysosome genes. The phosphorylation of TFEB prevents its nuclear localization and reduces autophagy through transcriptional regulation[54,55].
The age-dependent decline of autophagy has been linked to elevated mTOR activity observed in many, but not all, aging tissues[56,57]. The decline of autophagic activity in many aged tissues can be restored by mTOR inhibition[39]. The critical role of mTOR regulation of autophagy in aging is supported by the finding that the lifespan extension induced via mTOR inhibition can be attenuated by knocking down autophagy genes, such as Ulk1[48,58], hlh-30/Tfeb[59], and Atg5[49]. These studies show that the pro-longevity effect of mTOR inhibition is at least partly mediated by an autophagy-dependent mechanism. Furthermore, TGFβ/activin-regulated inhibition of mTORC2 has been recently shown as another mechanism for the age-dependent decline of autophagic activity in Drosophila cardiomyocytes[45]. Either knockdown of TGFβ/activin ligand daw or overexpression of mTORC2 subunit Rictor rescue autophagy in aged cardiomyocytes and preserved cardiac function with age[45]. However, the negative regulation of mTORC2 on autophagy has been previously reported. AKT inhibits autophagy via direct phosphorylation of Beclin-1, while overexpression of Rictor attenuates MIR211-induced autophagy in HeLa cells[60,61]. Besides bulk autophagy, mTOR signaling has also been linked to mitophagy regulation under oxidative stress[62]. However, how mTOR-regulated mitophagy contributes to cardiac aging remains to be further determined.
Regulation of lipid metabolism
Metabolic syndrome is well-known to increase the risk of cardiovascular diseases. Excessive dietary fat consumption or pathogenic liver lipogenesis promotes cardiac lipotoxicity in cardiomyocytes, which may lead to cardiomyopathy[63]. In animal models fed with a high-fat diet, fatty acid oxidation is upregulated, and mitochondrial energetics is reduced, predisposing to cardiomyopathy resembling those found in diabetes or cardiometabolic syndrome. The cardiac dysfunction may manifest as either reduced or preserved left ventricular ejection fraction (systolic function), and left ventricular diastolic function is commonly impaired[64-68]. Thus, maintaining the metabolic health of the heart is crucial for its normal function.
Besides its key role in amino acid sensing and protein synthesis, mTOR also regulates lipid metabolism (see reviews[69-71]). Genetic manipulations of either mTORC1 or mTORC2 signaling components can lead to aberrant lipid metabolism. Hyperactivation of mTORC1 via liver-specific TSC1 deletion blocks ketogenesis in fasted mice[72]. Deletion of TSC2 also leads to enhanced adipogenesis[73]. Additionally, mice with S6K1 or RAPTOR deletion show reduced adipogenesis and are resistant to high-fat diet-mediated weight gain[74,75]. It is known that mTORC1 regulates lipogenesis through transcriptional and post-transcriptional regulation of SREBP transcription factors[76,77]. Recently, mTORC1 has been found to regulate de novo lipogenesis via histone demethylase JMJD1C[78] and splicing regulator SRPK2[79]. Similar to mTORC1, mTORC2 also positively controls lipogenesis. The adipocytes with Rictor knock-out mice show elevated basal lipolysis, while liver-specific Rictor knock-out blocks insulin-induced hepatic lipogenesis[80,81], likely due to the dysregulated transcription of the key lipogenic genes.
A high-fat diet is a major cause of metabolic syndrome that predisposes to cardiovascular diseases. In Drosophila, high-fat diet-induced cardiomyopathy and excess fat accumulation can be attenuated by loss-of-function mutations of TOR[67]. In this context, both SREBP and PGC-1α are shown to be the downstream effectors in mediating TOR-regulated cardiac lipotoxicity[68]. In mice fed with a high-fat diet, cardiomyocyte autophagy is inhibited because of mTORC1 activation, while rapamycin or Rheb inactivation can restore autophagic activity and protect hearts from ischemia injury[82]. Consistent with this, rapamycin (RP) administration can also rescue obesity-associated cardiac hypertrophy, contractile dysfunction and fractional shortening in obese mouse models[83,84]. Further, mTORC1 inactivation by overexpressing PRAS40 prevents the development of diabetic cardiomyopathy and improves hepatic insulin sensitivity[85].
It has been shown that the aging heart is accompanied by a significant alteration in lipid metabolism. The old heart exhibits a decrease in fatty acid oxidation and an increase in glycolysis[86]. The reduced fatty acid oxidation in old hearts could lead to fat accumulation and, eventually, lipotoxicity and cardiomyopathy during aging. Recently, we found that a high-fat diet activates mTORC2 in Drosophila hearts, while loss of Rictor exaggerates cardiac contractile defects under high-fat diet treatment[87]. The cardiac protective role of mTORC2 might be due to its role in Drp1-mediated mitochondrial fission[87].
THE mTOR REGULATION OF ORGANISMAL AGING
In the aging process, the mTORC1 pathway is considered a major signaling mechanism. This significant role of mTOR signaling in aging was first demonstrated in C. elegans. Decreased expression of ceTOR (previously referred to as let-363, a homolog of mTOR) or daf-15 (a homolog of Raptor) aided in the life span extension of C. elegans[88,89]. mTOR contribution in this lifespan is further validated by the fact that the suppression of TOR signaling extended the lifespan of Saccharomyces (budding yeast)[90], Drosophila[91], and mice[92,93]. The mechanisms underlying the lifespan extension of mTORC1 inhibition may include suppression of protein synthesis (via eIF4E/4E-BP1 and S6K), enhancement of proteostasis (such as via ULK1 regulation of autophagy) and attenuation of oxidative stress[10]. In C. elegans, depletion of the eIF4F cap-binding complex component protein facilitates the lifespan extension process[94]. In mice, loss of the mTORC1 substrate S6 kinase (S6K1) extended lifespan and ameliorated several aging phenotypes in the musculoskeletal, immune, and metabolic systems[95]. In this context, the gene expression analysis of these mice revealed alterations resembling those observed in response to caloric restriction or AMPK activation[95].
It is pertinent to mention that Caloric Restriction (CR) is widely acknowledged as the most reproducible intervention for lifespan extension in numerous organisms, such as yeast, worm, fruit fly, and mice[96]. CR also extends the healthspan through the amelioration of various age-related diseases, including cardiovascular diseases[97], cancer[98], neurodegenerative diseases, retinal aging and macular degeneration[99,100], and age-dependent sensorineural hearing loss[101]. In non-human primates, moderate CR attenuated age-related pathological conditions, including diabetes, cancer, neurodegeneration, and cardiovascular diseases[102]. As briefly discussed above, hyperphagia with increased caloric intake resulted in lifespan shortening in various model organisms.
The mTORC1 is a master regulator of nutrient sensing[10]. Moreover, several studies support that mTORC1 mediates the beneficial anti-aging effects of CR. The overlapping mechanism of mTORC1 inhibition and CR is reinforced by the absence of additional life span extension by CR in yeast[90], worms[103], or flies[91] with decreased mTORC1 signaling. Downstream of mTORC1, translational modulation through 4E-BP is shown to mediate the protective effect of Dietary Restriction (DR)[37] in Drosophila. In this context, DR resulted in differential loading of mRNA onto ribosomes that later led to the preferential translation of mRNA of various mitochondrial proteins. This included the components of mitochondrial electron transport chains mediated by the upregulation of 4E-BP. The enhancement of mitochondrial activity and lifespan extension of Drosophila were dependent on 4E-BP[37]. Another study reported that muscle-specific overexpression of 4E-BP in Drosophila contributed to lifespan extension and proteostasis improvement[44]. Even though no apparent proof regarding the mediation of S6K1 on the beneficial effects of CR (as demonstrated for 4E-BP in Drosophila models) has surfaced, the contribution of S6K1 in the longevity is reflected in both the lifespan and healthspan extension in S6K1 knockout mice and the gene expression patterns that are similar to the CR effects[95].
The role of rapamycin (RP) as an inhibitor of mTORC1 highlights its ability to prolong both healthspan and lifespan in mammals and many model organisms that have been studied[49,104,105]. By inhibiting mTORC1, RP treatment led to several outcomes: global protein synthesis suppression, cell growth inhibition, activation of stress response pathway and autophagy[106]. Furthermore, mTOR complex I inhibition diminishes the energetic burden of protein translation, causes a reduction in oxidative stress, pauses the accumulation of deleterious metabolic by-products, and contributes to the enhancement of the autophagic removal of damaged macromolecules. Consequently, it leads to the improvement of cellular function[37,106].
It has been observed that the initiation of rapamycin in the later stages of life extended lifespan of genetically heterogeneous mice. It needs to be emphasized that the lifespan extension effect of RP has been reproducible by multiple independent observations reported by Harrison et al.[104]. This multi-institutional study also found gender and dose effects of RP in lifespan extension. It was revealed that each dose of RP increased the female lifespan more compared to the male counterparts[104,107]. Researchers attribute this gender difference to the sex difference in RP metabolism and blood levels[107]. Although RP was regarded to be a CR mimetic, it was not fully supported by extensive metabolomic and transcriptomic studies in mammalian white adipose tissue, liver, and blood. RP and CR did show some overlapping effects, yet there were distinctively unique and non-overlapping effects of CR and RP reflected in these tissues[108-110]. Indeed, it has been reported that subacute CR and RP discordantly altered mouse liver proteome homeostasis and reversed aging effects[111]. Further, RP demonstrates various endocrine and metabolic modifications in mice in a sex and dose-dependent manner, different from the CR effect[107]. However, both RP and CR attenuate protein oxidative harms and enhances overall protein quality[111]. Taken together, RP shares some overlapping mechanisms with CR, yet it also has some distinctive effects in multiple organ systems at the levels of proteomes and metabolomes.
MODEL ORGANISMS FOR CARDIAC AGING STUDIES
Drosophila cardiac aging model
Drosophila melanogaster, the fruit fly, has been widely used as an excellent genetic model to understand the mechanisms of cardiac aging. Drosophila not only provides a tractable genetic system, but the molecular signaling pathways governing heart development and aging are also highly conserved between flies and vertebrates[112-115]. The adult Drosophila heart is a linear tube consisting of 40-50 pairs of mature cardiomyocytes[116]. The first transcription factor (Tinman) that controls animal heart development was discovered in Drosophila[117], and this factor is highly conserved in vertebrates[118,119]. In addition, Drosophila hearts display an age-dependent decline in structure and function, similar to that found in mammalian hearts. For example, aged Drosophila hearts exhibit diastolic dysfunction, decreased fractional shortening, increased stiffness, increased collagen deposition, and impaired calcium handling, etc.[113]. These resemblances to mammalian cardiac aging make Drosophila an amenable genetic model in dissecting the mechanisms underlying cardiac aging.
The role of Drosophila as a model of cardiac aging is further supported by advances in innovative imaging analysis. For example, the Semi-automated Optical Heartbeat Analysis (SOHA) was developed to monitor fly heart wall movement using a high-speed digital camera and movement analysis algorithms[120]. The SOHA method offers high sensitivity in detecting subtle contractile defects, including changes in fractional shortening and cardiac arrhythmia[121]. Fluorescence-based optical heartbeat analysis on intact animals was developed by expressing fluorescence proteins in the hearts. Although the original method is limited by speed and resolution[122,123], a novel heart enhancer R94C02 has greatly improved the imaging resolution[124]. Optical Coherence Tomography (OCT) has been used as a noninvasive imaging technique to analyze the heart parameters from unanesthetized intact flies[125]. Atomic force microscopy (AFM), capable of evaluating the cardiomyocyte mechanical properties[126], has been applied to study age-related changes in cardiac stiffness[127,128] and cardiac remodeling of Troponin-T mutants in Drosophila. All of the above tools make the Drosophila heart system a powerful model for dissecting the determinants of cardiac aging.
Related to cardiac aging, long-lived Drosophila mutants in the insulin/insulin-like growth factor (IIS) signaling, such as InR and chico mutants, show preserved cardiac function with age[129]. The effects of IIS in cardiac aging are cell-autonomous, as cardiac-specific overexpression of dPTEN or dFOXO prevents age-related decline in cardiac performance[129]. The roles of TOR in Drosophila cardiac aging are demonstrated by genetic manipulation of its downstream target d4eBP and dS6K[130]. Both dS6K mutants and heart-specific d4eBP overexpression prevents the age-related decline of cardiac function and improves cardiac stress resistance, whereas heart-specific dTOR overexpression increases stress-induced heart failure at a young age[130]. Hyperactivation of TOR by Sestrin (dSesn) mutations results in dilated hearts and increased arrhythmia[20]. Sestrins belong to a family of exercise-inducible proteins and are key regulators in meditating exercise benefits in flies, including age-related cardiac protection[18-20]. Mechanistically, gene expression analysis of aging fly hearts showed upregulation of metalloproteases, genes involved in DNA replication and repair, and downregulation of genes in the mitochondrial matrix and carbohydrate metabolism[131]. A comparative meta-analysis with published rodent cardiac transcriptomics displays similarities in many age-related alterations between fly and rodent hearts, including extra-cellular matrix remodeling, mitochondrial metabolism, protein handling, and contractile functions[131].
Another recent study from our laboratory used Drosophila to uncover a novel role of TGF-β/activin signaling in regulating cardiac aging. We demonstrate that activin-mediated inhibition of mTORC2 is a novel mechanism responsible for the age-dependent decline of autophagy and cardiac health in Drosophila[45]. In summary, the sophisticated genetic tools and advanced imaging techniques will continue driving future discoveries using Drosophila as a model in cardiac aging research.
Murine models of cardiac aging
For studying cardiac aging, mice are considered the most valuable models. The extensive use of genetically modified mice offers invaluable tools to clarify the molecular mechanisms of cardiac aging. Since many of the laboratory mouse strains do not develop spontaneous hypertension, diabetes, or abnormal cholesterol with aging[132], the age-dependent changes in cardiac structures, function, or molecular compositions likely reflect intrinsic cardiac aging[133]. In the absence of the above-confounding factors, mice demonstrate cardiac aging changes that closely resemble the alterations in human cardiac aging (as reported in the Framingham Heart Study and Baltimore Longitudinal Study on Aging)[133-135]. Our longitudinal echocardiography study on a mouse longevity cohort[133] demonstrated an age-dependent increase in the left ventricular mass index (indicating the left ventricular hypertrophy) as well as an age-dependent decline in diastolic function measured by the ratio of early-to-late Tissue Doppler measurement of diastolic mitral annular velocity (Ea/Aa) and dilation of the left atrium. Only a modest reduction of systolic function from the young to the oldest group was observed[136]. These findings in C57Bl6/J mice were also confirmed in mice from other strain backgrounds, including C3H, BalbC, and hybrid strains (unpublished data). Histological examinations of old mouse hearts demonstrate increased interstitial fibrosis, cardiomyocyte hypertrophy or increased myocardial fiber size, and increased variation in myocyte fiber size, occasional cytoplasmic vacuolation, collapse of sarcomeres, mineralization, arteriosclerosis and arteriolosclerosis[137], increased cardiomyocyte apoptosis[138] and increased deposition of amyloid[139,140]. In humans, senile amyloidosis composed of wild-type transthyretin-derived amyloid fibrils accumulates in the heart of elderly patients. If the accumulation of amyloid is extensive, it could lead to cardiac hypertrophy, diastolic dysfunction and progressive heart failure[141]. The roles of mTORC1 in murine cardiac aging have been confirmed in many studies using caloric restriction or rapamycin[97,142]. We previously showed that short-term caloric restriction or rapamycin reversed age-dependent LV hypertrophy and ameliorated diastolic dysfunction in old mice, in conjunction with better preservation of mitochondrial proteome[97]. These mitochondrial-protective beneficial effects of mTORC1 inhibition are consistent with our prior observations that protecting mitochondria by mitochondrial targeted antioxidants attenuates heart failure in various mouse models[143-146]. Mice with genetic disruption of mTORC1 components have been extensively studied in the context of cardiac hypertrophy, heart failure and cardiomyopathy (see below).
In addition to mouse and rat models, the naked mole-rat (NMR) is a unique rodent about the size of mice (~40 g) with extraordinary longevity (> 37 years). Potential mechanisms underlying the longevity of NMR include: (1) high levels of autophagy throughout the majority of their lifespan[147](mTOR activation suppresses autophagy); (2) increased translational fidelity because of their unique 28S ribosomal RNA cleavage pattern[148]; (3) increased resistance to hypoxia and oxidative stress[149]; and (4) dampened inflammatory response[150]. Unlike mice that manifest several phenotypes of human cardiac aging, NMR maintains cardiac function and functional reserve capacity until late in life (~34 years), with less LV hypertrophy and less premature beat arrhythmia, and better-preserved diastolic function[151].
Large mammals in the study of cardiac aging
According to a study conducted on ~9,000 dogs of various breeds, the most common cause of death were cardiovascular diseases[152]. Chronic degenerative valvular heart diseases were the most prominent, whereby they caused death in ~75% of dogs (16+ years old)[153]. Other common cardiovascular diseases in aged dogs include dilated cardiomyopathy, amyloidosis, lipofuscinosis, and sick sinus syndrome. Cardiac aging in dogs is characterized by decreased contractility, impaired relaxation, and increased systolic and diastolic stiffness[154,155]. Age-related cardiac hypertrophy, increased myocardial stiffness, and reduced responsiveness to β-adrenergic stimulation are associated with progressive loss of cardiac reserve, thereby predisposing to the development of heart disease in aged dogs[156].
Dog Aging Project is an NIH-sponsored multi-institutional long-term longitudinal study related to aging in companion dogs[157]. The purpose of initiating this project was to gain an understanding of the ways genes, lifestyle, and environment influence aging. It is expected that the research would facilitate the extension of healthspan in both people and pets. A pilot short-term rapamycin intervention trial of the project was conducted on 24 companion dogs. The results revealed that a 10-week-long rapamycin treatment demonstrated a trend of improved diastolic and systolic functions in middle-aged companion dogs[158]. This pilot study is consistent with the reports that rapamycin initiated at middle to old age in mice can rejuvenate several cardiac aging phenotypes[97,159] and further reinforces the critical role of mTORC1 in dog cardiac aging. This ongoing study is currently recruiting more companion dogs to increase the sample size.
Similarly, primate models are indispensable to aging studies as they share similarities in complex physiological traits and demonstrate phylogenetic closeness to humans. Like the findings in humans, cardiovascular diseases are the most common cause of death in captive great apes[160]. The prevalence of cardiovascular diseases in primates increases in old age as well. This was proven by the longitudinal aging study conducted at the National Institute of Aging, whereby the researchers used an aging cohort of rhesus monkeys (Macaca mulatta). The report revealed that several cardiac aging changes in the rhesus monkeys resemble human cardiac aging, including degenerative calcifications of aortic and mitral valves, loss of cardiomyocytes, cardiomyocyte hypertrophy, accumulation of lipofuscin, and amplified interstitial fibrosis. In addition, an increased incidence of myocardial infarction, heart failure, and myocardial inflammation was observed[161-164]. In a 20-year longitudinal CR study initiated in adult rhesus monkeys, moderate CR has been shown to decrease the incidence of aging-related deaths and delay the onset of many age-associated pathologies[102]. In this study, CR reduced the incidence of diabetes (and improved insulin sensitivity), cancer and brain atrophy, and cardiovascular disease. The incidence of cardiovascular diseases, including valvular endocardiosis, cardiomyopathy, and myocardial fibrosis, was reduced by 50% in the CR group. Since mTORC1 is a major pathway suppressed by CR, these findings emphasize that mTORC1 also plays important roles in primate cardiovascular aging. Besides the rhesus monkey, the common marmoset (Callithrix jacchus) is the shortest-lived anthropoid primate (average lifespan: 5-7 years). They develop several aging pathologies resembling those of human beings, including cancer, amyloidosis, diabetes, and chronic kidney diseases. Histological examinations showed increased myocardial fibrosis and some features of cardiomyopathy in old marmosets over 10 years of age[165,166].
A recent comparative study in multiple species of mammals reported that cardiac protein abundance of mTOR, Raptor, and PRAS40 and the phosphorylation of PRAS40Thr246 are inversely correlated with the maximal lifespans of mammals[167]. At chronological ages of 15-30% of their maximal lifespan, long-lived mammals (horse, 46 years; cow, 30 years; pig, 27 years) tend to have lower mTORC1 than the shorter-lived mammals (mice, rats, guinea pigs, gerbils and rabbits). This correlative multi-species study of mTORC1 signals in the hearts also supports the essential role of mTOR in cardiac aging.
mTORC1 IN CARDIAC AGING AND HEART FAILURE
Studies reveal that TOR plays a critical role in Drosophila cardiac aging[168]. Downstream of dTOR signal, d4eBP overexpression is adequate to protect cardiac function against age-related decline while enhancing cardiac stress resistance[130]. Conversely, d4eBP null mutant flies exhibit an early increase in stress-induced failure rate. Similarly, upregulation of dEif4e (which is inhibited by d4eBP) in the heart mimics the age-related increase in cardiac arrhythmias. Another effector of dTOR and insulin signaling, dS6K, may influence cardiac aging non-autonomously through its activity in the insulin-producing cells (systemic/metabolic benefit), but not directly in the myocardial tissue. This is because myocardial dnS6K inflicts no significant effect on cardiac function, like the neutral effect of mouse S6K1/S6K2 double knock-out in response to cardiac hypertrophy stimuli[169].
The mTORC1 hyperactivation leads to pathological growth and cardiac dysfunction in response to pressure overload in rodents. This mTORC1 activation induces phosphorylation of p70s6K and 4EBP1, thus stimulating ribosome biogenesis and protein synthesis. At the same time, it also activates ULK1 to reduce autophagy as a result. Thus, mTORC1 activation causes phosphorylation of 4EBP, ultimately releasing the sequestration of eIF4E (4EBP is an eIF4E Binding Protein), exposing the phosphorylation sites of eIF4E. The latter has been shown to be indispensable for Drosophila growth through increased protein translation[170]. Furthermore, the upregulation of Eif4E alone recapitulated increased TOR effects on insulin signaling and cardiac aging in flies. On the other hand, 4EBP overexpression in Drosophila helped in protection against cardiac functional aging, promotion of cardiac stress resistance, and maintenance of a normal heart rate[130]. In mammalian cells, the overexpression of eIF4E catalyzes fibroblast transformation and increases cell size. However, it is later reversed by increased expression of 4E-BP[171].
The signaling mechanisms of mTORC1 in heart failure are perplexing. Cardiac-specific ablation of mTOR led to dilated cardiomyopathy and early mortality[172], thereby indicating the critical roles of mTOR activity for myocardial growth and proliferation during embryonic and early postnatal stages[173]. Inducible ablation of mTOR in adult cardiomyocytes (by tamoxifen induction of adult α-MHC-MerCreMer/Mtorfl/fl mice) also led to fatal dilated cardiomyopathy, thus suggesting the functional significance of mTOR in the maintenance of cardiac physiology and homeostasis[174]. These inducible-MHC-mTOR-/- hearts displayed accumulation of 4EBP1, which later inhibited protein translation to cause suppression of cardiomyocytes protein synthesis afterward[174]. While these studies support the critical roles of mTOR in cardiac growth, development and homeostasis, moderate mTOR suppression may be beneficial for cardiomyocyte maturation[175]. In human inducible pluripotent stem cells (iPS)-derived cardiomyocytes (which are comparable to the fetal stage), mTOR inhibition by Torin 1 shifts cells to a quiescent state and enhances the maturation of these cardiomyocytes. Torin 1 treatment of these iPS-cardiomyocytes decreased p21 and increased p53, cardiac troponin I and Kir2.1 cardiac potassium channel, leading to enhanced contractility and maximum oxygen consumption rate[175].
Several components of the mTORC1 pathway have been examined in relation to heart failure. Inducible ablation of Raptor in adult cardiomyocytes by tamoxifen induction of adult α-MHC-MerCreMer/raptorfl/fl aggravated heart failure in response to 1-week of pressure overload. It needs to be noted here that the stated process was completed in the absence of adaptive hypertrophy, consistent with an increase in total and de-phosphorylated 4EBP (a suppressor of protein translation). These inducible-MHC-Raptor-/- mice also developed spontaneous heart failure with declining ejection fraction (noted 38 days after Raptor ablation), in association with abnormal mitochondria, switch of substrate utilization from fatty acid to glucose oxidation, and increased cardiomyocytes apoptosis[176]. These findings suggest the critical role of mTORC1 in cardiac homeostasis and adaptive cardiomyocyte growth in response to pressure overload.
Whereas mTORC1 is essential for cardiac growth and maintenance during development as well as adaptive cardiac hypertrophy in response to stress, excessive mTORC1 activation during chronic stress led to pathological hypertrophy, accumulation of damaged proteins, and heart failure[177]. Inhibition of mTORC1 by RP restores several changes (as mentioned above) and ameliorates heart failure induced by various stressors, including those induced by pressure overload (aortic constriction model)[178], Adriamycin[179], nephrectomy (chronic kidney disease)[180], alcohol[181] or genetic mutations[182,183]. The downstream signaling mechanisms of mTORC1 include the regulation of metabolic pathways via mTORC1 target proteins, such as 4EBP1, S6K1 and ULK1. In mice, pressure overload due to transverse aortic constriction activated phosphorylation of ribosomal S6 protein (ribosome biogenesis and protein synthesis) and eukaryotic translation initiation factor-4E (eIF4E; critical for protein translation). The beneficial effect of RP in protecting against pressure-overload-induced heart failure is associated with suppression of S6K, phosphorylation of S6, and eIF4E[184], suggesting a potentially critical role of S6K in mediating pathological cardiac hypertrophy. However, cardiac-specific deletion of both S6K1 and S6K2 in mice failed to show a significant effect on the progression of physiological (induced by exercise) or pathological (by pressure overload) cardiac hypertrophy. This implies that the development of cardiac hypertrophy has no critical dependence on S6Ks[178].
The role of 4EBP1, another important downstream target of mTORC1, was tested in our previous study[185]. Because mTORC1 inhibition led to suppression of eIF4E and enhancement of 4EBP1, in order to recapitulate the effect of mTORC1 inhibition by RP, we applied pressure-overload heart failure using various genetic mouse models and examined the effect of enhanced 4EBP1[185]. The first model: c-4EBP1Tg mice with ~ 9-fold increase in cardiac 4EBP1 protein and mildly decreased cardiac protein translation. These mice exhibited aggravated cardiac systolic dysfunction in both pressure overload and Gαq overexpression-induced heart failure models. The second model: mice with ~ 3-fold increase in a constitutively active mutant 4EBP1 (4EBP1mut, A37/A46), which is resistant to phosphorylation/inactivation by mTOR inhibition, thereby resulting in marked suppression of protein translation. These mice experienced exaggerated heart failure in response to pressure overload (worse than 4EBP1Tg) in the absence of adaptive cardiac hypertrophy (as expected from strong inhibition of protein synthesis). The third model: mice with c-Raptor+/- with decreased but not completely abolished cardiac mTORC1 activity and intact protein translation. These mice ameliorated cardiac systolic function in both pressure overload or Gαq overexpression-induced heart failure models, in parallel with better preservation of cardiac proteome, particularly proteins involved in mitochondrial function, glucose metabolism, and the TCA cycle. Our findings in 3 mouse models suggested that modest inhibition of mTORC1 by RP or c-Raptor+/- is cardioprotective, independent of the effect on protein translation. In contrast, suppression of protein translation by activating 4EBP1 is harmful in the setting of pressure overload or Gαq overexpression-induced heart failure models[185]. This is because maintaining protein synthesis is required for adaptive cardiac hypertrophy as a critical compensatory mechanism to cope with cardiac stressors[186,187].
All in all, both hyperactivation and strong suppression of mTORC1 could be deleterious[173,174,176,188]. Nevertheless, fine-tuning of mTORC1 in different contexts may be beneficial. An example of fine-tuning of mTORC1 activity is by modulating TSC2, an upstream constitutive inhibitor of mTORC1. The inhibitory effect of TSC2 on mTORC1 is modified by phosphorylation from several kinases, including AMPK and GSK3-β (inhibitors of mTORC1), as well as ERK and Akt (both are stimulators of mTORC1). Research from David Kass’s laboratory identified Serine1365 of TSC2 as a phosphorylation target site of PKG1. Phosphorylation-silencing mutation S1365A-TSC2 aggravated pressure-overload-induced heart failure, due to increased mTORC1 activation that was resistant to PKG1 rescue. In contrast, phosphorylation-mimicking mutation S1365E-TSC2 ameliorated the mentioned heart failure phenotypes. These findings indicate that S1365-TSC phosphorylation is both required and sufficient for the beneficial cardioprotective effect of PKG1 in a pressure overload setting[189]. Interestingly, it further showed that mice carrying S1365A-TSC2 knock-in mutations conferred protection against ischemia-reperfusion injury by mTORC1 activation, as the process switched the cardiac substrate utilization from fatty acid oxidation to glycolysis[190].
Rapamycin (RP), as an inhibitor of mTORC1, demonstrates its ability to protect against cardiac aging, as confirmed by multiple laboratories. In a study conducted by Flynn et al., late-life RP treatment for three months improved cardiovascular function and attenuated age-associated cardiac inflammation and fibrosis[142]. Our studies reported that short-term RP initiated late in life closely resembles the effect of CR in rejuvenating the heart, including regression of age-dependent cardiac hypertrophy, improvement of diastolic function, and preservation of cardiac mitochondrial proteome. It also improves overall protein quality[97]. One of the plausible underlying mechanisms of improvement of cardiac protein quality is by enhancing autophagy. RP inhibits ULK phosphorylation and induces autophagy. Interestingly, this process was only observed during the first week of RP treatment as autophagic markers were comparable to baseline levels after two weeks or longer treatment of RP[159]. These findings were concomitant with the dynamic changes of mitochondrial biogenesis markers. The transient induction of autophagy and mitochondrial biogenesis by RP suggests that damaged mitochondria were replaced by new mitochondria, thereby helping in the restoration of mitochondrial quality and enhancement of proteostasis[159]. The mitochondrial function improvement and overall protein quality may also contribute to the persistent beneficial effect on cardiac function, even following cessation of brief (8 weeks) RP treatment in aged mice from 22 to 24 months old[191].
The “rapamycin memory” discussed above is not limited to cardiac aging. Transient rapamycin treatment for 3 months, initiated for ~20-21 months-old mice, is sufficient to increase life expectancy by ~40%-60% and improve several measures of healthspan in middle-aged mice[192]. A recent study reported a long-lasting geroprotection from brief rapamycin treatment in early adulthood[193]. This was the result of a persistent increase in intestinal autophagy in Drosophila. This “memory” was confirmed by enhanced gut barrier function and Paneth cell architecture in mice exposed to short-term RP treatment[193].
mTORC2 AND CARDIAC AGING AND HEART FAILURE
Unlike mTORC1, it has been challenging to understand the role of mTORC2 in cardiac function and health, since the specific pharmacological inhibitors targeting mTORC2 are lacking and the upstream activation mechanism of mTORC2 is still not fully understood. Genetic ablations of Rictor in mice using cardiomyocyte-specific Cre lead to dilated hearts with systolic dysfunction at 6 months of age[194]. The young Rictor knock-out mice develop cardiomyopathy shortly after pressure overload, and the hearts become dilated and hypertrophic[194,195]. ShRNA-mediated knockdown of Rictor increases cardiomyocyte death, pathological remodeling, and cardiac dysfunction upon ischemia damage[196]. We recently showed that mTORC2 protects Drosophila hearts from high-fat diet-induced cardiomyopathy[87]. These studies suggest a cardioprotective effect of mTORC2 in response to various stresses. The protective role of mTORC2 might be due to its regulation of the Hippo pathway, since the phosphorylation of MST1 is elevated in Rictor knock-out cardiomyocytes and MST1 inhibition by overexpressing a dominant-negative MST1 rescues the cardiac dysfunction of Rictor knock-out mice[194]. In addition, our studies in Drosophila demonstrate mitochondrial dynamics as another mechanism for mTORC2-mediated cardiac protection[87].
Besides participating in cell proliferation, cytoskeleton reorganization, and lipid metabolism, mTORC2 is known as a key stress response pathway. Drosophila mutants of Rictor and Sin1 exhibit decreased tolerance to heat stress[197]. The mTORC2 is activated upon high-fat diet treatment[87] and in response to oxidative stress[198], whereas it is inhibited by ER stress[199]. The mTORC2 has also been shown to interact with the Pink1 pathway to regulate mitochondrial homeostasis in Drosophila indirect flight muscle[200] and human SHSY5Y neuroblastoma cells[201]. These findings suggest that mTORC2 also plays an important role in mitochondria quality control (e.g., mitophagy). Indeed, mTORC2 and AKT signaling have been recently implicated in the regulation of autophagy[45,202]. The role of mTORC2 in lifespan regulation is likely attributable to its cytoprotective effects. For example, genetic deletion of Rictor decreases lifespan in male mice[203] and cardiac-specific overexpression of Rictor prolongs Drosophila lifespan[45]. However, conflicting results have been found in C. elegans[105,204]. Different from mTORC1, the effects of mTORC2 in stress resistance and lifespan regulation have not been unequivocally established in multiple organism models and warrant future investigations.
It is well reported that rapamycin-mediated inhibition of mTORC1 attenuates age-related cardiac fibrosis and inflammation, cardiac hypertrophy, and diastolic dysfunction[97,142]. However, the role of mTORC2 in cardiac aging is poorly understood. We recently showed that heart-specific overexpression of Drosophila Rictor preserves cardiac function and autophagic flux during aging[45], which is consistent with the notion that activation of mTORC2 is cardioprotective and mTORC2 inhibition is detrimental.
CONCLUSION
The mTOR is a central pathway regulating aging and longevity across multiple model organisms by regulating growth, protein synthesis, lipid metabolism, autophagy, and protein quality control during the aging process. As a sensor kinase, the mTORC1 activity is finely tuned by the levels of intracellular nutrients and energy, growth factors and various cellular stresses. In the heart, the hyperactivation of mTORC1 leads to pathological growth (cardiac hypertrophy) and cardiac dysfunction, as seen in aging and in response to pressure overload stress. Moderate suppression of mTORC1 by calorie restriction, rapamycin or some genetic models of reduced mTORC1 has been shown to ameliorate cardiac aging and pressure-overload-induced heart failure. In contrast, cardiac-specific ablation of mTORC1 leads to dilated cardiomyopathy, as it may suppress protein synthesis required for adaptive cardiac hypertrophy. The role of mTORC2 in cardiac aging is less defined. In contrast to the detrimental effect of mTORC1 activation, overexpression of the mTORC2 component in Drosophila is cardioprotective; however, the role of mTORC2 in mammals remains to be elucidated.
DECLARATIONS
Authors’ contributionsConceived and wrote the paper: Dai DF, Kang P, Bai H
Availability of data and materialsNot applicable.
Financial support and sponsorshipThis work was supported by grants from the National Institutes of Health (NIH): HL145138, DK133118 (both to Dao-Fu Dai) and AHA #858512 (Dao-Fu Dai); R00AG048016 and R01AG058741 (both to Hua Bai).
Conflicts of interestAll authors declared that there are no conflicts of interest.
Ethical approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Copyright© The Author(s) 2023.
REFERENCES
1. Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 1991;253:905-9.
2. Wang L, Rhodes CJ, Lawrence JC Jr. Activation of mammalian target of rapamycin (mTOR) by insulin is associated with stimulation of 4EBP1 binding to dimeric mTOR complex I. J Biol Chem 2006;281:24293-303.
3. Yip CK, Murata K, Walz T, Sabatini DM, Kang SA. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol Cell 2010;38:768-74.
4. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature 2013;493:338-45.
5. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol 2005;15:702-13.
6. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115:577-90.
7. Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008;30:214-26.
8. Efeyan A, Zoncu R, Chang S, et al. Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature 2013;493:679-83.
9. Kalender A, Selvaraj A, Kim SY, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 2010;11:390-401.
10. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell 2017;168:960-76.
11. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL. Regulation of TORC1 by rag GTPases in nutrient response. Nat Cell Biol 2008;10:935-45.
12. Sancak Y, Peterson TR, Shaul YD, et al. The rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008;320:1496-501.
13. Bar-Peled L, Chantranupong L, Cherniack AD, et al. A tumor suppressor complex with GAP activity for the rag GTPases that signal amino acid sufficiency to mTORC1. Science 2013;340:1100-6.
14. Zhenyukh O, Civantos E, Ruiz-Ortega M, et al. High concentration of branched-chain amino acids promotes oxidative stress, inflammation and migration of human peripheral blood mononuclear cells via mTORC1 activation. Free Radic Biol Med 2017;104:165-77.
15. Brugarolas J, Lei K, Hurley RL, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004;18:2893-904.
16. Ma Y, Vassetzky Y, Dokudovskaya S. mTORC1 pathway in DNA damage response. Biochim Biophys Acta Mol Cell Res 2018;1865:1293-311.
17. Deldicque L, Theisen D, Francaux M. Regulation of mTOR by amino acids and resistance exercise in skeletal muscle. Eur J Appl Physiol 2005;94:1-10.
18. Kim M, Sujkowski A, Namkoong S, et al. Sestrins are evolutionarily conserved mediators of exercise benefits. Nat Commun 2020;11:190.
19. Sujkowski A, Wessells R. Exercise and sestrin mediate speed and lysosomal activity in drosophila by partially overlapping mechanisms. Cells 2021;10:2479.
20. Lee JH, Budanov AV, Park EJ, et al. Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 2010;327:1223-8.
21. Chen CC, Jeon SM, Bhaskar PT, et al. FoxOs inhibit mTORC1 and activate akt by inducing the expression of Sestrin3 and Rictor. Dev Cell 2010;18:592-604.
22. Liu P, Gan W, Chin YR, et al. PtdIns(3,4,5)P3-Dependent activation of the mTORC2 kinase complex. Cancer Discov 2015;5:1194-209.
23. Hsu PP, Kang SA, Rameseder J, et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 2011;332:1317-22.
24. Harrington LS, Findlay GM, Gray A, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 2004;166:213-23.
25. Shah OJ, Wang Z, Hunter T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 2004;14:1650-6.
26. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006;124:471-84.
27. López-Maury L, Marguerat S, Bähler J. Tuning gene expression to changing environments: from rapid responses to evolutionary adaptation. Nat Rev Genet 2008;9:583-93.
28. Hannan KM, Brandenburger Y, Jenkins A, et al. mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol Cell Biol 2003;23:8862-77.
29. Mayer C, Grummt I. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene 2006;25:6384-91.
30. Candiracci J, Migeot V, Chionh YH, et al. Reciprocal regulation of TORC signaling and tRNA modifications by Elongator enforces nutrient-dependent cell fate. Sci Adv 2019;5:eaav0184.
31. Lee J, Moir RD, McIntosh KB, Willis IM. TOR signaling regulates ribosome and tRNA synthesis via LAMMER/Clk and GSK-3 family kinases. Mol Cell 2012;45:836-43.
33. Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 2006;314:467-71.
34. Dennis PB, Jaeschke A, Saitoh M, Fowler B, Kozma SC, Thomas G. Mammalian TOR: a homeostatic ATP sensor. Science 2001;294:1102-5.
35. Um SH, D'Alessio D, Thomas G. Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 2006;3:393-402.
36. Aguilar V, Alliouachene S, Sotiropoulos A, et al. S6 kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase. Cell Metab 2007;5:476-87.
37. Zid BM, Rogers AN, Katewa SD, et al. 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila. Cell 2009;139:149-60.
38. Richter JD, Sonenberg N. Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 2005;433:477-80.
39. Hansen M, Rubinsztein DC, Walker DW. Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol 2018;19:579-93.
40. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009;43:67-93.
41. Chang JT, Kumsta C, Hellman AB, Adams LM, Hansen M. Spatiotemporal regulation of autophagy during
42. Kaushik S, Arias E, Kwon H, et al. Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Rep 2012;13:258-65.
43. Del Roso A, Vittorini S, Cavallini G, et al. Ageing-related changes in the
44. Demontis F, Perrimon N. FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell 2010;143:813-25.
45. Chang K, Kang P, Liu Y, et al. TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2. Autophagy 2020;16:1807-22.
46. Taneike M, Yamaguchi O, Nakai A, et al. Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 2010;6:600-6.
47. Meléndez A, Tallóczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B. Autophagy genes are essential for dauer development and life-span extension in
48. Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C. A role for autophagy in the extension of lifespan by dietary restriction in
49. Bjedov I, Toivonen JM, Kerr F, et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 2010;11:35-46.
50. Fernández ÁF, Sebti S, Wei Y, et al. Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature 2018;558:136-40.
52. Morselli E, Maiuri MC, Markaki M, et al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis 2010;1:e10.
53. Hosokawa N, Hara T, Kaizuka T, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 2009;20:1981-91.
54. Martina JA, Chen Y, Gucek M, Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 2012;8:903-14.
55. Roczniak-Ferguson A, Petit CS, Froehlich F, et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal 2012;5:ra42.
56. Ho TT, Warr MR, Adelman ER, et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature 2017;543:205-10.
57. Baar EL, Carbajal KA, Ong IM, Lamming DW. Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice. Aging Cell 2016;15:155-66.
58. Lapierre LR, Gelino S, Meléndez A, Hansen M. Autophagy and lipid metabolism coordinately modulate life span in germline-less
59. Lapierre LR, De Magalhaes Filho CD, McQuary PR, et al. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in
60. Wang RC, Wei Y, An Z, et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 2012;338:956-9.
61. Ozturk DG, Kocak M, Akcay A, et al. MITF-MIR211 axis is a novel autophagy amplifier system during cellular stress. Autophagy 2019;15:375-90.
62. Bartolomé A, García-Aguilar A, Asahara SI, et al. MTORC1 regulates both general autophagy and mitophagy induction after oxidative phosphorylation uncoupling. Mol Cell Biol 2017;37:e00441-17.
64. Ouwens DM, Boer C, Fodor M, et al. Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats. Diabetologia 2005;48:1229-37.
67. Birse RT, Choi J, Reardon K, et al. High-fat-diet-induced obesity and heart dysfunction are regulated by the TOR pathway in Drosophila. Cell Metab 2010;12:533-44.
68. Diop SB, Bisharat-Kernizan J, Birse RT, Oldham S, Ocorr K, Bodmer R. PGC-1/Spargel counteracts high-fat-diet-induced obesity and cardiac lipotoxicity downstream of TOR and brummer ATGL lipase. Cell Rep 2015;10:1572-84.
69. Caron A, Richard D, Laplante M. The roles of mTOR complexes in lipid metabolism. Annu Rev Nutr 2015;35:321-48.
70. Lamming DW, Sabatini DM. A central role for mTOR in lipid homeostasis. Cell Metab 2013;18:465-9.
71. Szwed A, Kim E, Jacinto E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol Rev 2021;101:1371-426.
72. Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 2010;468:1100-4.
73. Zhang HH, Huang J, Düvel K, et al. Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway. PLoS One 2009;4:e6189.
74. Carnevalli LS, Masuda K, Frigerio F, et al. S6K1 plays a critical role in early adipocyte differentiation. Dev Cell 2010;18:763-74.
75. Porstmann T, Santos CR, Griffiths B, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 2008;8:224-36.
76. Owen JL, Zhang Y, Bae SH, et al. Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. Proc Natl Acad Sci USA 2012;109:16184-9.
77. Peterson TR, Sengupta SS, Harris TE, et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 2011;146:408-20.
78. Viscarra JA, Wang Y, Nguyen HP, Choi YG, Sul HS. Histone demethylase JMJD1C is phosphorylated by mTOR to activate de novo lipogenesis. Nat Commun 2020;11:796.
79. Lee G, Zheng Y, Cho S, et al. Post-transcriptional regulation of de novo lipogenesis by mTORC1-S6K1-SRPK2 signaling. Cell 2017;171:1545-58.e18.
80. Hagiwara A, Cornu M, Cybulski N, et al. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab 2012;15:725-38.
81. Kumar A, Lawrence JC Jr, Jung DY, et al. Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 2010;59:1397-406.
82. Sciarretta S, Zhai P, Shao D, et al. Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome. Circulation 2012;125:1134-46.
83. Guo R, Zhang Y, Turdi S, Ren J. Adiponectin knockout accentuates high fat diet-induced obesity and cardiac dysfunction: role of autophagy. Biochim Biophys Acta 2013;1832:1136-48.
84. Das A, Durrant D, Koka S, Salloum FN, Xi L, Kukreja RC. Mammalian target of rapamycin (mTOR) inhibition with rapamycin improves cardiac function in type 2 diabetic mice: potential role of attenuated oxidative stress and altered contractile protein expression. J Biol Chem 2014;289:4145-60.
85. Völkers M, Doroudgar S, Nguyen N, et al. PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity. EMBO Mol Med 2014;6:57-65.
86. Lakatta EG, Yin FC. Myocardial aging: functional alterations and related cellular mechanisms. Am J Physiol 1982;242:H927-41.
87. Liu P, Chang K, Requejo G, Bai H. mTORC2 protects the heart from high-fat diet-induced cardiomyopathy through mitochondrial fission in Drosophila. Front Cell Dev Biol 2022;10:866210.
88. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Müller F. Genetics: influence of TOR kinase on lifespan in
89. Jia K, Chen D, Riddle DL. The TOR pathway interacts with the insulin signaling pathway to regulate
90. Kaeberlein M, Powers RW 3rd, Steffen KK, et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 2005;310:1193-6.
91. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 2004;14:885-90.
92. Lamming DW, Ye L, Katajisto P, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 2012;335:1638-43.
93. Wu JJ, Liu J, Chen EB, et al. Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep 2013;4:913-20.
94. Henderson ST, Bonafè M, Johnson TE. daf-16 protects the nematode
95. Selman C, Tullet JM, Wieser D, et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 2009;326:140-4.
97. Dai DF, Karunadharma PP, Chiao YA, et al. Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart. Aging Cell 2014;13:529-39.
98. Hursting SD, Dunlap SM, Ford NA, Hursting MJ, Lashinger LM. Calorie restriction and cancer prevention: a mechanistic perspective. Cancer Metab 2013;1:10.
99. Obin M, Pike A, Halbleib M, Lipman R, Taylor A, Bronson R. Calorie restriction modulates age-dependent changes in the retinas of brown norway rats. Mech Ageing Dev 2000;114:133-47.
100. Izuta Y, Imada T, Hisamura R, et al. Ketone body 3-hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina. Aging Cell 2018;17:e12699.
101. Someya S, Yamasoba T, Weindruch R, Prolla TA, Tanokura M. Caloric restriction suppresses apoptotic cell death in the mammalian cochlea and leads to prevention of presbycusis. Neurobiol Aging 2007;28:1613-22.
102. Colman RJ, Anderson RM, Johnson SC, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009;325:201-4.
103. Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C. Lifespan extension by conditions that inhibit translation in
104. Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;460:392-5.
105. Robida-Stubbs S, Glover-Cutter K, Lamming DW, et al. TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab 2012;15:713-24.
106. Quarles EK, Rabinovitch PS. Transient and late-life rapamycin for healthspan extension. Aging 2020;12:4050-1.
107. Miller RA, Harrison DE, Astle CM, et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 2014;13:468-77.
108. Fok WC, Bokov A, Gelfond J, et al. Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver. Aging Cell 2014;13:311-9.
109. Yu Z, Wang R, Fok WC, Coles A, Salmon AB, Pérez VI. Rapamycin and dietary restriction induce metabolically distinctive changes in mouse liver. J Gerontol A Biol Sci Med Sci 2015;70:410-20.
110. Fok WC, Zhang Y, Salmon AB, et al. Short-term treatment with rapamycin and dietary restriction have overlapping and distinctive effects in young mice. J Gerontol A Biol Sci Med Sci 2013;68:108-16.
111. Karunadharma PP, Basisty N, Dai DF, et al. Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects. Aging Cell 2015;14:547-57.
113. Blice-Baum AC, Guida MC, Hartley PS, Adams PD, Bodmer R, Cammarato A. As time flies by: investigating cardiac aging in the short-lived Drosophila model. Biochim Biophys Acta Mol Basis Dis 2019;1865:1831-44.
114. Lints TJ, Parsons LM, Hartley L, Lyons I, Harvey RP. Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development 1993;119:419-31.
115. Komuro I, Izumo S. Csx: a murine homeobox-containing gene specifically expressed in the developing heart. Proc Natl Acad Sci USA 1993;90:8145-9.
116. Rotstein B, Paululat A. On the morphology of the drosophila heart. J Cardiovasc Dev Dis 2016;3:15.
117. Bodmer R. The gene tinman is required for specification of the heart and visceral muscles in Drosophila. Development 1993;118:719-29.
118. Tonissen KF, Drysdale TA, Lints TJ, Harvey RP, Krieg PA. XNkx-2.5, a Xenopus gene related to Nkx-2.5 and tinman: evidence for a conserved role in cardiac development. Dev Biol 1994;162:325-8.
119. Evans SM, Yan W, Murillo MP, Ponce J, Papalopulu N. Tinman, a drosophila homeobox gene required for heart and visceral mesoderm specification, may be represented by a family of genes in vertebrates: XNkx-2.3, a second vertebrate homologue of tinman. Development 1995;121:3889-99.
120. Fink M, Callol-Massot C, Chu A, et al. A new method for detection and quantification of heartbeat parameters in Drosophila, zebrafish, and embryonic mouse hearts. Biotechniques 2009;46:101-13.
121. Ocorr K, Fink M, Cammarato A, Bernstein S, Bodmer R. Semi-automated optical heartbeat analysis of small hearts. J Vis Exp ;2009:1435.
122. Lalevée N, Monier B, Sénatore S, Perrin L, Sémériva M. Control of cardiac rhythm by ORK1, a Drosophila two-pore domain potassium channel. Curr Biol 2006;16:1502-8.
123. Monnier V, Iché-Torres M, Rera M, et al. dJun and Vri/dNFIL3 are major regulators of cardiac aging in Drosophila. PLoS Genet 2012;8:e1003081.
124. Klassen MP, Peters CJ, Zhou S, Williams HH, Jan LY, Jan YN. Age-dependent diastolic heart failure in an
125. Wolf MJ, Amrein H, Izatt JA, Choma MA, Reedy MC, Rockman HA. Drosophila as a model for the identification of genes causing adult human heart disease. Proc Natl Acad Sci USA 2006;103:1394-9.
126. Viswanathan MC, Kaushik G, Engler AJ, Lehman W, Cammarato A. A Drosophila melanogaster model of diastolic dysfunction and cardiomyopathy based on impaired troponin-T function. Circ Res 2014;114:e6-17.
127. Kaushik G, Fuhrmann A, Cammarato A, Engler AJ.
128. Kaushik G, Zambon AC, Fuhrmann A, et al. Measuring passive myocardial stiffness in Drosophila melanogaster to investigate diastolic dysfunction. J Cell Mol Med 2012;16:1656-62.
129. Wessells RJ, Fitzgerald E, Cypser JR, Tatar M, Bodmer R. Insulin regulation of heart function in aging fruit flies. Nat Genet 2004;36:1275-81.
130. Wessells R, Fitzgerald E, Piazza N, et al. d4eBP acts downstream of both dTOR and dFoxo to modulate cardiac functional aging in Drosophila. Aging Cell 2009;8:542-52.
131. Cannon L, Zambon AC, Cammarato A, et al. Expression patterns of cardiac aging in Drosophila. Aging Cell 2017;16:82-92.
132. Zheng F, Plati AR, Potier M, et al. Resistance to glomerulosclerosis in B6 mice disappears after menopause. Am J Pathol 2003;162:1339-48.
133. Dai DF, Santana LF, Vermulst M, et al. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 2009;119:2789-97.
134. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a “set up” for vascular disease. Circulation 2003;107:139-46.
135. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation 2003;107:346-54.
136. Dai DF, Chen T, Johnson SC, Szeto H, Rabinovitch PS. Cardiac aging: from molecular mechanisms to significance in human health and disease. Antioxid Redox Signal 2012;16:1492-526.
137. Treuting PM, Linford NJ, Knoblaugh SE, et al. Reduction of age-associated pathology in old mice by overexpression of catalase in mitochondria. J Gerontol A Biol Sci Med Sci 2008;63:813-22.
138. Yan L, Vatner DE, O'Connor JP, et al. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 2007;130:247-58.
139. Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail 2014;2:113-22.
140. Westermark P, Johansson B, Natvig JB. Senile cardiac amyloidosis: evidence of two different amyloid substances in the ageing heart. Scand J Immunol 1979;10:303-8.
141. Ng B, Connors LH, Davidoff R, Skinner M, Falk RH. Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med 2005;165:1425-9.
142. Flynn JM, O'Leary MN, Zambataro CA, et al. Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell 2013;12:851-62.
143. Dai DF, Hsieh EJ, Liu Y, et al. Mitochondrial proteome remodelling in pressure overload-induced heart failure: the role of mitochondrial oxidative stress. Cardiovasc Res 2012;93:79-88.
144. Dai DF, Johnson SC, Villarin JJ, et al. Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res 2011;108:837-46.
145. Dai DF, Chen T, Szeto H, et al. Mitochondrial targeted antioxidant Peptide ameliorates hypertensive cardiomyopathy. J Am Coll Cardiol 2011;58:73-82.
146. Dai DF, Hsieh EJ, Chen T, et al. Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail 2013;6:1067-76.
147. Triplett JC, Tramutola A, Swomley A, et al. Age-related changes in the proteostasis network in the brain of the naked mole-rat: Implications promoting healthy longevity. Biochim Biophys Acta 2015;1852:2213-24.
148. Azpurua J, Ke Z, Chen IX, et al. Naked mole-rat has increased translational fidelity compared with the mouse, as well as a unique 28S ribosomal RNA cleavage. Proc Natl Acad Sci USA 2013;110:17350-5.
149. Faulkes CG, Eykyn TR, Aksentijevic D. Cardiac metabolomic profile of the naked mole-rat-glycogen to the rescue. Biol Lett 2019;15:20190710.
150. Hilton HG, Rubinstein ND, Janki P, et al. Single-cell transcriptomics of the naked mole-rat reveals unexpected features of mammalian immunity. PLoS Biol 2019;17:e3000528.
151. Can E, Smith M, Boukens BJ, Coronel R, Buffenstein R, Riegler J. Naked mole-rats maintain cardiac function and body composition well into their fourth decade of life. Geroscience 2022;44:731-46.
152. Eichelberg H, Seine R. Life expectancy and cause of death in dogs. I. The situation in mixed breeds and various dog breeds. Berl Munch Tierarztl Wochenschr 1996;109:292-303.
153. Van Vleet JF. Age-related non-neoplastic lesions of the heart. In: Mohr U, Patholbiology of the ageing dog; 2001. pp. 101-7.
154. Templeton GH, Platt MR, Willerson JT, Weisfeldt ML. Influence of aging on left ventricular hemodynamics and stiffness in beagles. Circ Res 1979;44:189-94.
155. Templeton GH, Willerson JT, Platt MR, Weisfeldt M. Contraction duration and diastolic stiffness in aged canine left ventricle. Recent Adv Stud Cardiac Struct Metab 1976;11:169-73.
156. Guglielmini C. Cardiovascular diseases in the ageing dog: diagnostic and therapeutic problems. Vet Res Commun 2003;27 Suppl 1:555-60.
157. Kaeberlein M, Creevy KE, Promislow DE. The dog aging project: translational geroscience in companion animals. Mamm Genome 2016;27:279-88.
158. Urfer SR, Kaeberlein TL, Mailheau S, et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience 2017;39:117-27.
159. Chiao YA, Kolwicz SC, Basisty N, et al. Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging 2016;8:314-27.
160. Lowenstine LJ, McManamon R, Terio KA. Comparative pathology of aging great apes: bonobos, chimpanzees, gorillas, and orangutans. Vet Pathol 2016;53:250-76.
161. Lane MA, Ingram DK, Roth GS. Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk. Toxicol Sci 1999;52:41-8.
162. Lane MA, Mattison J, Ingram DK, Roth GS. Caloric restriction and aging in primates: relevance to humans and possible CR mimetics. Microsc Res Technol 2002;59:335-8.
163. Mattison JA, Lane MA, Roth GS, Ingram DK. Calorie restriction in rhesus monkeys. Exp Gerontol 2003;38:35-46.
164. Roth GS, Mattison JA, Ottinger MA, Chachich ME, Lane MA, Ingram DK. Aging in rhesus monkeys: relevance to human health interventions. Science 2004;305:1423-6.
165. Tardif SD, Mansfield KG, Ratnam R, Ross CN, Ziegler TE. The marmoset as a model of aging and age-related diseases. ILAR J 2011;52:54-65.
166. Ross CN, Davis K, Dobek G, Tardif SD. Aging phenotypes of common marmosets (
167. Mota-Martorell N, Jove M, Pradas I, et al. Gene expression and regulatory factors of the mechanistic target of rapamycin (mTOR) complex 1 predict mammalian longevity. Geroscience 2020;42:1157-73.
168. Luong N, Davies CR, Wessells RJ, et al. Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell Metab 2006;4:133-42.
169. McMullen JR, Shioi T, Zhang L, et al. Deletion of ribosomal S6 kinases does not attenuate pathological, physiological, or insulin-like growth factor 1 receptor-phosphoinositide 3-kinase-induced cardiac hypertrophy. Mol Cell Biol 2004;24:6231-40.
170. Lachance PE, Miron M, Raught B, Sonenberg N, Lasko P. Phosphorylation of eukaryotic translation initiation factor 4E is critical for growth. Mol Cell Biol 2002;22:1656-63.
171. Lazaris-Karatzas A, Montine KS, Sonenberg N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap. Nature 1990;345:544-7.
172. Zhu Y, Pires KM, Whitehead KJ, et al. Mechanistic target of rapamycin (Mtor) is essential for murine embryonic heart development and growth. PLoS One 2013;8:e54221.
173. Murakami M, Ichisaka T, Maeda M, et al. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 2004;24:6710-8.
174. Zhang D, Contu R, Latronico MV, et al. MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J Clin Invest 2010;120:2805-16.
175. Garbern JC, Helman A, Sereda R, et al. Inhibition of mTOR signaling enhances maturation of cardiomyocytes derived from human-induced pluripotent stem cells via p53-induced quiescence. Circulation 2020;141:285-300.
176. Shende P, Plaisance I, Morandi C, et al. Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice. Circulation 2011;123:1073-82.
177. Shen WH, Chen Z, Shi S, et al. Cardiac restricted overexpression of kinase-dead mammalian target of rapamycin (mTOR) mutant impairs the mTOR-mediated signaling and cardiac function. J Biol Chem 2008;283:13842-9.
178. McMullen JR, Sherwood MC, Tarnavski O, et al. Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 2004;109:3050-5.
179. Yu SY, Liu L, Li P, Li J. Rapamycin inhibits the mTOR/p70S6K pathway and attenuates cardiac fibrosis in adriamycin-induced dilated cardiomyopathy. Thorac Cardiovasc Surg 2013;61:223-8.
180. Haller ST, Yan Y, Drummond CA, et al. Rapamycin attenuates cardiac fibrosis in experimental uremic cardiomyopathy by reducing marinobufagenin levels and inhibiting downstream pro-fibrotic signaling. J Am Heart Assoc 2016;5:e004106.
181. Tu X, Wang C, Ru X, Jing L, Zhou L, Jing L. Therapeutic effects of rapamycin on alcoholic cardiomyopathy. Exp Ther Med 2017;14:2763-70.
182. Gu S, Tan J, Li Q, et al. Downregulation of LAPTM4B contributes to the impairment of the autophagic flux via unopposed activation of mTORC1 signaling during myocardial ischemia/reperfusion injury. Circ Res 2020;127:e148-65.
183. Packer M. Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure. Eur Heart J 2020;41:3856-61.
184. Gao XM, Wong G, Wang B, et al. Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis. J Hypertens 2006;24:1663-70.
185. Dai DF, Liu Y, Basisty N, et al. Differential effects of various genetic mouse models of the mechanistic target of rapamycin complex I inhibition on heart failure. Geroscience 2019;41:847-60.
186. Moreira-Gonçalves D, Henriques-Coelho T, Fonseca H, et al. Intermittent cardiac overload results in adaptive hypertrophy and provides protection against left ventricular acute pressure overload insult. J Physiol 2015;593:3885-97.
187. Shimizu I, Minamino T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol 2016;97:245-62.
188. Gangloff YG, Mueller M, Dann SG, et al. Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol Cell Biol 2004;24:9508-16.
189. Ranek MJ, Kokkonen-Simon KM, Chen A, et al. PKG1-modified TSC2 regulates mTORC1 activity to counter adverse cardiac stress. Nature 2019;566:264-9.
190. Oeing CU, Jun S, Mishra S, et al. MTORC1-regulated metabolism controlled by TSC2 limits cardiac reperfusion injury. Circ Res 2021;128:639-51.
191. Quarles E, Basisty N, Chiao YA, et al. Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. Aging Cell 2020;19:e13086.
192. Bitto A, Ito TK, Pineda VV, et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. Elife 2016;5:e16351.
193. Juricic P, Lu Y, Leech T, et al. Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy. Nat Aging 2022;2:824-36.
194. Sciarretta S, Zhai P, Maejima Y, et al. mTORC2 regulates cardiac response to stress by inhibiting MST1. Cell Rep 2015;11:125-36.
195. Shende P, Xu L, Morandi C, et al. Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy. Cardiovasc Res 2016;109:103-14.
196. Völkers M, Konstandin MH, Doroudgar S, et al. Mechanistic target of rapamycin complex 2 protects the heart from ischemic damage. Circulation 2013;128:2132-44.
197. Jevtov I, Zacharogianni M, van Oorschot MM, et al. TORC2 mediates the heat stress response in Drosophila by promoting the formation of stress granules. J Cell Sci 2015;128:2497-508.
198. Cai W, Andres DA. mTORC2 is required for rit-mediated oxidative stress resistance. PLoS One 2014;9:e115602.
199. Chen CH, Shaikenov T, Peterson TR, et al. ER stress inhibits mTORC2 and Akt signaling through GSK-3β-mediated phosphorylation of rictor. Sci Signal 2011;4:ra10.
200. Wu Z, Sawada T, Shiba K, et al. Tricornered/NDR kinase signaling mediates PINK1-directed mitochondrial quality control and tissue maintenance. Genes Dev 2013;27:157-62.
201. Murata H, Sakaguchi M, Jin Y, et al. A new cytosolic pathway from a Parkinson disease-associated kinase, BRPK/PINK1: activation of AKT via mTORC2. J Biol Chem 2011;286:7182-9.
202. Ballesteros-Álvarez J, Andersen JK. mTORC2: The other mTOR in autophagy regulation. Aging Cell 2021;20:e13431.
203. Lamming DW, Mihaylova MM, Katajisto P, et al. Depletion of rictor, an essential protein component of mTORC2, decreases male lifespan. Aging Cell 2014;13:911-7.
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Dai DF, Kang P, Bai H. The mTOR signaling pathway in cardiac aging . J Cardiovasc Aging 2023;3:24. http://dx.doi.org/10.20517/jca.2023.10
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Dai DF, Kang P, Bai H. The mTOR signaling pathway in cardiac aging . The Journal of Cardiovascular Aging. 2023; 3(3): 24. http://dx.doi.org/10.20517/jca.2023.10
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Dai, Dao-Fu, Ping Kang, Hua Bai. 2023. "The mTOR signaling pathway in cardiac aging " The Journal of Cardiovascular Aging. 3, no.3: 24. http://dx.doi.org/10.20517/jca.2023.10
ACS Style
Dai, D.F.; Kang P.; Bai H. The mTOR signaling pathway in cardiac aging . J. Cardiovasc. Aging. 2023, 3, 24. http://dx.doi.org/10.20517/jca.2023.10
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