Research Progress of the mTOR Pathway in Heart Failure Caused by Myocardial Aging

WANG Yujia¹,²,³, ZHANG Jinying¹,²,³, TANG Junnan¹,²,³*

¹Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
²Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou 450052, China
³Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou 450052, China

Corresponding Author: TANG Junnan, Professor; E-mail: fcctangjn@zzu.edu.cn

Abstract

Heart failure represents the end-stage of numerous cardiac diseases with poor prognosis, and its risk increases significantly with age and myocardial cell aging. The mammalian target of rapamycin (mTOR) pathway plays a key role in the pathophysiology of cardiomyocyte aging. This article reviews the latest research progress on the mTOR pathway in heart failure caused by myocardial cell aging and explores potential intervention strategies to delay cardiomyocyte aging. The continued activation of mTOR complex 1 (mTORC1) during the aging process drives pathological cardiac changes and accelerates the progression of heart failure by regulating protein synthesis, lipid metabolism, and inhibiting autophagy. Conversely, inhibiting the overactivation of mTORC1 can slow cardiac aging and extend lifespan in elderly animals. This article provides new insights into alleviating heart failure caused by aging and could help reduce the societal burden of this disease.

Keywords: Heart failure; Cardiac aging; Mammalian target of rapamycin; Protein synthesis; Lipid metabolism; Autophagy

Introduction

In recent years, as China's population aging has deepened, the incidence of heart failure (HF) has increased annually. Currently, China's population aged 60 and above has reached 264 million, accounting for 18.7% of the total population. The number of HF patients has grown from 4.5 million in 2016 to 8.9 million in 2022, with the number of elderly HF patients doubling every decade [1]. Age-related HF has become a major challenge for medical diagnosis and treatment systems; however, current approaches can only delay disease progression rather than achieve effective cure.

Cardiomyocyte aging manifests as protein misfolding and accumulation, cellular hypertrophy, and increased apoptosis [2], which lead to various cardiac diseases and ultimately present as HF. Studies have shown that the mammalian target of rapamycin (mTOR) pathway plays a critical role in the physiology and pathology of cardiomyocyte aging. Particularly, mTOR complex 1 (mTORC1) participates in cardiac development and regulates protein synthesis, lipid metabolism, and autophagy, thereby influencing cardiomyocyte aging. This review will summarize the research progress on the role of the mTOR pathway in heart failure caused by myocardial cell aging and discuss interventions to delay cardiomyocyte aging.

Funding: National Natural Science Foundation of China (82222007, 82170281)
Citation: WANG YJ, ZHANG JY, TANG JN. Research progress of mTOR pathway in heart failure caused by myocardial aging [J]. Chinese General Practice, 2025. DOI: 10.12114/j.issn.1007-9572.2024.0650. [Epub ahead of print].

1. Myocardial Cell Aging Causes Heart Failure

Aging leads to pathological remodeling of cardiomyocytes and the interstitium, characterized by increased cardiomyocyte apoptosis and necrosis, enlarged cardiomyocyte volume, and other pathological changes. These alterations not only directly impair cardiac function but also further exacerbate cardiac dysfunction by inducing compensatory hypertrophy of residual cardiomyocytes and compensatory fibrosis of cardiac tissue [3]. Evidence indicates that cardiomyocyte number declines with age [4]. TAKEUCHI et al. [5] demonstrated that the left ventricular mass-to-volume ratio in healthy individuals increases significantly with age, with reduced left ventricular compliance, further confirming the impact of aging on cardiac structure.

Cardiomyocyte aging is a key driving factor for multiple cardiovascular diseases, including myocardial fibrosis, arrhythmia, and ischemic heart disease, ultimately leading to HF [6]. In myocardial fibrosis, senescent cells secrete large amounts of pro-fibrotic factors such as transforming growth factor-β, inducing excessive proliferation of fibroblasts and increased collagen deposition [7]. Myocardial fibrotic changes reduce myocardial flexibility, impair cardiac reserve capacity, cause diastolic dysfunction, and hinder normal ventricular filling [8]. Additionally, the fibrotic process alters cardiac electrical signal conduction pathways, thereby increasing the risk of arrhythmias [9]. Ischemic heart disease further exacerbates cardiomyocyte aging and necrosis through mechanisms such as oxidative stress and inflammatory responses [10]. With advancing age, the proportion of senescent cardiomyocytes increases, and these pathological changes gradually accumulate, eventually preventing the heart from effectively adapting to stressors such as exercise or acute illness [11], significantly reducing the heart's ability to regulate cardiac output and ultimately leading to HF.

2. Role of the mTOR Pathway in Myocardial Cell Aging

2.1 Structure and Basic Function of the mTOR Pathway

In mammals, mTOR binds to specific adapter proteins to form mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The common core components of both mTORC1 and mTORC2 include mTOR, the mTOR-interacting protein DEP domain, and the mammalian lethal with SEC13 protein 8 (LST8) homolog. Additionally, mTORC1 comprises protein kinase B (Akt) substrate 40 and mTOR regulatory-associated protein (Raptor), while mTORC2 includes mitogen-activated protein kinase-associated protein 1 and rapamycin-insensitive companion of mTOR (Rictor) [12]. Both mTORC1 and mTORC2 can be activated by growth factor signals, and mTORC2 activity is also influenced by mTORC1.

mTORC1 can be activated by nutrients such as amino acids and growth factor signals, while its activity is suppressed when cellular energy is depleted. Upstream regulation of mTORC1 primarily occurs through adenosine monophosphate-activated protein kinase (AMPK) and the tuberous sclerosis complex (TSC), a key negative regulator of mTORC1 [13]. Downstream targets of mTORC1 include sterol regulatory element-binding protein (SREBP), S6 kinase (S6K1), and eukaryotic translation initiation factor 4E-binding protein, which regulate various cellular behaviors and functions including protein synthesis, lipid metabolism, and autophagy [14]. Furthermore, mTORC1 can regulate mTORC2 through three negative feedback pathways and one positive feedback pathway: mTORC1 phosphorylates and activates growth factor receptor-bound protein 10, negatively regulating the insulin/insulin-like growth factor (IGF-1) signaling pathway upstream of mTORC2 and hindering mTORC2 activation [15]; the mTORC1 downstream target S6K1 can also inhibit mTORC2 through phosphorylation of insulin receptor substrate 1 (IRS1) [16]; mTORC1 activation can disrupt mTORC2 integrity through E3 ubiquitin ligase TRAF2, enhancing mTORC1 assembly [17]; and mTORC1 can promote CD122 expression, sensitizing NK cells to interleukin (IL)-15, whose signaling promotes mTORC2 activation [18].

Due to the lack of specific inhibitors for mTORC2, research on mTORC2 remains incomplete [19-20]. mTORC2 can be activated by growth factor signals but is relatively insensitive to nutrients. The most significant effect of mTORC2 activation is the activation of the Akt pathway, promoting the expression of aging-related proteins [21]. mTORC2 can activate serum- and glucocorticoid-regulated protein kinase 1 (SGK1), which has been shown to promote cardiomyocyte survival while inhibiting myocardial hypertrophy; however, chronic activation of SGK1 during HF can lead to adverse ventricular remodeling [22-23]. mTORC2 can also regulate cell polarity and cytoskeletal organization by modulating protein kinase C-α and ras homolog family member A65. Additionally, mTORC2 can regulate mTORC1 through two negative feedback pathways and one positive feedback pathway [20]: mTORC2 can negatively regulate IRS1 and solute carrier family 7 member 5 to inhibit mTORC1 activation signals, while mTORC2 can upregulate mTORC1 through activation of the IGF-Akt axis.

mTOR plays an indispensable role during growth and development; however, moderate inhibition of mTOR activity in old age is protective for the heart, reducing cardiac aging phenotypes and extending lifespan [14]. Mice with cardiac-specific mTOR inhibition mediated by α-myosin-Cre recombinase die within weeks after birth due to severe cardiac dilation, dysfunction, and HF [24]. Studies have found that the expression abundance of mTOR complexes in the heart is negatively correlated with maximum lifespan in mammals [25]. mTOR can drive cardiovascular aging, promote metabolic disorders, cellular hypertrophy, and fibrosis, ultimately leading to age-related HF [26]. Inhibition of mTOR expression can reduce cardiac aging phenotypes such as cardiac hypertrophy and diastolic dysfunction in rodents and rhesus monkeys [27].

2.2 mTORC1 Promotes Protein Synthesis

Overall, mTORC1 promotes protein synthesis, thereby regulating compensatory cardiac hypertrophy and maintaining cardiac function under pressure overload. However, persistent activation of mTORC1 in the aging heart leads to pathological myocardial hypertrophy [27]. mTORC1 plays a key role in the progression of cardiac hypertrophy through two distinct mechanisms that promote protein synthesis. On one hand, mTORC1 promotes mRNA translation through downstream substrates and effectors. Phosphorylation of S6K1 at the Thr389 site leads to S6K1 activation, which then phosphorylates programmed cell death protein 4 (PDCD4) and causes its degradation, relieving PDCD4's inhibition of protein translation and promoting protein synthesis [28]. On the other hand, S6K1 promotes ribosome biogenesis by upregulating transcription of tRNA-encoding genes, ribosome biogenesis factors, and ribosomal proteins, thereby driving protein synthesis [29]. In addition to S6K1, mTORC1 activation also phosphorylates 4E-binding protein 1, releasing it from eukaryotic translation initiation factor 4E (eIF4E), exposing eIF4E's phosphorylation sites, and relieving inhibition of cap-dependent translation to promote protein synthesis [30].

Furthermore, mTOR can function as a downstream target of certain genes in cardiac hypertrophy. Researchers have confirmed through mouse transverse aortic constriction models and in vitro cell experiments that kallikrein 11 promotes protein synthesis through the mTOR signaling pathway, thereby promoting cardiac hypertrophy [31]. A study on tripartite motif protein 44 (TRIM44, which has E3 ubiquitin ligase activity) in mouse in vivo and in vitro models showed [32] that TRIM44 deficiency in cardiomyocytes inhibits the Akt/mTORC1 cascade associated with cardiac hypertrophy, thereby promoting cardiac aging through pathways such as promoting protein synthesis, enhancing lipogenesis, and inhibiting autophagy.

2.3 mTORC1 Regulates Lipid Metabolism

Cardiac aging is accompanied by significant alterations in lipid metabolism. The aged heart exhibits decreased fatty acid oxidation and increased glycolysis. Reduced fatty acid oxidation can lead to lipid accumulation, causing lipotoxicity and cardiomyopathy during aging, and increasing the risk of HF [33]. mTORC1 is closely associated with lipogenesis and oxidative decomposition. mTORC1 has been shown to activate the transcription factor sterol regulatory element-binding protein in rat hepatocytes, thereby activating acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase involved in lipogenesis, leading to increased fat production [34]. Regarding fatty acid oxidative decomposition, mTORC1 can promote the shift from fatty acid oxidation to glycolysis by enhancing hypoxia-inducible factor 1α expression [35]. NACARELLI et al. [36] found that rapamycin-treated cells showed increased fatty acid β-oxidation and catabolism, while SOLIMAN et al. [37] found that increased mTOR activity could lead to decreased expression of adipose triglyceride lipase, increased de novo lipogenesis, and inhibition of fat breakdown. In summary, mTORC1 can promote lipogenesis while inhibiting fatty acid oxidative decomposition, thereby causing lipotoxicity during aging. Therefore, moderate inhibition of mTORC1 is beneficial.

2.4 mTORC1 Can Inhibit Autophagy

Studies have shown that autophagy is reduced in the aging heart, leading to accumulation of dysfunctional organelles and toxic proteins, myofibril disarray, and mitochondrial swelling and destruction, which cause cardiomyopathy phenotypes and overall cardiac dysfunction. Activating autophagy can extend lifespan and reduce age-related cardiac hypertrophy and fibrosis [38]. mTORC1 negatively regulates autophagy at both transcriptional and post-translational levels, reducing autophagosome and autolysosome formation [39]. At the transcriptional level, activated mTORC1 reduces expression of autophagy proteins such as ATG7 by regulating transcription factor EB, thereby inhibiting autophagy [40]. mTORC1 can also negatively regulate lysosomal biogenesis by modulating transcription factors E3 and ZKSCAN3 [41]. At the post-translational level, mTORC1 phosphorylates unc-51-like kinase 1 (ULK1) and ATG13, thereby inhibiting the activity of the ULK1-ATG13-FIP200 complex, which is critical for autophagosome formation [42]. Cardiac-specific mTOR knockout mice and animal models of genetic cardiomyopathy have confirmed these mechanisms.

2.5 mTORC2 and Cardiac Aging

As previously mentioned, the primary effect of mTORC2 activation is activation of the Akt pathway, promoting expression of aging-related proteins. Akt can activate the mTOR/glycogen synthase kinase 3β/P70 ribosomal protein S6 kinase pathway, inhibiting hypertrophy-related protein synthesis and improving cardiac hypertrophy. Regarding autophagy, CHANG et al. [43] found that knocking down upstream inhibitory signaling molecules of mTORC2 in Drosophila revealed that mTORC2 promotes autophagy, thereby slowing cardiac aging. In contrast, in Caenorhabditis elegans, inhibiting mTORC2 and its downstream effectors increased autophagy activity [44], and SGK1 inhibition in mice also promoted autophagosome formation [45].

In terms of lipid metabolism, LIU et al. [46] found that high-fat diet in Drosophila promoted recruitment of dynamin-related protein 1, thereby promoting mitochondrial proliferation and fat metabolism. Knocking down the Rictor subunit of mTORC2 inhibited this process. mTORC2 may mediate the redistribution of subcutaneous white adipose tissue to visceral adipose tissue in elderly individuals, thereby increasing the risk of cardiovascular disease [47-49]. For overall lifespan, knockout of the Rictor subunit of mTORC2 shortened lifespan in male mice but had no effect on female mice [50]. Subsequently, ARRIOLA et al. [51] performed ovariectomy on female mice with liver-specific Rictor knockout and found that the ovariectomized group showed significantly increased median lifespan, but castration of male mice with Rictor knockout did not alleviate their shortened median lifespan. Therefore, exploring the role of mTORC2 in aging requires attention to specific tissues, organs, and sex factors to avoid confounding results.

Furthermore, most existing mTOR inhibitors cannot selectively target mTORC2 [19-20], and current studies have difficulty reaching consistent conclusions. Therefore, the molecular mechanisms of selective mTORC2 inhibition and its effects on aging remain to be further investigated in the future.

3. Improving Myocardial Cell Aging

The role of mTORC1 in organismal lifespan and cardiac aging has been established, and inhibiting mTORC1 expression holds promise for improving aging. However, for mTORC2, inhibition produces some side effects such as insulin resistance and diabetes [52-53]. Studies have shown that treatment with the mTORC1 inhibitor rapamycin can improve prolonged diastolic relaxation time and reduce myocardial stiffness in aged mice [54]. Mice receiving rapamycin treatment from late life have longer average lifespan, while mice receiving rapamycin from early life show reduced age-related learning and memory deficits [55]. Mice with downregulated insulin and IGF-1 signaling exhibit reduced mTORC1-S6K1 activity and extended lifespan [56]. These studies demonstrate that inhibiting mTORC1 activity can delay cardiac functional decline and extend lifespan in multiple organisms.

Clinically, rapamycin is currently used primarily to prevent transplant rejection [57]. The effects of rapamycin on human cardiac aging require further investigation. In the aging heart, decreased defense capacity and immune impairment are important causes of cardiomyopathy [58]. Rapamycin can immunomodulate T cells by inhibiting differentiation of Th1, Th2, and Th17 cells while promoting T cell differentiation, thereby potentially delaying aging [59]. A phase II clinical trial is underway to determine whether rapamycin can improve cardiac function in elderly HF patients with preserved ejection fraction (NCT04996719). Another clinical trial evaluating whether rapamycin can improve immune, cognitive, and cardiac function in older adults is also being advanced (NCT02874924).

In addition to mTOR inhibitors, caloric restriction (CR) can also inhibit mTORC1 expression. CR primarily exerts anti-aging and lifespan-extending effects by inhibiting the mTORC1 pathway. When cellular energy is depleted, adenosine monophosphate (AMP)-activated protein kinase (AMPK) is activated and inhibits mTORC1 activity through phosphorylation of tuberous sclerosis complex 2 (TSC2) or Raptor [60]. Studies have found that adding a single essential amino acid, methionine, to the diet of Drosophila under dietary restriction is sufficient to extend lifespan, while caloric intake above optimal levels shortens lifespan, demonstrating the effectiveness of CR in extending lifespan [61]. In primates, CR has been further proven to extend lifespan and delay age-related diseases, including age-related malignancies, cardiovascular aging, neurodegenerative diseases, and other degenerative conditions [62]. In humans, multiple studies have shown that CR can improve cardiac metabolism, reverse age-dependent cardiac hypertrophy, improve diastolic dysfunction and impaired myocardial function, and extend lifespan [63-64].

Conclusion

The mTOR pathway plays an important role in cardiac physiology and pathology, critically regulating cardiac development, structure, and functional maintenance. During aging, persistent activation of mTORC1 causes pathological cardiac changes by regulating protein synthesis, lipid metabolism, and autophagy, leading to a series of cardiac diseases and ultimately HF. Inhibiting mTORC1 activation during aging has been proven to delay cardiac aging and extend lifespan in multiple organisms. However, future efforts need to further advance clinical trials of mTORC1 inhibitors for improving cardiac function in aging, and the molecular mechanisms of selective mTORC2 inhibition and its effects on aging also require further investigation. This review primarily summarizes and discusses the mechanisms of the mTOR pathway in heart failure caused by myocardial cell aging and potential interventions, providing new insights for future strategies to delay HF induced by myocardial cell aging.

Author Contributions: WANG Yujia was responsible for conceptualization and manuscript writing; ZHANG Jinying and TANG Junnan were responsible for manuscript revision, quality control, and review.

Conflict of Interest: The authors declare no conflict of interest.

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(Received: 2024-11-21; Revised: 2025-03-03)
(Editor: ZOU Lin)