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Masliukov, P.M. Signaling Pathways in Hypothalamic Neurons with Aging. Encyclopedia. Available online: https://encyclopedia.pub/entry/50330 (accessed on 05 September 2024).
Masliukov PM. Signaling Pathways in Hypothalamic Neurons with Aging. Encyclopedia. Available at: https://encyclopedia.pub/entry/50330. Accessed September 05, 2024.
Masliukov, Petr M.. "Signaling Pathways in Hypothalamic Neurons with Aging" Encyclopedia, https://encyclopedia.pub/entry/50330 (accessed September 05, 2024).
Masliukov, P.M. (2023, October 16). Signaling Pathways in Hypothalamic Neurons with Aging. In Encyclopedia. https://encyclopedia.pub/entry/50330
Masliukov, Petr M.. "Signaling Pathways in Hypothalamic Neurons with Aging." Encyclopedia. Web. 16 October, 2023.
Signaling Pathways in Hypothalamic Neurons with Aging
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This entry is adapted from the peer-reviewed paper 10.3390/cimb45100523

The hypothalamus is an important regulator of autonomic and endocrine functions also involved in aging regulation. The aging process in the hypothalamus is accompanied by disturbed intracellular signaling including insulin/insulin-like growth factor-1 (IGF-1)/growth hormone (GH), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/the mammalian target of rapamycin (mTOR), mitogen activated protein kinase (MAPK), janus kinase (JAK)/signal transducer and activator of transcription (STAT), AMP-activated protein kinase (AMPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB), and nitric oxide (NO). 

hypothalamus aging signaling pathways

1. Introduction

The hypothalamus is the regulatory hub controlling homeostasis, reproduction, circadian rhythms, and the endocrine system [1][2]. At the end of the XXth Century, it was proposed that hypothalamus participates in the aging regulation. According to this theory, age-related raising of the hypothalamus threshold for homeostatic signals leads to aging and the appearance of age-related disease in different species [3][4]. The advancement of new research techniques, including cutting-edge approaches in genetics, molecular biology, and neuroscience, allowed the study of the role of the hypothalamus in aging mechanisms in more detail [5][6][7]. It has been suggested that the age-related loss of hypothalamic stem cells plays a major role in the development of hypothalamic neuroinflammation and mammalian aging [8][9].
The process of aging is associated with many chronic pathological conditions such as vascular diseases, diabetes mellitus, cancer, and metabolic syndrome. It has been established that aging is accompanied by disturbances of signaling cascades including insulin/insulin-like growth factor-1 (IGF-1)/growth hormone (GH), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/the mammalian target of rapamycin (mTOR), mitogen activated protein kinase (MAPK), janus kinase (JAK)/signal transducer and activator of transcription (STAT), AMP-activated protein kinase (AMPK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB). These pathways regulate energy balance, cellular plasticity, mechanisms supporting homeostasis, growth, reproduction, and inflammation [10][11][12]. 

2. Insulin/IGF-1/GH Signaling

The insulin-like growth factor (IGF) family includes three known ligands (IGF-1, IGF-2, and insulin). In contrast to invertebrates, mammals, such as mice and humans, have two distinct receptors for insulin and IGF-1, each of which is encoded by a separate gene. While insulin primarily controls the metabolism, IGFs are responsible for long-lasting effects on the regulation of growth, development, and differentiation of cells and tissues [13].
Insulin is synthetized by beta cells in the pancreas and crosses the blood–brain barrier by a saturable mechanism. Insulin in the CNS has opposite effects compared to the periphery, increasing blood glucose levels, decreasing feeding and body weight, and even decreasing the blood levels of insulin [14]. Some recent data indicate that brain insulin downregulates expression of genes involved in glucose metabolism, reduces oxidative stress, regulates the expression of glutamate receptors, upregulates GABA receptors, and suppresses multiple neuropeptides, which contribute to synaptic plasticity and neuronal activity, particularly in the hypothalamus [15].
In vitro biological effects of IGFs are relatively weak and often are observed in the presence of other hormones or growth factors. Possibly, IGFs act as permissive factors to augment the signals of other factors [16].
Insulin can bind to the IGF-1 receptor (IGF-1R) but IGFs bind less well to the insulin receptor (IR) [16]. When IGF-1Rs and IRs are produced in the same cells, some of them form a hybrid receptor [17]. Although structurally, the IGF-1R and the IR are highly homologous, the homology of their C-terminal regions is relatively low [16][17]. IGF-1Rs and IRs are found throughout the CNS including the hypothalamus, and their relative distributions vary, but overlap [18][19]. IRs’ expression is higher than that for IGF-1Rs in the ARN [14]. 
In contrast to the invertebrate system, mammalian IGF-1 production is regulated by GH secretion from the pituitary. In vivo, many physiological effects of GH are mediated by GH-induced hepatic IGF-1 and local IGF-1 [20]. The secretion of GH is stimulated by GHRH and ghrelin and inhibited by SS. GH exerts its effects by interacting with the GH receptor (GHR), a member of the cytokine receptor superfamily. The GHR is expressed in multiple tissues, including muscle, adipose, heart, kidney, intestine, and bone, with expression being most abundant in the liver [21]. GH secretion is inhibited by IGF-1 in a feedback loop and modulated by other hormones including insulin [22]. Short-term treatment with GH results in rapid insulin-like effects, including the stimulation of lipogenesis and inhibition of lipolysis [23]. However, long-term use of GH counteracts the effects of insulin and induces insulin resistance and diabetes [24][25].
IR signaling is mediated by the action of insulin receptor substrate (IRS) on two canonical pathways, the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/the mammalian target of rapamycin (mTOR) signaling pathway, and Ras/mitogen activated kinase (MAPK) cascades [26]. The PI3K/AKT/mTOR signaling pathway is critically important in the regulation of different biological processes such as cell cycle, metabolism, and signal transduction [27][28][29].
GH binding with GHR activates the tyrosine kinase janus kinase 2 (JAK2), which phosphorylates several tyrosine residues on the intracellular domain of the receptor and initiates a multitude of signaling cascades. Activation of the GHR/JAK2 complex leads to activation of signal transducers and activators of transcription (STATs), ERK/MAPK, and PI3K/AKT pathways [21][30].
GH and IGF-1 levels in the blood peak in adolescence and then progressively decline, becoming scarcely detectable in the elderly [31]. The level of GHRH in the median eminence decreases in aged rats, while the SS level in the median eminence, as well as GHRH and SS level in the neuronal somata remains intact [32]. It was proposed that SS-induced inhibition of GH was sensitized in aged rats, indicating a possible cause for the age-related decrease in GH level in plasma [33]. However, the percentage of SS-immunoreactive neurons in the mediobasal hypothalamus, as well as their number, does not change in males and females with aging [34].
In both humans and mice, a substantial increase in GH levels is associated with high risks of diseases and reduced life expectancy [35][36].
Reduced activity of the insulin/IGF1 signaling increases longevity, improves health in aged animals from worms and flies to mice [37][38][39]. However, global reduction in insulin signaling by the deletion of IR, IGF1R, or IGF1 leads to early mortality [40][41]. Total disruption of insulin signaling also has defects such as metabolic syndrome, and reduced body size and fertility [42]. Total deletion of IR receptors in peripheral tissues after adulthood leads to a significant reduction in male life span [43]. On the other hand, insulin in the brain acts as a neuroprotector, lowering damage induced by ischemia, β-amyloid toxicity, oxidative stress, and apoptosis [44]. Brain insulin resistance and low levels of brain insulin often lead to metabolic and cognitive dysfunctions, including obesity, type 2 diabetes, and Alzheimer’s disease [45][46].
Reduced expression of the IGF-1R in the C57BL/6 mice caused only a 5% prolongation of lifespan in females [47]. However, its partial reduction in fat can lead to lifespan extension [48].
Hypothalamic insulin resistance caused by overnutrition occurs more rapidly than in other insulin-sensitive tissues [49]. Nevertheless, selective ablation of IR in the different populations of hypothalamic neurons, including AGRP and POMC cells, has only a moderate effect on energy balance [50][51]. In addition, mice lacking the IR in the MCH neurons of the LHA had a lean phenotype and exhibited improved locomotor activity and insulin sensitivity under a high-fat diet [52].
There is a link between the IGF-1 and GLP-1 signaling pathways. GLP-1, apart from regulating food intake, prevents neuronal death mediated by amyloidogenesis, cerebral glucose deprivation, neuroinflammation, and apoptosis through modulation of PI3/Akt mTOR and MAPK/ERK [53]. GLP-1 downregulation causes oligodendrocyte deterioration, demyelination, glial hyperactivity, immunological dysregulation, and neuroexcitation in the brain [54]. IGF-1 resistance and GLP-1 deficiency impair protective cellular signaling mechanisms, contributing to the progression of neurodegenerative diseases [53][55]. The anti-inflammatory effect of GLP-1 was lost in astrocytes with IGF1-R knockout [56].

3. PI3K/mTOR/AKT Pathway

The binding of IGF-I or insulin to the α subunit of its specific receptor on a target cell membrane leads to the conformational change in the β subunit, resulting in the activation of receptor tyrosine kinase activity [15][57]. The activated receptor in turn phosphorylates specific substrates, in particular insulin receptor substrate (IRS) and Src homology collagen (Shc) [16]. It is known that mice have four IRS proteins (IRS1-IRS4) but IRS3 is absent in humans [58]. Tyrosine phosphorylated substrates (pIRS-1, pIRS-2, pShc, pGab1) are recognized by some SH-2 domain containing molecules, including growth factor receptor-bound 2 (Grb2), a p85 regulatory subunit of PI3-kinase, and SHP2/Syp. Grb2 is required for IGF-I-induced Ras-MAPK pathway activation [16]. The interaction between IRS and SHP-2 is important for the crosstalk between IGF-I and the integrin pathway [59].
The PI3K family includes three classes, from I to III [60]. PI3K itself is a heterodimer consisting of regulatory p85 and catalytic p110 subunits. At rest, it is in an inactive state in the cytoplasm of the cell. The p85 regulatory domain of PI3K (p85-PI3K) binds the phosphorylated domains of IRS-1, activating PI3K [61]. The activated enzyme catalyzes the synthesis of phosphatidylinositol-3,4,5-triphosphate (PIP3) from the membrane phosphatidylinositol 4,5-bisphosphate (PIP2). PIP3 provides anchoring of phosphoinositol-dependent protein kinase (PDK-1/2) in the membrane. Membrane-bound PDK-1/2 is activated and, in turn, catalyzes the phosphorylation of inactive AKT. The activation of PI3K induces AKT phosphorylation at two residues: Thr 308 in the kinase domain and Ser473 in the hydrophobic motif. Phosphorylated AKT (pAKT) acquires catalytic properties, dissociates from the membrane, and provides phosphorylation of various intracellular proteins in the cytoplasm and nucleus [62][63]. AKT regulates the activity of some longevity genes, such as mTOR, NF-κB and forkhead box O (FOXO). AKT stimulates mTOR and NF-κB, and inhibits FOXO factors [64].
An important downstream target of AKT is mTOR. mTOR is a serine/threonine protein kinase that is a part of two different protein complexes: the mTOR complex 1 (mTORC1) and the mTOR complex 2 (mTORC2). mTORC1 is inhibited by rapamycin, promotes protein synthesis and autophagy, and integrates hormonal and environmental signals. mTORC2 is involved in the insulin signaling pathway. In addition to mTOR protein kinase, mTORC1 includes RAPTOR protein and AKT PRAS40 substrate; mTORC2—RICTOR protein and other specific protein subunits such as mSin1 and Protor-1/2. In addition, both mTORC1 and mTORC2 also have the same components: mLST8/GβL as well as the DEPTOR regulatory protein [65].
With aging, the PI3K/AKT/mTOR signaling pathway dysregulates in many tissues including the brain and hypothalamus. There are some reports about changes in separate parts of this system, and selective action may reduce aging manifestations.
IRS-1 and IRS-2 are functionally different. IRS-1 knockdown or overexpression did not affect the IGF signals but IRS-2 knockdown impaired the IGF-1 signals and IGF bioactivities [66][67]. Age-related diseases such as obesity, skin pathology, osteoporosis, sarcopenia, and glucose intolerance were less common in IRS-1 complete knockout mice [68]. Nevertheless, the lifespan of mice was not increased by selective IRS-1 deletion in the liver, muscles, fat, or neurons. Compared to IRS1 deletion in the muscle, liver, and fat, neuron-selective IRS1 knockout increased energy consumption, movement activity, and insulin responsiveness, particularly in aged male mice [69].
There are contradictory data on the role of IRS-2 in aging regulation. Taguchi et al. (2007) reported that mice heterozygous for a null mutation in the IRS-2 in the whole body or separately in the brain had an increased life span [70]. However, using the same mouse model, Selman et al. (2008) observed no evidence for life-span extension and even shortened survival time [71]. It is suggested that IRS-1 is more involved in mitogenic signaling whereas IRS-2 is more important in the regulation of metabolism [72]. In this case, a more severe lifespan-prolonging effect in IRS-1 mutants could be due to lowered cell division while IRS-2 mutants may not demonstrate lifespan extension due to metabolic disturbances [43].
Leptin and insulin action can differently modulate PI3K activity in hypothalamic neurons. It is important for metabolic syndrome, which is a common manifestation of aging [73][74][75]. In the ARN, leptin directly activates PI3K in POMC neurons, but indirectly inhibits it in AGRP neurons [76]. Insulin, vice versa, stimulates PI3K signaling in both POMC and AGRP neurons [77]. Selective inactivation of PI3K reduced leptin-stimulated excitation of hypothalamic POMC neurons in the ARN and caused suppression of food intake [78]. Leptin and insulin influence to decrease food intake was interrupted by PI3K inhibitors [79]. In turn, pharmacological inhibition of PI3K eliminated insulin-induced activation of mTOR [80]. However, the exact role of PI3K in hypothalamic neurons in the regulation of metabolism during aging has yet not been fully established. In C. elegans, mutants lacking any active PI3K are extremely long lived and stress resistant [81].
Despite many studies having demonstrated that aging is closely related to the PI3K/AKT signaling pathway, the detailed mechanism underlying it is still not completely understood. Often constitutive activation of AKT signaling leads to tissue overgrowth and is frequently observed in cancer cells, whereas reduced AKT activity is associated with diabetes and growth defects [82][83]. In aging, the occurrence of diabetes and obesity is associated with insulin resistance [84], which leads to the downregulation of AKT and upregulation of FOXOs. In addition, AKT demonstrates differential actions in separate organs [85][86].
There are different results concerning AKT modulation and aging in the brain. Some studies showed a reduction in AKT activity, others found an increase in its phosphorylation status with the aging process [87][88]. In addition, there are contradictory data on AKT expression in Alzheimer’s disease with evidence of increased and decreased AKT activity [89][90]. In the hypothalamus of rodents, the expression of AKT does not change or there are small disturbances with aging [91][92]. On the other hand, activation of the PI3K/AKT/mTOR pathway in the hypothalamus leads to a comparable weight increase, and obesity is often observed with aging [76].
AKT phosphorylates FOXO, induces its nuclear translocation, and inhibits its action in vitro and in vivo. FOXO performs a considerable role in aging and age-related diseases including neurodegenerative and oncological pathology [93]. FOXO overexpression promotes longevity in many species including mammals by combined autocrine and paracrine effects [92]. However, there are contradictory facts that FOXO activity elevates with aging. Tumor necrosis factor (TNF)-α raises the FOXO1 activity by preventing its phosphorylation. Enlarged FOXO1 activity suppresses the gnrh1 gene and activates the NF-κB inflammatory signaling, preventing GnRH secretion [94].
Hypothalamic FOXO1 increases food intake and body weight by stimulating the transcription of orexigenic NPY/AGRP and suppressing POMC neurons in the ARN [29][95][96]. Nevertheless, dietary disturbances are not necessarily associated with the changes in PI3K/AKT/mTOR and FOXO signaling [96].
Different studies have shown that inactivation of mTOR signaling can prolong the duration of life, which might explain the lifespan extension of mice with rapamycin therapy [97][98]. Diet-induced hyperactivation of mTORC1 induces metabolic disturbances, including obesity and type 2 diabetes, as well as cancer and neurodegenerative diseases [99][100][101]. Upregulation of mTORC1 and mTORC2 inhibitory protein DEPTOR in hypothalamic neurons reduced obesity and improves glucose metabolism [102]. Nevertheless, the expression of mTOR in separate hypothalamic nuclei is different through aging. The proportion of mTOR-IR decreased in DMN and VMN neurons and increased in the ARN in 12-month-old and 24-month-old rats [103].
Loss of RICTOR, a part of the mTORC2 complex, results in a sex-specific reduction in male life expectancy even when the intervention is initiated at maturity, in contrast to deletion of IRS1 [104]. Moreover, both male and female mice exhibited a decreased lifespan, activity, glucose tolerance, and insulin responsiveness after knockout of RICTOR in the hypothalamus [105].
In addition to mTOR, AKT through different pathways could trigger the activation of the NF-κB system, which inhibits apoptosis, autophagy, and stimulates inflammatory responses, which is very important for aging [106].

5. Ras/Raf/MEK/ERK Pathway

The mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) pathway is reported to be associated with cell proliferation, differentiation, migration, senescence, and apoptosis. Insulin is also able to modulate cell growth and proliferation through induction of Shc and its downstream targets Ras, ERK, and mitogen-activated protein kinase (MAPK). In the Ras/MAPK signaling pathway, activated IRSs interact with growth factor receptor-bound protein 2 (Grb2). The tyrosine 891 in IRS-1 is known to be a Grb2 binding site phosphorylated by IGF/insulin stimuli, which is important for the activation of the Ras-MAPK cascade [107]. Grb2, in turn, can activate MAPK cascades via an interaction with the Ras guanine nucleotide exchange factor SOS. Subsequently, SOS activates the small G protein Ras, which in turn recruits MAPK3, also known as Raf kinase. The Raf kinase phosphorylates and activates a MAPK/ERK kinase (MEK1 or MEK2). The MEK phosphorylates and activates a mitogen-activated protein kinase (MAPK). MAPK is referred to as extracellular signal-regulated kinase (ERK). ERK (MAPK) further phosphorylates different proteins in the cytoplasm or transcription factors in the nucleus [108].
This pathway is more often activated by IGF-1R compared to IR [109]. Moreover, different IRα isoforms stimulate specific downstream pathways: the IR-A isoform better activates the Shc/Ras/ERK/MAPK signaling, while the IR-B stimulates PI3K/Akt/mTOR [110][111].
There is evidence of ERK/MAPK impairment in the brain pathology. ERK/MAPK stimulation decreases neuronal injury following ischemia-hypoxia [112]. Treatment of brain-derived neurotrophic factor (BDNF) leads to elevation of ERK/MAPK activity during 12 h after ischemic-hypoxic injury. Resveratrol and fisetin also activate ERK/MAPK and inhibit cell death in a model of Huntington’s disease [113].
During aging, the expression of phosphorylated ERK1/2 and MAPK was reduced in the rat cerebral cortex, striatum, and hippocampus [114]. However, ERK1/2 phosphorylation was increased in the hypothalamus of aged rats [115].
In the hypothalamus, insulin decreases mRNA expression of orexigenic neuropeptides NPY and AgRP through an ERK/MAPK dependent mechanism, [116]. Obese mice also exhibit an increased hypothalamic expression of the MAPK phosphatase 3 associated with a reduced phosphorylation of ERK [117][118].
In the SCN of the hypothalamus, nocturnal light activates ERK/MAPK [119], and inhibition of ERK/MAPK prevents the light response [120]. Thus, ERK/MAPK is an important signal pathway involved in clock function. Rhythmicity in the SCN declines with aging, and impairment in the ERK/MAPK pathway can play an important role in this process. However, there are no direct data about changes in the ERK/MAPK expression in the SCN with aging.

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Petr M. Masliukov
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