The mechanistic target of rapamycin complex 1 (mTORC1) is indispensable for preserving cellular and organismal homeostasis by balancing the anabolic and catabolic processes in response to various environmental cues, such as nutrients, growth factors, energy status, oxygen levels, and stress. Dysregulation of mTORC1 signaling is associated with the progression of many types of human disorders including cancer, age-related diseases, neurodegenerative disorders, and metabolic diseases. The way mTORC1 senses various upstream signals and converts them into specific downstream responses remains a crucial question with significant impacts for our perception of the related physiological and pathological process. In this review, we discuss the recent molecular and functional insights into the nutrient sensing of the mTORC1 signaling pathway, along with the emerging role of deregulating nutrient-mTORC1 signaling in cancer and age-related disorders.

Pharmacological inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway with rapamycin can extend lifespan in several organisms. Although this includes the nematode Caenorhabditis elegans, effects in this species are relatively weak and sometimes difficult to reproduce. Here we test effects of drug dosage and timing of delivery to establish the upper limits of its capacity to extend life, and investigate drug effects on age-related pathology and causes of mortality. Liposome-mediated rapamycin treatment throughout adulthood showed a dose-dependent effect, causing a maximal 21.9% increase in mean lifespan, but shortening of lifespan at the highest dose, suggesting drug toxicity. Rapamycin treatment of larvae delayed development, weakly reduced fertility and modestly extended lifespan. By contrast, treatment initiated later in life robustly increased lifespan, even from day 16 (or ~70 yr in human terms). The rapalog temsirolimus extended lifespan similarly to rapamycin, but effects of everolimus were weaker. As in mouse, rapamycin had mixed effects on age-related pathologies, inhibiting one (uterine tumor growth) but not several others, suggesting a segmental antigeroid effect. These findings should usefully inform future experimental studies with rapamycin and rapalogs in C. elegans.

Lysosomes are essential degradative organelles and signaling hubs within cells, playing a crucial role in the regulation of macroautophagy/autophagy. Dysfunction of lysosomes and impaired autophagy are closely associated with the development of various neurodegenerative diseases. Enhancing lysosomal activity and boosting autophagy levels holds great promise as effective strategies for treating these diseases. However, there remains a lack of methods to dynamically regulate lysosomal activity and autophagy levels in living cells or animals. In our recent work, we applied optogenetics to manipulate lysosomal physiology and function, developing three lysosome-targeted optogenetic tools: lyso-NpHR3.0, lyso-ArchT, and lyso-ChR2. These new actuators enable light-dependent regulation of key aspects such as lysosomal membrane potential, lumenal pH, hydrolase activity, degradation processes, and Ca2+ dynamics in living cells. Notably, lyso-ChR2 activation induces autophagy via the MTOR pathway while it promotes Aβ clearance through autophagy induction in cellular models of Alzheimer disease. Furthermore, lyso-ChR2 activation reduces Aβ deposition and alleviates Aβ-induced paralysis in Caenorhabditis elegans models of Alzheimer disease. Our lysosomal optogenetic actuators offer a novel method for dynamically regulating lysosomal physiology and autophagic activity in living cells and animals.

Type 1 and type 2 diabetic patients experience alterations in the Central Nervous System, leading to cognitive deficits. Cognitive deficits have been also observed in animal models of diabetes such as impaired sensory perception, as well as deficits in working and spatial memory functions. It has been suggested that a reduction of insulin-like growth factor-I (IGF-I) and/or insulin levels may induce these neurological disorders. We have studied synaptic plasticity in the primary somatosensory cortex of young streptozotocin (STZ)-diabetic mice. We focused on the influence of reduced IGF-I brain levels on cortical synaptic plasticity. Unit recordings were conducted in layer 2/3 neurons of the primary somatosensory (S1) cortex in both control and STZ-diabetic mice under isoflurane anesthesia. Synaptic plasticity was induced by repetitive whisker stimulation. Results showed that repetitive stimulation of whiskers (8 Hz induction train) elicited a long-term potentiation (LTP) in layer 2/3 neurons of the S1 cortex of control mice. In contrast, the same induction train elicited a long-term depression (LTD) in STZ-diabetic mice that was dependent on NMDA and metabotropic glutamatergic receptors. The reduction of IGF-I brain levels in diabetes could be responsible of synaptic plasticity impairment, as evidenced by improved response facilitation in STZ-diabetic mice following the application of IGF-I. This hypothesis was further supported by immunochemical techniques, which revealed a reduction in IGF-I receptors in the layer 2/3 of the S1 cortex in STZ-diabetic animals. The observed synaptic plasticity impairments in STZ-diabetic animals were accompanied by decreased performance in a whisker discrimination task, along with reductions in IGF-I, GluR1, and NMDA receptors observed in immunochemical studies. In conclusion, impaired synaptic plasticity in the S1 cortex may stem from reduced IGF-I signaling, leading to decreased intracellular signal pathways and thus, glutamatergic receptor numbers in the cellular membrane.

Lung squamous cell carcinoma (LUSC) is one of the most common malignant tumors of the respiratory. Pyroptosis plays an essential role in cancer, but there is limited research investigating pyroptosis in LUSC. In this study, pyroptosis-related genes were observed to have extensive multiomics alterations in LUSC through analysis of the TCGA database. Utilizing machine learning for selection and verifying expression levels, GSDMC was chosen as the critical gene for further experiments. Our research found that GSDMC is overexpressed in LUSC tissues and cells, and is associated with poor prognosis. Knockdown of GSDMC in LUSC inhibits cell proliferation, invasion, metastasis, chemotherapeutic sensitivity, and reduced tumor formation in nude mice, accompanied by downregulation of proliferative and EMT-related protein expression. However, these effects were counteracted in cells where GSDMC is overexpressed. Mechanistically, the oncogenic role of GSDMC is primarily achieved through the activation of the AKT/mTOR pathway, and this effect can be significantly reversed by rapamycin. Finally, SMAD4\'s interaction with the promoter region of GSDMC results in the suppression of GSDMC expression. In summary, our study through bioinformatics and experimental approaches not only proves that SMAD4 regulates the protumorigenic role of GSDMC through transcriptional targeting, but also indicates the possibility of developing the SMAD4/GSDMC/AKT/mTOR signaling axis as a potential biomarker and treatment target for LUSC.

The progress made in aging research using laboratory organisms is undeniable. Yet, with few exceptions, these studies are conducted in a limited number of isogenic strains. The path from laboratory discoveries to treatment in human populations is complicated by the reality of genetic variation in nature. To model the effect of genetic variation on the action of the drug rapamycin, here we use the growth of Drosophila melanogaster larvae. We screened 140 lines from the Drosophila Genetic References Panel for the extent of developmental delay and found wide-ranging variation in their response, from lines whose development time is nearly doubled by rapamycin, to those that appear to be completely resistant. Sensitivity did not associate with any single genetic marker, nor with any gene. However, variation at the level of genetic pathways was associated with rapamycin sensitivity and might provide insight into sensitivity. In contrast to the genetic analysis, metabolomic analysis showed a strong response of the metabolome to rapamycin, but only among the sensitive larvae. In particular, we found that rapamycin altered levels of amino acids in sensitive larvae, and in a direction strikingly similar to the metabolome response to nutrient deprivation. This work demonstrates the need to evaluate interventions across genetic backgrounds and highlights the potential of omic approaches to reveal biomarkers of drug efficacy and to shed light on mechanisms underlying sensitivity to interventions aimed at increasing lifespan.

Glucose transporter-2 (GLUT2), a unique high capacity/low affinity, highly efficient membrane transporter and sensor, regulates hypothalamic astrocyte glucose phosphorylation and glycogen metabolism. The phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway participates in glucose homeostasis, but its sensitivity to glucose-sensory cues is unknown. Current research used a hypothalamic astrocyte primary culture model to investigate whether glucoprivation causes PI3K/Akt/mTOR pathway activation in one or both sexes by GLUT2-dependent mechanisms. Glucoprivation did not alter astrocyte PI3K levels, yet up-regulated both phosphorylated derivatives in female and down-regulated male p60 phosphoprotein expression. GLUT2 siRNA pretreatment diminished glucoprivic patterns of PI3K and phospho-PI3K expression in each sex. Astrocyte Akt and phospho-Akt/Thr308 proteins exhibited divergent, sex-contingent responses to GLUT2 gene knockdown or glucoprivation. GLUT2 siRNA pretreatment exacerbated glucoprivic-associated Akt diminution in the female, and either amplified (male) or reversed (female) glucoprivic regulation of phospho-Akt/Thr308 expression. GLUT2 gene silencing down- (male) or up-(female) regulated mTOR protein, and phospho-mTOR protein in male. Male astrocyte mTOR and phospho-mTOR profile were refractory to glucoprivation, but glucose-deprived females showed GLUT2-independent mTOR inhibition and GLUT2-dependent phospho-mTOR up-augmentation. Results identify a larger number of glucoprivic-sensitive PI3K/Akt/mTOR pathway proteins in female versus male astrocytes, and document divergent responses of common glucose-sensitive targets. GLUT2 stimulates phosphoPI3K protein expression in each sex, but imposes differential control of PI3K, Akt, phospho-Akt/Thr308, mTOR, and phospho-mTOR profiles in male versus female. Data implicate GLUT2 as a driver of distinctive pathway protein responses to glucoprivation in female, but not male.

Pyrroline-5-carboxylate reductase (PYCR) is pivotal in converting pyrroline-5-carboxylate (P5C) to proline, the final step in proline synthesis. Three isoforms, PYCR1, PYCR2, and PYCR3, existed and played significant regulatory roles in tumor initiation and progression. In this study, we first assessed the molecular and immune characteristics of PYCRs by a pan-cancer analysis, especially focusing on their prognostic relevance. Then, a kidney renal clear cell carcinoma (KIRC)-specific prognostic model was established, incorporating pathomics features to enhance predictive capabilities. The biological functions and regulatory mechanisms of PYCR1 and PYCR2 were investigated by in vitro experiments in renal cancer cells. The PYCRs\' expressions were elevated in diverse tumors, correlating with unfavorable clinical outcomes. PYCRs were enriched in cancer signaling pathways, significantly correlating with immune cell infiltration, tumor mutation burden (TMB), and microsatellite instability (MSI). In KIRC, a prognostic model based on PYCR1 and PYCR2 was independently validated statistically. Leveraging features from H&E-stained images, a pathomics feature model reliably predicted patient prognosis. In vitro experiments demonstrated that PYCR1 and PYCR2 enhanced the proliferation and migration of renal carcinoma cells by activating the mTOR pathway, at least in part. This study underscores PYCRs\' pivotal role in various tumors, positioning them as potential prognostic biomarkers and therapeutic targets, particularly in malignancies like KIRC. The findings emphasize the need for a broader exploration of PYCRs\' implications in pan-cancer contexts.

Methylsulfinyl hexyl isothiocyanate (6-MSITC) isolated from Eutrema japonicum is a promising candidate for the treatment of breast cancer, colorectal and stomach cancer, metabolic syndrome, heart diseases, diabetes, and obesity due to its anti-inflammatory and antioxidant properties. Also, its neuroprotective properties, improving cognitive function and protecting dopaminergic neurons, make it an excellent candidate for treating neurodegenerative diseases like dementia, Alzheimer\'s, and Parkinson\'s disease. 6-MSITC acts on many signaling pathways, such as PPAR, AMPK, PI3K/AKT/mTOR, Nrf2/Keap1-ARE, ERK1/2-ELK1/CHOP/DR5, and MAPK. However, despite the very promising results of in vitro and in vivo animal studies and a few human studies, the molecule has not yet been thoroughly tested in the human population. Nonetheless, wasabi should be classified as a \"superfood\" for the primary and secondary prevention of human diseases. This article reviews the current state-of-the-art research on 6-MSITC and its potential clinical uses, discussing in detail the signaling pathways activated by the molecule and their interactions.

OBJECTIVE: This paper aims to present a unique perspective that emphasizes the intricate interplay between energy, dietary proteins, and amino acid composition, underscoring their mutual dependence for health-related considerations. Energy and protein synthesis are fundamental to biological processes, crucial for the sustenance of life and the growth of organisms.
RESULTS: We explore the intricate relationship between energy metabolism, protein synthesis, regulatory mechanisms, protein sources, amino acid availability, and autophagy in order to elucidate how these elements collectively maintain cellular homeostasis. We underscore the vital role this dynamic interplay has in preserving cell life.
CONCLUSIONS: A deeper understanding of the link between energy and protein synthesis is essential to comprehend fundamental cellular processes. This insight could have a wide-ranging impact in several medical fields, such as nutrition, metabolism, and disease management.