scholarly journals The Multifaceted Role of Nutrient Sensing and mTORC1 Signaling in Physiology and Aging

2021 ◽  
Vol 2 ◽  
Author(s):  
Stephanie A. Fernandes ◽  
Constantinos Demetriades
Keyword(s):  
Amino Acids ◽  
Nutrient Sensing ◽  
Cancer Type ◽  
Growth Factor Signaling ◽  
Cellular Mechanisms ◽  
Comprehensive Overview ◽  
Critical Determinant ◽  
Age Related ◽  
Mtorc1 Signaling

The mechanistic Target of Rapamycin (mTOR) is a growth-related kinase that, in the context of the mTOR complex 1 (mTORC1), touches upon most fundamental cellular processes. Consequently, its activity is a critical determinant for cellular and organismal physiology, while its dysregulation is commonly linked to human aging and age-related disease. Presumably the most important stimulus that regulates mTORC1 activity is nutrient sufficiency, whereby amino acids play a predominant role. In fact, mTORC1 functions as a molecular sensor for amino acids, linking the cellular demand to the nutritional supply. Notably, dietary restriction (DR), a nutritional regimen that has been shown to extend lifespan and improve healthspan in a broad spectrum of organisms, works via limiting nutrient uptake and changes in mTORC1 activity. Furthermore, pharmacological inhibition of mTORC1, using rapamycin or its analogs (rapalogs), can mimic the pro-longevity effects of DR. Conversely, nutritional amino acid overload has been tightly linked to aging and diseases, such as cancer, type 2 diabetes and obesity. Similar effects can also be recapitulated by mutations in upstream mTORC1 regulators, thus establishing a tight connection between mTORC1 signaling and aging. Although the role of growth factor signaling upstream of mTORC1 in aging has been investigated extensively, the involvement of signaling components participating in the nutrient sensing branch is less well understood. In this review, we provide a comprehensive overview of the molecular and cellular mechanisms that signal nutrient availability to mTORC1, and summarize the role that nutrients, nutrient sensors, and other components of the nutrient sensing machinery play in cellular and organismal aging.

Regulated proteolysis of p62/SQSTM1 enables differential control of autophagy and nutrient sensing

2018 ◽  
Vol 11 (559) ◽  
pp. eaat6903 ◽  
Author(s):  
Julia Sanchez-Garrido ◽  
Vanessa Sancho-Shimizu ◽  
Avinash R. Shenoy
Keyword(s):  
Nutrient Sensing ◽  
Caspase 8 ◽  
Rimmed Vacuoles ◽  
Sequestosome 1 ◽  
Inflammatory Conditions ◽  
Mtorc1 Signaling ◽  
Differential Control ◽  
Antimicrobial Immunity ◽  
Lateral Sclerosis

The multidomain scaffold protein p62 (also called sequestosome-1) is involved in autophagy, antimicrobial immunity, and oncogenesis. Mutations in SQSTM1, which encodes p62, are linked to hereditary inflammatory conditions such as Paget’s disease of the bone, frontotemporal dementia (FTD), amyotrophic lateral sclerosis, and distal myopathy with rimmed vacuoles. Here, we report that p62 was proteolytically trimmed by the protease caspase-8 into a stable protein, which we called p62TRM. We found that p62TRM, but not full-length p62, was involved in nutrient sensing and homeostasis through the mechanistic target of rapamycin complex 1 (mTORC1). The kinase RIPK1 and caspase-8 controlled p62TRM production and thus promoted mTORC1 signaling. An FTD-linked p62 D329G polymorphism and a rare D329H variant could not be proteolyzed by caspase-8, and these noncleavable variants failed to activate mTORC1, thereby revealing the detrimental effect of these mutations. These findings on the role of p62TRM provide new insights into SQSTM1-linked diseases and mTORC1 signaling.

scholarly journals The NLRP3 Inflammasome as a Critical Actor in the Inflammaging Process

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1552
Author(s):  
Maria Sebastian-Valverde ◽  
Giulio M. Pasinetti
Keyword(s):  
Nlrp3 Inflammasome ◽  
Low Grade ◽  
Cellular Mechanisms ◽  
Pyrin Domain ◽  
Human Lifespan ◽  
Age Related ◽  
Inflammatory State ◽  
Chronic Activation ◽  
Receptor Family

As a consequence of the considerable increase in the human lifespan over the last century, we are experiencing the appearance and impact of new age-related diseases. The causal relationships between aging and an enhanced susceptibility of suffering from a broad spectrum of diseases need to be better understood. However, one specific shared feature seems to be of capital relevance for most of these conditions: the low-grade chronic inflammatory state inherently associated with aging, i.e., inflammaging. Here, we review the molecular and cellular mechanisms that link aging and inflammaging, focusing on the role of the innate immunity and more concretely on the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, as well as how the chronic activation of this inflammasome has a detrimental effect on different age-related disorders.

scholarly journals Royal Jelly and Its Components Promote Healthy Aging and Longevity: From Animal Models to Humans

2019 ◽  
Vol 20 (19) ◽  
pp. 4662 ◽  
Author(s):  
Kunugi ◽  
Mohammed Ali
Keyword(s):  
Healthy Aging ◽  
Royal Jelly ◽  
Pantothenic Acid ◽  
Activity Level ◽  
Natural Phenomenon ◽  
Growth Factor Signaling ◽  
Cellular Mechanisms ◽  
Health Maintenance ◽  
Positive Effects ◽  
Age Related

Aging is a natural phenomenon that occurs in all living organisms. In humans, aging is associated with lowered overall functioning and increased mortality out of the risk for various age-related diseases. Hence, researchers are pushed to find effective natural interventions that can promote healthy aging and extend lifespan. Royal jelly (RJ) is a natural product that is fed to bee queens throughout their entire life. Thanks to RJ, bee queens enjoy an excellent reproductive function and lengthened lifespan compared with bee workers, despite the fact that they have the same genome. This review aimed to investigate the effect of RJ and/or its components on lifespan/healthspan in various species by evaluating the most relevant studies. Moreover, we briefly discussed the positive effects of RJ on health maintenance and age-related disorders in humans. Whenever possible, we explored the metabolic, molecular, and cellular mechanisms through which RJ can modulate age-related mechanisms to extend lifespan. RJ and its ingredients—proteins and their derivatives e.g., royalactin; lipids e.g., 10-hydroxydecenoic acid; and vitamins e.g., pantothenic acid—improved healthspan and extended lifespan in worker honeybees Apis mellifera, Drosophila Melanogaster flies, Gryllus bimaculatus crickets, silkworms, Caenorhabditis elegans nematodes, and mice. The longevity effect was attained via various mechanisms: downregulation of insulin-like growth factors and targeting of rapamycin, upregulation of the epidermal growth factor signaling, dietary restriction, and enhancement of antioxidative capacity. RJ and its protein and lipid ingredients have the potential to extend lifespan in various creatures and prevent senescence of human tissues in cell cultures. These findings pave the way to inventing specific RJ anti-aging drugs. However, much work is needed to understand the effect of RJ interactions with microbiome, diet, activity level, gender, and other genetic variation factors that affect healthspan and longevity.

The Differential Role of Smell and Taste For Eating Behavior

Perception ◽  
2017 ◽  
Vol 46 (3-4) ◽  
pp. 307-319 ◽  
Author(s):  
Sanne Boesveldt ◽  
Kees de Graaf
Keyword(s):  
Eating Behavior ◽  
Food Choice ◽  
Experimental Studies ◽  
Real Life ◽  
Food Product ◽  
Nutrient Sensing ◽  
Oral Exposure ◽  
Eating Rate ◽  
Comprehensive Overview

Food choice and food intake are guided by both sensory and metabolic processes. The senses of taste and smell play a key role in the sensory effects on choice and intake. This article provides a comprehensive overview of, and will argue for, the differential role of smell and taste for eating behavior by focusing on appetite, choice, intake, and satiation. The sense of smell mainly plays a priming role in eating behavior. It has been demonstrated that (orthonasal) odor exposure induces appetite specifically for the cued food. However, the influence of odors on food choice and intake is less clear, and may also depend on awareness or intensity of the odors, or personality traits of the participants. Taste on the other hand, has a clear role as a (macro)nutrient sensing system, during consumption. Together with texture, taste is responsible for eating rate, and thus in determining the oral exposure duration of food in the mouth, thereby contributing to satiation. Results from these experimental studies should be taken to real-life situations, to assess longer-term effects on energy intake. With this knowledge, it will be possible to steer people’s eating behavior, as well as food product development, toward a less obesogenic society.

scholarly journals mTORC1 as the main gateway to autophagy

2017 ◽  
Vol 61 (6) ◽  
pp. 565-584 ◽  
Author(s):  
Yoana Rabanal-Ruiz ◽  
Elsje G. Otten ◽  
Viktor I. Korolchuk
Keyword(s):  
Amino Acids ◽  
Nutrient Sensing ◽  
Biomedical Sciences ◽  
Energy Sensor ◽  
As Stress ◽  
Amino Acid Sensing ◽  
Amp Activated Protein Kinase ◽  
Cellular Components ◽  
Synthesis And Degradation

Cells and organisms must coordinate their metabolic activity with changes in their environment to ensure their growth only when conditions are favourable. In order to maintain cellular homoeostasis, a tight regulation between the synthesis and degradation of cellular components is essential. At the epicentre of the cellular nutrient sensing is the mechanistic target of rapamycin complex 1 (mTORC1) which connects environmental cues, including nutrient and growth factor availability as well as stress, to metabolic processes in order to preserve cellular homoeostasis. Under nutrient-rich conditions mTORC1 promotes cell growth by stimulating biosynthetic pathways, including synthesis of proteins, lipids and nucleotides, and by inhibiting cellular catabolism through repression of the autophagic pathway. Its close signalling interplay with the energy sensor AMP-activated protein kinase (AMPK) dictates whether the cell actively favours anabolic or catabolic processes. Underlining the role of mTORC1 in the coordination of cellular metabolism, its deregulation is linked to numerous human diseases ranging from metabolic disorders to many cancers. Although mTORC1 can be modulated by a number of different inputs, amino acids represent primordial cues that cannot be compensated for by any other stimuli. The understanding of how amino acids signal to mTORC1 has increased considerably in the last years; however this area of research remains a hot topic in biomedical sciences. The current ideas and models proposed to explain the interrelationship between amino acid sensing, mTORC1 signalling and autophagy is the subject of the present review.

scholarly journals Loss of major nutrient sensing and signaling pathways suppresses starvation lethality in electron transport chain mutants

2021 ◽  
Author(s):  
Alisha G. Lewis ◽  
Robert Caldwell ◽  
Jason V. Rogers ◽  
Maria Ingaramo ◽  
Rebecca Y. Wang ◽  
...  
Keyword(s):  
Electron Transport ◽  
Signaling Pathways ◽  
Electron Transport Chain ◽  
Nutrient Sensing ◽  
Ph Homeostasis ◽  
Inner Mitochondrial Membrane ◽  
Age Related ◽  
Transport Chain ◽  
Major Nutrient

The electron transport chain (ETC) is a well-studied and highly conserved metabolic pathway that produces ATP through generation of a proton gradient across the inner mitochondrial membrane coupled to oxidative phosphorylation. ETC mutations are associated with a wide array of human disease conditions and to aging-related phenotypes in a number of different organisms. In this study, we sought to better understand the role of the ETC in aging using a yeast model. A panel of ETC mutant strains that fail to survive starvation was used to isolate suppressor mutants that survive. These suppressors tend to fall into major nutrient sensing and signaling pathways, suggesting that the ETC is involved in proper starvation signaling to these pathways in yeast. These suppressors also partially restore ETC-associated gene expression and pH homeostasis defects, though it remains unclear if these phenotypes directly cause the suppression or are simply effects. This work further highlights the complex cellular network connections between metabolic pathways and signaling events in the cell, and their potential roles in aging and age-related diseases.

scholarly journals The emerging role of mTORC1 signaling in placental nutrient-sensing

Placenta ◽  
2012 ◽  
Vol 33 ◽  
pp. e23-e29 ◽  
Author(s):  
T. Jansson ◽  
I.L.M.H. Aye ◽  
D.C.I. Goberdhan
Keyword(s):  
Nutrient Sensing ◽  
Mtorc1 Signaling

scholarly journals Cerebral microhemorrhages: mechanisms, consequences, and prevention

2017 ◽  
Vol 312 (6) ◽  
pp. H1128-H1143 ◽  
Author(s):  
Zoltan Ungvari ◽  
Stefano Tarantini ◽  
Angelia C. Kirkpatrick ◽  
Anna Csiszar ◽  
Calin I. Prodan
Keyword(s):  
Western World ◽  
Neuronal Function ◽  
Cellular Mechanisms ◽  
Structural Determinants ◽  
Age Related ◽  
Proposed Model ◽  
Intracerebral Hemorrhages ◽  
Cerebral Microhemorrhages ◽  
Brain Microvasculature

The increasing prevalence of multifocal cerebral microhemorrhages (CMHs, also known as “cerebral microbleeds”) is a significant, newly recognized problem in the aging population of the Western world. CMHs are associated with rupture of small intracerebral vessels and are thought to progressively impair neuronal function, potentially contributing to cognitive decline, geriatric psychiatric syndromes, and gait disorders. Clinical studies show that aging and hypertension significantly increase prevalence of CMHs. CMHs are also now recognized by the National Institutes of Health as a major factor in Alzheimer’s disease pathology. Moreover, the presence of CMHs is an independent risk factor for subsequent larger intracerebral hemorrhages. In this article, we review the epidemiology, detection, risk factors, clinical significance, and pathogenesis of CMHs. The potential age-related cellular mechanisms underlying the development of CMHs are discussed, with a focus on the structural determinants of microvascular fragility, age-related alterations in cerebrovascular adaptation to hypertension, the role of oxidative stress and matrix metalloproteinase activation, and the deleterious effects of arterial stiffening, increased pulse pressure, and impaired myogenic autoregulatory protection on the brain microvasculature. Finally, we examine potential treatments for the prevention of CMHs based on the proposed model of aging- and hypertension-dependent activation of the reactive oxygen species-matrix metalloproteinases axis, and we discuss critical questions to be addressed by future studies.

scholarly journals mTOR and Aging: An Old Fashioned Dress

2019 ◽  
Vol 20 (11) ◽  
pp. 2774 ◽  
Author(s):  
Giovanni Stallone ◽  
Barbara Infante ◽  
Concetta Prisciandaro ◽  
Giuseppe Grandaliano
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Nutrient Sensing ◽  
Protective Effects ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Age Related ◽  
Signalling Network ◽  
Evolutionarily Conserved ◽  
Mtor Signalling

Aging is a physiologic/pathologic process characterized by a progressive impairment of cellular functions, supported by the alterations of several molecular pathways, leading to an increased cell susceptibility to injury. This deterioration is the primary risk factor for several major human pathologies. Numerous cellular processes, including genomic instability, telomere erosion, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, stem cell exhaustion, and altered intercellular signal transduction represent common denominators of aging in different organisms. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved nutrient sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Studies in flies, worms, yeast, and mice support the hypothesis that the mTOR signalling network plays a pivotal role in modulating aging. mTOR is emerging as the most robust mediator of the protective effects of various forms of dietary restriction, which has been shown to extend lifespan and slow the onset of age-related diseases across species. Herein we discuss the role of mTor signalling network in the development of classic age-related diseases, focused on cardiovascular system, immune response, and cancer.

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