Deregulated Nutrient Sensing

Deregulated nutrient sensing is one of the hallmarks of aging, characterized by the dysregulation in the mechanisms that cells and organisms use to detect and respond to nutrients. Nutrient sensing pathways play a crucial role in maintaining metabolic homeostasis and influence key processes related to growth, development, reproduction, and longevity. As organisms age, the efficiency and accuracy of these pathways often decline, leading to impaired metabolic responses and contributing to age-related diseases and decreased lifespan.

Key Nutrient Sensing Pathways

Several critical nutrient-sensing pathways are known to be involved in the regulation of metabolism and aging:

Insulin and IGF-1 Signaling (IIS): IIS is crucial for controlling growth and metabolism in response to nutrient availability. Dysregulation of IIS is associated with various metabolic disorders, including diabetes and obesity, and modulating this pathway has been shown to affect lifespan in various organisms.^[1]
mTOR Pathway: The mechanistic target of rapamycin (mTOR) pathway integrates signals from nutrients, growth factors, and energy status to regulate growth, protein synthesis, and autophagy. Overactivation of mTOR is linked to accelerated aging and age-related diseases, while its inhibition has been associated with lifespan extension.^[2]
AMP-Activated Protein Kinase (AMPK): AMPK is activated under low energy conditions and helps restore energy balance by promoting catabolic processes and inhibiting anabolic processes. It plays a critical role in maintaining energy homeostasis and is considered a key target for treating metabolic diseases.^[3]
Sirtuins: Sirtuins are NAD+-dependent deacetylases that respond to changes in the cellular energy state and regulate various metabolic processes, including the response to calorie restriction. They are implicated in the aging process and the development of age-related diseases.^[4]

Amino acids regulate multiple interacting nutrient sensing pathways. The adequate sensing of amino acid availability is significant for the effective regulation of protein synthesis and catabolism. An important way of amino acid control for nutrient sensing is via the amino acid sensing taste receptors, members of the T1R and T2R families of G-protein-coupled receptors. Amino acid taste receptors in humans exhibit a high affinity to glutamate, with other L-amino acids also acting as ligands.^[5]^[1]

Consequences of Deregulated Nutrient Sensing

Deregulated nutrient sensing can lead to several adverse effects on health and longevity:

Insulin resistance: One of the predominant nutrient sensing dysfunctions that occur upon human aging is insulin resistance. This condition emerges due to factors such as oxidative stress, inflammation, enzymatic activity disorders, and fatty acids accumulation, contributing to a decline in insulin sensitivity. As a consequence, the body gradually loses its capability to regulate blood sugar level, exacerbating conditions like atherosclerosis and fatty liver disease.^[6]
Metabolic Disorders: Dysregulation can contribute to the development of metabolic diseases such as diabetes, obesity, and metabolic syndrome.
Decreased Adaptability: Impaired nutrient sensing reduces the organism's ability to adapt to changes in nutrient availability, leading to suboptimal metabolic responses and increased vulnerability to environmental changes.
Accelerated Aging: Deregulated pathways are associated with accelerated cellular and organismal aging, promoting age-related phenotypes and reducing lifespan.
Age-related Diseases: Dysregulation is implicated in the pathogenesis of various age-related diseases, including cancer, neurodegenerative disorders, and cardiovascular diseases.

Therapeutic Interventions

Modulating nutrient sensing pathways offers potential therapeutic avenues for extending healthspan and treating age-related diseases:

Dietary Interventions: Calorie restriction and intermittent fasting have been shown to beneficially modulate nutrient sensing pathways, leading to improved health and longevity.^[7]
Pharmacological Agents: Drugs targeting these pathways, such as metformin (AMPK activator), rapamycin (mTOR inhibitor), and sirtuin activators, are being explored for their potential to mimic the beneficial effects of dietary interventions and treat age-related metabolic disorders.
Lifestyle Modifications: Exercise and dietary adjustments can influence the activity of nutrient sensing pathways and are recommended for maintaining metabolic health and preventing age-related diseases.

References

↑ ^1.0 ^1.1 Efeyan A et al.: Nutrient-sensing mechanisms and pathways. Nature 2015. (PMID 25592535) [PubMed] [DOI] [Full text] The ability to sense and respond to fluctuations in environmental nutrient levels is a requisite for life. Nutrient scarcity is a selective pressure that has shaped the evolution of most cellular processes. Different pathways that detect intracellular and extracellular levels of sugars, amino acids, lipids and surrogate metabolites are integrated and coordinated at the organismal level through hormonal signals. During food abundance, nutrient-sensing pathways engage anabolism and storage, whereas scarcity triggers homeostatic mechanisms, such as the mobilization of internal stores through autophagy. Nutrient-sensing pathways are commonly deregulated in human metabolic diseases.
↑ Coutin J.What Causes Aging? How Much Have We Learned in Recent Years? https://medium.com/@jessecoutin/what-causes-aging-how-much-have-we-learned-in-recent-years-93b85e6a594a (accessed Feb 16, 2023).
↑ Cummings NE & Lamming DW: Regulation of metabolic health and aging by nutrient-sensitive signaling pathways. Mol Cell Endocrinol 2017. (PMID 27884780) [PubMed] [DOI] [Full text] All organisms need to be capable of adapting to changes in the availability and composition of nutrients. Over 75 years ago, researchers discovered that a calorie restricted (CR) diet could significantly extend the lifespan of rats, and since then a CR diet has been shown to increase lifespan and healthspan in model organisms ranging from yeast to non-human primates. In this review, we discuss the effects of a CR diet on metabolism and healthspan, and highlight emerging evidence that suggests that dietary composition - the precise macronutrients that compose the diet - may be just as important as caloric content. In particular, we discuss recent evidence that suggests protein quality may influence metabolic health. Finally, we discuss key metabolic pathways which may influence the response to CR diets and altered macronutrient composition. Understanding the molecular mechanisms responsible for the effects of CR and dietary composition on health and longevity may allow the design of novel therapeutic approaches to age-related diseases.
↑ Falcón P et al.: Nutrient Sensing and Redox Balance: GCN2 as a New Integrator in Aging. Oxid Med Cell Longev 2019. (PMID 31249645) [PubMed] [DOI] [Full text] Aging is a complex process in which the accumulation of molecular, cellular, and organism dysfunction increases the probability of death. Several pieces of evidence have revealed a contribution of stress responses in aging and in aging-related diseases, in particular, the key role of signaling pathways associated to nutritional stress. Here, we review the possible interplay between amino acid sensing and redox balance maintenance mediated by the nutritional sensor general control nonderepressive 2 (GCN2). We discuss this new dimension of nutritional stress sensing consequences, standing out GCN2 as a central coordinator of key cellular processes that assure healthy homeostasis in the cell, raising GCN2 as a novel interesting target, that when activated, could imply pleiotropic benefits, particularly GCN2 intervention and its new unexplored therapeutic role as a player in the aging process.
↑ Nelson G et al.: An amino-acid taste receptor. Nature 2002. (PMID 11894099) [PubMed] [DOI] The sense of taste provides animals with valuable information about the nature and quality of food. Mammals can recognize and respond to a diverse repertoire of chemical entities, including sugars, salts, acids and a wide range of toxic substances. Several amino acids taste sweet or delicious (umami) to humans, and are attractive to rodents and other animals. This is noteworthy because L-amino acids function as the building blocks of proteins, as biosynthetic precursors of many biologically relevant small molecules, and as metabolic fuel. Thus, having a taste pathway dedicated to their detection probably had significant evolutionary implications. Here we identify and characterize a mammalian amino-acid taste receptor. This receptor, T1R1+3, is a heteromer of the taste-specific T1R1 and T1R3 G-protein-coupled receptors. We demonstrate that T1R1 and T1R3 combine to function as a broadly tuned L-amino-acid sensor responding to most of the 20 standard amino acids, but not to their D-enantiomers or other compounds. We also show that sequence differences in T1R receptors within and between species (human and mouse) can significantly influence the selectivity and specificity of taste responses.
↑ What Is Deregulated Nutrient Sensing? https://www.gowinglife.com/what-is-deregulated-nutrient-sensing-the-hallmarks-of-ageing-series/ (accessed Mar 20, 2023).
↑ Fontana L & Partridge L: Promoting health and longevity through diet: from model organisms to humans. Cell 2015. (PMID 25815989) [PubMed] [DOI] [Full text] Reduced food intake, avoiding malnutrition, can ameliorate aging and aging-associated diseases in invertebrate model organisms, rodents, primates, and humans. Recent findings indicate that meal timing is crucial, with both intermittent fasting and adjusted diurnal rhythm of feeding improving health and function, in the absence of changes in overall intake. Lowered intake of particular nutrients rather than of overall calories is also key, with protein and specific amino acids playing prominent roles. Nutritional modulation of the microbiome can also be important, and there are long-term, including inter-generational, effects of diet. The metabolic, molecular, and cellular mechanisms that mediate both improvement in health during aging to diet and genetic variation in the response to diet are being identified. These new findings are opening the way to specific dietary and pharmacological interventions to recapture the full potential benefits of dietary restriction, which humans can find difficult to maintain voluntarily.

[pmid25592535-1] 1.0 ^1.1 Efeyan A et al.: Nutrient-sensing mechanisms and pathways. Nature 2015. (PMID 25592535) [PubMed] [DOI] [Full text] The ability to sense and respond to fluctuations in environmental nutrient levels is a requisite for life. Nutrient scarcity is a selective pressure that has shaped the evolution of most cellular processes. Different pathways that detect intracellular and extracellular levels of sugars, amino acids, lipids and surrogate metabolites are integrated and coordinated at the organismal level through hormonal signals. During food abundance, nutrient-sensing pathways engage anabolism and storage, whereas scarcity triggers homeostatic mechanisms, such as the mobilization of internal stores through autophagy. Nutrient-sensing pathways are commonly deregulated in human metabolic diseases.

[2] Coutin J.What Causes Aging? How Much Have We Learned in Recent Years? https://medium.com/@jessecoutin/what-causes-aging-how-much-have-we-learned-in-recent-years-93b85e6a594a (accessed Feb 16, 2023).

[pmid27884780-3] Cummings NE & Lamming DW: Regulation of metabolic health and aging by nutrient-sensitive signaling pathways. Mol Cell Endocrinol 2017. (PMID 27884780) [PubMed] [DOI] [Full text] All organisms need to be capable of adapting to changes in the availability and composition of nutrients. Over 75 years ago, researchers discovered that a calorie restricted (CR) diet could significantly extend the lifespan of rats, and since then a CR diet has been shown to increase lifespan and healthspan in model organisms ranging from yeast to non-human primates. In this review, we discuss the effects of a CR diet on metabolism and healthspan, and highlight emerging evidence that suggests that dietary composition - the precise macronutrients that compose the diet - may be just as important as caloric content. In particular, we discuss recent evidence that suggests protein quality may influence metabolic health. Finally, we discuss key metabolic pathways which may influence the response to CR diets and altered macronutrient composition. Understanding the molecular mechanisms responsible for the effects of CR and dietary composition on health and longevity may allow the design of novel therapeutic approaches to age-related diseases.

[pmid31249645-4] Falcón P et al.: Nutrient Sensing and Redox Balance: GCN2 as a New Integrator in Aging. Oxid Med Cell Longev 2019. (PMID 31249645) [PubMed] [DOI] [Full text] Aging is a complex process in which the accumulation of molecular, cellular, and organism dysfunction increases the probability of death. Several pieces of evidence have revealed a contribution of stress responses in aging and in aging-related diseases, in particular, the key role of signaling pathways associated to nutritional stress. Here, we review the possible interplay between amino acid sensing and redox balance maintenance mediated by the nutritional sensor general control nonderepressive 2 (GCN2). We discuss this new dimension of nutritional stress sensing consequences, standing out GCN2 as a central coordinator of key cellular processes that assure healthy homeostasis in the cell, raising GCN2 as a novel interesting target, that when activated, could imply pleiotropic benefits, particularly GCN2 intervention and its new unexplored therapeutic role as a player in the aging process.

[pmid11894099-5] Nelson G et al.: An amino-acid taste receptor. Nature 2002. (PMID 11894099) [PubMed] [DOI] The sense of taste provides animals with valuable information about the nature and quality of food. Mammals can recognize and respond to a diverse repertoire of chemical entities, including sugars, salts, acids and a wide range of toxic substances. Several amino acids taste sweet or delicious (umami) to humans, and are attractive to rodents and other animals. This is noteworthy because L-amino acids function as the building blocks of proteins, as biosynthetic precursors of many biologically relevant small molecules, and as metabolic fuel. Thus, having a taste pathway dedicated to their detection probably had significant evolutionary implications. Here we identify and characterize a mammalian amino-acid taste receptor. This receptor, T1R1+3, is a heteromer of the taste-specific T1R1 and T1R3 G-protein-coupled receptors. We demonstrate that T1R1 and T1R3 combine to function as a broadly tuned L-amino-acid sensor responding to most of the 20 standard amino acids, but not to their D-enantiomers or other compounds. We also show that sequence differences in T1R receptors within and between species (human and mouse) can significantly influence the selectivity and specificity of taste responses.

[6] What Is Deregulated Nutrient Sensing? https://www.gowinglife.com/what-is-deregulated-nutrient-sensing-the-hallmarks-of-ageing-series/ (accessed Mar 20, 2023).

[pmid25815989-7] Fontana L & Partridge L: Promoting health and longevity through diet: from model organisms to humans. Cell 2015. (PMID 25815989) [PubMed] [DOI] [Full text] Reduced food intake, avoiding malnutrition, can ameliorate aging and aging-associated diseases in invertebrate model organisms, rodents, primates, and humans. Recent findings indicate that meal timing is crucial, with both intermittent fasting and adjusted diurnal rhythm of feeding improving health and function, in the absence of changes in overall intake. Lowered intake of particular nutrients rather than of overall calories is also key, with protein and specific amino acids playing prominent roles. Nutritional modulation of the microbiome can also be important, and there are long-term, including inter-generational, effects of diet. The metabolic, molecular, and cellular mechanisms that mediate both improvement in health during aging to diet and genetic variation in the response to diet are being identified. These new findings are opening the way to specific dietary and pharmacological interventions to recapture the full potential benefits of dietary restriction, which humans can find difficult to maintain voluntarily.

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Deregulated Nutrient Sensing

Contents

Key Nutrient Sensing Pathways

Consequences of Deregulated Nutrient Sensing

Therapeutic Interventions

See Also

References