Health (Commonwealth Union) – When looking into the complex biological nature of ageing characterized by a progressive decline in physiological functions and an increased risk of developing age-related diseases, all aspects of the hallmarks of ageing are taken into consideration. Over the years, extensive research has been conducted to understand the molecular mechanisms underlying the aging process. Among the various factors, nutrient sensing pathways have emerged as key regulators of cellular metabolism and lifespan. Deregulated nutrient sensing has been implicated in the development of numerous age-related diseases, including diabetes, cancer, and neurodegenerative disorders. In this article, we will provide a comprehensive review of the current understanding of deregulated nutrient sensing in relation to aging and discuss potential therapeutic strategies to target these pathways for anti-aging interventions.
Nutrient Sensing Pathways: The nutrient sensing pathways are a group of highly conserved signaling networks that regulate cellular responses to nutrient availability. These pathways play a crucial role in maintaining metabolic homeostasis and promoting cellular health. Some of the key nutrient sensing pathways include the insulin/IGF-1 signaling (IIS) pathway, the mechanistic target of rapamycin (mTOR) pathway, and the sirtuin pathway.
Insulin/IGF-1 Signaling (IIS) Pathway: The IIS pathway is involved in regulating glucose and energy homeostasis in response to nutrient availability. This pathway consists of a series of proteins that transmit signals from insulin and insulin-like growth factor-1 (IGF-1) receptors to various downstream effectors, ultimately controlling cell growth, proliferation, and survival.
Mechanistic Target of Rapamycin (mTOR) Pathway: The mTOR pathway is a central regulator of cellular growth, proliferation, and metabolism. mTOR forms two distinct protein complexes, mTORC1 and mTORC2, which respond to various nutrient-derived signals, including amino acids, glucose, and growth factors.
Sirtuin Pathway: Sirtuins are a family of NAD+-dependent deacetylases that play a crucial role in regulating cellular metabolism, stress resistance, and genomic stability. The sirtuin pathway is activated under conditions of low nutrient availability and energy stress, promoting cellular survival and longevity.
Deregulated Nutrient Sensing in Aging Deregulated nutrient sensing has been implicated in the development of various age-related diseases. Imbalances in these pathways can lead to metabolic dysfunction, inflammation, and oxidative stress, which contribute to the aging process.
IIS Pathway: Overactivation of the IIS pathway has been associated with increased oxidative stress, inflammation, and insulin resistance, which are hallmarks of aging. Mutations in the insulin receptor (INSR) and insulin-like growth factor 1 receptor (IGF1R) have been shown to extend lifespan in various model organisms, including yeast, worms, and flies.
mTOR Pathway: mTOR is a key regulator of cellular growth and metabolism, and its dysregulation has been implicated in various age-related diseases, including cancer, diabetes, and neurodegenerative disorders. Rapamycin, an mTOR inhibitor, has been shown to extend lifespan and improve health span in multiple animal models, highlighting the potential of targeting the mTOR pathway for anti-aging interventions.
Sirtuin Pathway: The sirtuin pathway plays a crucial role in regulating cellular metabolism, stress resistance, and genomic stability. Dysregulation of sirtuins has been implicated in the development of various age-related diseases, including metabolic syndrome, cardiovascular disease, and neurodegenerative disorders. Activation of sirtuins through calorie restriction or pharmacological intervention has been shown to extend lifespan and improve health span in various model organisms.
Therapeutic Strategies Targeting Nutrient Sensing Pathways Given the central role of nutrient sensing pathways in aging and age-related diseases, targeting these pathways has emerged as a promising strategy for anti-aging interventions. Several therapeutic approaches have been proposed, including calorie restriction, pharmacological interventions, and gene therapy.
Calorie Restriction: Calorie restriction is a dietary intervention that involves reducing caloric intake without causing malnutrition. This intervention has been shown to extend lifespan and improve health span in various model organisms, including yeast, worms, flies, and rodents. The beneficial effects of calorie restriction are mediated, at least in part, through the activation of sirtuins and the inhibition of mTOR.
Pharmacological Interventions: Several pharmacological agents have been identified that target nutrient sensing pathways for anti-aging interventions. Rapamycin, an mTOR inhibitor, has been shown to extend lifespan and improve health span in multiple animal models. Resveratrol, a sirtuin activator, has also been proposed as a potential anti-aging compound, although its efficacy in humans remains to be established.
Gene Therapy: Gene therapy approaches have been proposed to target nutrient sensing pathways for anti-aging interventions. For example, overexpression of sirtuins or downregulation of IIS pathway components has been shown to extend lifespan and improve health span in various model organisms. However, the feasibility and safety of these approaches in humans remain to be determined.
Understanding the molecular mechanisms underlying these pathways has led to the identification of several therapeutic strategies for anti-aging interventions. While calorie restriction, pharmacological interventions, and gene therapy approaches have shown promise in preclinical studies, further research is needed to establish their safety and efficacy in humans. Ultimately, targeting nutrient sensing pathways holds great potential for improving health span and combating the burden of age-related diseases.
