Aging is a dynamic biological process with varied influences from genetic, metabolic, and environmental factors. Nutrient-sensing pathways are the most important regulators of aging and longevity because they assess and respond to energy and nutrient availability in and around the cell. Nutrient-sensing pathways that exist in evolutionarily conserved signaling networks in cells (e.g., insulin/IGF-1 signaling (IIS), target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and sirtuins (SIRT1–7)) act as molecular gatekeepers of the availability of cellular growth, stress resistance, autophagy, mitochondrial function, and metabolic homeostasis. Dysregulation in nutrient-sensing pathways causes age-related functional decline and chronic diseases such as cancer, diabetes, cardiovascular disorders, and neurodegeneration. This chapter aims to present a broad overview of nutrient-sensing pathways and their importance in regulating longevity. We essentially sift through some of the molecular mechanisms that underlie nutrient-sensing pathways, their signaling and cross talk, and their eventual influence on cell signaling. We also examine how dietary interventions such as caloric restriction, intermittent fasting, and macronutrient manipulation influence nutrient sensing in relation to fulfilling and extending lifespan and health span across species. We also explore a pharmacological approach with potential to influence these nutrient-sensing pathways with mTOR inhibitors, AMPK activators, and sirtuin enhancers while developing the note of translational potential and clinical significance of such pathways. We combine results from model organisms and from human studies to show the importance of nutrition sensing in healthy aging and the prevention of age-associated diseases. We also highlight contemporary tools such as omics technologies, artificial intelligence, and computational modeling that offer exciting opportunities to better understand longevity networks and to improve personalized interventions for healthy aging. We discuss ethical and societal implications of extending lifespan with an emphasis on reducing inequities and being thoughtful and responsible in the application of innovations that extend lifespan. By providing an integrated perspective of how nutrient-sensing pathways regulate aging and longevity, we suggest the potential of these pathways as therapeutic targets/ foundational components in the search to maximize human health span and improve quality of life.