Dietary restriction (DR) and reduced growth factor signaling both enhance resistance to oxidative stress, reduce macromolecular damage, and extend lifespan in model organisms. In rodents, DR and decreased growth factor signaling reduce tumor incidence and slow cognitive decline. DR reduces cancer and cardiovascular disease in monkeys and metabolic traits associated with diabetes, cardiovascular disease, and cancer in humans. Neoplasias and diabetes are rare in humans with mutations in the growth hormone receptor. DR and reduced growth factor signaling may slow aging through evolutionarily conserved mechanisms. The review discusses these pathways in model organisms, their links to disease prevention in mammals, and potential negative side effects of interventions aimed at extending healthy lifespan. DR extends lifespan in yeast, flies, worms, fish, rodents, and rhesus monkeys. In rodents and monkeys, it delays loss of function and reduces disease incidence. In humans, it reduces metabolic markers of several diseases. Understanding these mechanisms could lead to drug targets for aging-related diseases. Genetic alterations and nutritional interventions that extend lifespan are discussed, focusing on conserved effects across organisms. In yeast, nutrient-sensing pathways like Ras-AC-PKA and Tor-Sch9 regulate lifespan. Deletion of these pathways extends lifespan by reducing oxidative stress and increasing cellular protection. In C. elegans, reduced IIS and TOR signaling extend lifespan, with DAF-16 and HSF-1 playing key roles. In Drosophila, reduced IIS and TOR signaling also extend lifespan, with FOXO and other transcription factors involved. In rodents, DR reduces aging-related diseases and extends lifespan, with effects on IIS, TOR, and other pathways. In primates, DR reduces age-related deaths and disease incidence in rhesus monkeys. DR in humans reduces metabolic markers and may have similar benefits, though effects vary between species. DR can have negative side effects, including impaired immunity and wound healing. Further research is needed to determine the role of GH and IGF-I signaling in aging and disease, and to evaluate the safety and effectiveness of DR in humans.Dietary restriction (DR) and reduced growth factor signaling both enhance resistance to oxidative stress, reduce macromolecular damage, and extend lifespan in model organisms. In rodents, DR and decreased growth factor signaling reduce tumor incidence and slow cognitive decline. DR reduces cancer and cardiovascular disease in monkeys and metabolic traits associated with diabetes, cardiovascular disease, and cancer in humans. Neoplasias and diabetes are rare in humans with mutations in the growth hormone receptor. DR and reduced growth factor signaling may slow aging through evolutionarily conserved mechanisms. The review discusses these pathways in model organisms, their links to disease prevention in mammals, and potential negative side effects of interventions aimed at extending healthy lifespan. DR extends lifespan in yeast, flies, worms, fish, rodents, and rhesus monkeys. In rodents and monkeys, it delays loss of function and reduces disease incidence. In humans, it reduces metabolic markers of several diseases. Understanding these mechanisms could lead to drug targets for aging-related diseases. Genetic alterations and nutritional interventions that extend lifespan are discussed, focusing on conserved effects across organisms. In yeast, nutrient-sensing pathways like Ras-AC-PKA and Tor-Sch9 regulate lifespan. Deletion of these pathways extends lifespan by reducing oxidative stress and increasing cellular protection. In C. elegans, reduced IIS and TOR signaling extend lifespan, with DAF-16 and HSF-1 playing key roles. In Drosophila, reduced IIS and TOR signaling also extend lifespan, with FOXO and other transcription factors involved. In rodents, DR reduces aging-related diseases and extends lifespan, with effects on IIS, TOR, and other pathways. In primates, DR reduces age-related deaths and disease incidence in rhesus monkeys. DR in humans reduces metabolic markers and may have similar benefits, though effects vary between species. DR can have negative side effects, including impaired immunity and wound healing. Further research is needed to determine the role of GH and IGF-I signaling in aging and disease, and to evaluate the safety and effectiveness of DR in humans.