The α-Klotho protein, produced in the kidneys, brain, and other tissues, plays a crucial role in maintaining homeostasis and preventing chronic pathologies, often age-related. Klotho acts as a coreceptor for fibroblast growth factor 23 (FGF23), regulating phosphate and calcium homeostasis. It also has endocrine properties, with soluble Klotho (s-Klotho) binding to FGF receptors and other signaling molecules. Klotho counteracts inflammation and aging by inhibiting key pathways such as NF-κB and the NLRP3 inflammasome, reducing oxidative stress, and mitigating fibrosis. Low Klotho levels are associated with sarcopenia, a loss of muscle mass common in aging and chronic diseases. Klotho therapy has shown potential in treating various diseases, including diabetes, atherosclerosis, and neurodegenerative disorders like Alzheimer's disease. The review highlights the multifaceted roles of Klotho in inflammation, aging, and disease prevention, emphasizing its therapeutic potential.The α-Klotho protein, produced in the kidneys, brain, and other tissues, plays a crucial role in maintaining homeostasis and preventing chronic pathologies, often age-related. Klotho acts as a coreceptor for fibroblast growth factor 23 (FGF23), regulating phosphate and calcium homeostasis. It also has endocrine properties, with soluble Klotho (s-Klotho) binding to FGF receptors and other signaling molecules. Klotho counteracts inflammation and aging by inhibiting key pathways such as NF-κB and the NLRP3 inflammasome, reducing oxidative stress, and mitigating fibrosis. Low Klotho levels are associated with sarcopenia, a loss of muscle mass common in aging and chronic diseases. Klotho therapy has shown potential in treating various diseases, including diabetes, atherosclerosis, and neurodegenerative disorders like Alzheimer's disease. The review highlights the multifaceted roles of Klotho in inflammation, aging, and disease prevention, emphasizing its therapeutic potential.