Aging affects the structure and functions of all organs and systems in the organism. In the elderly, significant changes in hormonal levels are observed. These translate to a predisposition for chronic diseases, including cardiovascular, neurodegenerative, and metabolic disorders. Therefore, tremendous scientific effort is focused on investigating molecular mechanisms and drugs with the potential to reduce hormonal changes in old age and their impact. Sirtuin 1 (SIRT1), a member of the sirtuin family of deacetylases, has been extensively studied as a regulator of multiple pathways related to antioxidant properties, optimal immune response, and metabolism. SIRT1 plays a key role in regulating various hormonal pathways and maintaining homeostasis. In the present study, we review the interplay between SIRT1 and hormonal regulations, including the endocrine role of the hypothalamic–pituitary–thyroid, –adrenal, –gonadal, and –liver axes, of other endocrine glands, and of non-endocrine tissues in the aging organism. The application of natural SIRT1 activators, such as resveratrol, curcumin, paeonol, and Buyang Huanwu Decoction, for the treatment of aging and senescence is discussed. SIRT1 activators improve mitochondrial function, reduce oxidative stress, and promote longevity, but their clinical application is limited by low bioavailability and poor permeability across biological barriers. For this reason, advanced delivery strategies are being considered, including nose-to-brain drug delivery and nanotechnology-based formulations.