The hypothalamic-pituitary-somatotropic (HPS) axis, which includes growth hormone (GH) and insulin-like growth factor 1 (IGF-1), is one of three endocrine systems that show a decline in hormone concentration with age. Among the hypothalamic hormones involved in the aging process, GH-releasing hormone (GHRH) and somatostatin (SST) are most affected, resulting in several age-related changes. The pathophysiology of GH decline in the aging process is unclear, specifically, whether it results from decreased GHRH or increased SST levels. Similarly, it is not known whether quantitative changes in hypothalamic peptides (including SST) precede or follow age-related pathological behavioral changes. SST is produced mainly by cells of the central nervous system (CNS) and the gastrointestinal (GI) tract, which are functionally interconnected systems that undergo significant changes during aging. The physical changes in the aging organism are considered physiological, and experimental evidence indicates that a large proportion of these changes are the result of declining hormonal activity (including the SST system). It is particularly important to understand the role of SST in diseases of old age, which affect both cognitive processes and memory (e.g., Alzheimer's and Parkinson's diseases) and the proper functioning of the GI tract and pancreas (e.g., obesity, type 2 diabetes mellitus, and colorectal cancer). This narrative review discusses systemic and peripheral changes in SST production and secretion observed in aging individuals and their potential association with selected diseases of old age, especially CNS and GI tract diseases. Understanding the role of SST expression with age will enable the better application of this neuropeptide in the diagnosis and treatment of diseases of old age (including cancers).