Although there are numerous hypotheses explaining the nature of aging and associated processes, two concepts are dominant: (i) aging is a result of cell-autonomous processes, such as the accumulation of DNA mutations, aberrant methylations, protein defects, and shortening of telomeres, leading to either inhibition of cellular proliferation and death of non-dividing terminally differentiated cells or tumor development; (ii) aging is a result of a central program that is switched on at a specific stage of organismic development. The microRNA-based endocrine regulation hypothesis combines the two above concepts by proposing central regulation of cell death occurrences via hypothalamus-pituitary gland (PG)-secreted miRNA hormones, the expression and/or secretion of which are regulated by sex hormones. This hypothesis explains such well-known phenomena as inverse comorbidity of either cancer or Alzheimer’s (AD) and other neurodegenerative diseases; higher AD morbidity and lower frequency of many common types of cancer in women vs. men; higher risk of early AD and lower risk of cancer in subjects with Down syndrome; longer life expectancy in women vs. men and much lower sex-dependent differences, if any, in other mammals; increased lifespans due to hypophysectomy or PG hypofunction; and parabiotic effects of blood or plasma transfusions between young and old animals.