Hypophysectomy in young male Wistar rats aged 70 days, followed by cortisone acetate replacement therapy throughout life, retarded the rate of aging of tail tendon collagen fibres, inhibited the development of certain diseases of old age (renal disease, cardiac enlargement, hind limb paralysis, and various endocrine and non-endocrine tumors) and significantly prolonged the duration of life. Almost identical anti-aging effects were obtained by lowering the food intake of intact rats to that of hypophysectomized rats, from age 70 days until death. Hypophysectomy in middle age, at 400 days, even with cortisone acetate replacement therapy, produced a sharp increase in the mortality rate; the surviving rats exhibited significantly reduced aging of collagen fibres and of the kidney as measured by protein excretion. Food restriction begun at 400 days also inhibited renal aging, but had no demonstrable effect on collagen aging during the first 100 days. These studies suggest that procedures such as hypophysectomy and food restriction do not switch off an aging mechanism in youth but probably exert a continuing inhibitory influence on certain aging processes throughout life.