This project has as its primary focus to achieve basic understanding of the influence of undernutrition without malnutrition -- chronic energy intake restriction (CEIR) which greatly increases life span and health span of rats and of mice of long-lived, and of short-lived autoimmune- prone and cancer-prone strains. We are attempting especially to analyze the mechanisms which underlie prevention by CEIR of retrovirus-induced mammary adenocarcinoma, certain autoimmunities, vascular diseases, malignancies and immunodeficiency disorders that develop with aging in mice of certain genetically short-lived strains, as well as the immunodeficiency associated with aging in mice of some long-lived strains. Particularly, we have discovered that CEIR down-regulates (tunes down) many forms of what we call vegetative and reproduction associated cellular proliferation -- while at the same time CEIR up-regulates cellular proliferation that is associated with liver regenerative repair following partial hepatectomy. Our experiments will attempt to analyze at the molecular level in one representative long-lived and in one representative short-lived strain and in one strain of mice in which females develop mammary adenocarcinoma in high frequency, how CEIR influences expression and production of growth factors that in turn influence and control cell proliferation in mammary gland epithelium, skin and esophageal and intestinal epithelium. We will also analyze how CEIR influences the expression and production of complete hepatic growth factors and a new augmentor of liver regeneration and how these actions influence hepatic cellular regeneration after partial hepatectomy. It is our view that the influence of CEIR on these crucial vegetative and adaptive proliferations play crucial roles in the action of CEIR to prolong life, prolong the span of health and prevent development of diseases which occur with aging such as cancers and autoimmunities.