Even though it has been evident for decades that aging is a fundamental risk factor in cancer development, we still don't fully understand the causes for this increase. A primary reason for this incomplete understanding is because we still don't know a significant amount about progressive changes that occur in our tissues on the cellular and molecular levels as we get older. To address this critical and unresolved issue, we have been working towards characterizing these changes for several years. Published and ongoing studies in our laboratory have demonstrated an aging associated, and sometime dramatic, accumulation of senescent cells displaying dysfunctional telomeres in various tissues of long lived mammals, including humans. Significantly, cells that had undergone Telomere Dysfunction Induced cellular Senescence (TDIS) also secrete a large number of signaling molecules and matrix remodeling enzymes, suggesting that these cells not only increasing alter structural components of the tissue, but also generate a tissue microenvironment that may promote growth of inactive cancer cells. Indeed, components of this Senescence Associated Secretory Phenotype (SASP) have been demonstrated to promote growth of cancers in animal model systems, although antiproliferative properties of this SASP have also been reported. We have uncovered the reasons for the opposing effects of the SASP on cell proliferation. In this application we will therefore explore whether and to what extent TDIS and the accompanying SASP of stromal and pre- malignant human cells alters tissue microenvironment and therefore contributes to increasing cancer incidences in the aging population. We will 1) identify signaling molecules that trigger TDIS and SASP in somatic human cells, 2) characterize signaling pathways that mediate TDIS in response to extracellular factors, and 3) determine the biological significance of paracrine signaling mediated-TDIS in cancer development. Our comprehensive and multifaceted study will reveal the contributions of the stromal and tumor SASP to aging associated increases in cancer incidences and will therefore provide critical knowledge essential for combating aging associated cancer development.