Epigenetics of Aging:
Discovering the Damage Accumulated Over Time
Aging associates with defective organ maintenance and increased tissue dysfunction as well as with a higher risk for pathological conditions development, including cancers. Colorectal cancers (CRCs) and leukemias are two of the most frequent and lethal neoplasms and their incidence is exponentially increasing during aging. Several studies demonstrated that Intestinal Stem Cells (ISCs) as well as Hematopoietic Stem Cells (HSCs) often represent the cell of origin of cancers and that clonal dominance of mutant stem cells appears frequently during aging.
Emerging evidence indicates that genetic and epigenetic factors impact on the functionality and homeostasis of adult stem cells during aging, favoring in this way the selective advantage of dominant clones and the cancer onset. Among these factors, DNA methylation (a stable and heritable epigenetic modification) has been associated with aging induced diseases and cancer development. Recent discovery that DNA methylation can be actively removed by the TET proteins has pointed out the importance of this epigenetic modification in several biological models. Interestingly, two of the principal enzymes responsible for the establishment/removing of DNA methylation (DNMT3A and TET2) are the principal targets of genetic mutations during aging and cancer development.
The focus of our lab is the functional characterization of epigenome alterations that occur during adult stem cell aging. The main aims are
- to define epigenetic alterations of stem cells during aging (focusing on DNA methylation changes together with principal histone modifications)
- to characterize the mechanistic basis of the evolution of these changes, and
- to understand the functional consequences of aging induced epigenetic alterations on stem cell function in organ homeostasis and delineate their role in promoting clonal dominance and neoplastic transformation.