Mechanisms that Regulate Thymic Involution and Age-Assoc

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One of the consequences of an aging immune system is the process of thymic involution. The thymus undergoes a progressive reduction in size due to profound changes in its architecture associated with thymic epithelia atrophy and decreased thymopoiesis. This decline is systemically followed by decreased numbers of circulating naive T cells and cell-mediated immune responses which may play a role in the increased tumorigenesis, autoimmunity, and infectious diseases observed within an aging host. Despite the extensive study of the pathophysiology of the aging thymus, the precise molecular mechanism involved in the involution process remains unclear. In an effort to profile molecular changes that occur within the aging thymus, microarray analysis was performed using RNA derived from thymus isolated from mice of varying ages. Using mRNA derived from the thymi of 2, 4, 6, 12 and 18 month old BALB/c mice, microarray analysis was performed using three distinct custom-made cDNA microarrays developed within our laboratory as well as 22K oligonucleotide murine arrays. The success of this project relies upon the reliability of the molecular profiling aged cells from defined aged sources, both from culture and freshly isolated aged cells. The first milestone will be the definitive characterization and selection of genes associated with thymic involution. We have performed a series analysis of gene expression in the thymi and spleens of mice of varying ages and have initiated studies examining expression differences in mice of distinct H-2 and genetic backgrounds as well as known involution mouse models. Our current data would suggest that thymic involution may be strain- and gender-dependent and may in part be associated with distinct nutritional and stress-related factors rather than simply aging. A number of genes associated with DNA repair, oxidative stress, apoptosis, and inflammation were found to be significantly upregulated with thymic aging. We are currently analyzing the data obtained from the gene profiles of aged spleens, thymi, bone marrow, immune cell subsets and thymocytes from mice of various ages given ad libitum or caloric restricted diets as well as from aged mice infused with GH, ghrelin, leptin and interleukin-7. We have recently found that ghrelin and leptin infusions reverse age-associated thymic involution. Array analysis of the thymi of such treated mice may yield valuable data on the common molecular processes involved in thymic regeneration. It is unclear whether certain lymphoid organs or cellular components play a critical role in longevity and lifespan. The overall goal of this project is to produce a comprehensive gene expression profile in the thymus, spleen, and lymph nodes during the aging process to identify unique and common genes and functionally related groups of genes that are expressed in age-dependent manner in these different organ systems. We have initially focused our efforts on the thymus, as its involution is believed to be one of the most significant obstacles to overcome in addressing the immunological deficits associated with aging.