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 26,000 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. Subsequently, we plan to conduct a series analysis of gene expression in the thymi and spleens of mice of varying ages, H-2 and genetic backgrounds, and known involution mouse models. Our current data would suggest that thymic involution may be strain dependent and may in part be associated with distinct genetic factors rather than simply aging. We are currently analyzing the data obtained from the gene profiles of aged spleens, thymi, bone marrow, B cells, T cells and thymocytes from mice of various ages as well as from aged mice infused with GH, ghrelin or leptin. We have recently found that such hormone infusions reverse age-associated thymic involution and may yield valuable data on the molecular processes involkved with thymic regneration. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000766-03
Application #
6815354
Study Section
(LI)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2003
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Lustig, Ana; Carter, Arnell; Bertak, Dorothy et al. (2009) Transcriptome analysis of murine thymocytes reveals age-associated changes in thymic gene expression. Int J Med Sci 6:51-64
Yang, Hyunwon; Dixit, Vishwa D; Patel, Kalpesh et al. (2008) Reduction in hypophyseal growth hormone and prolactin expression due to deficiency in ghrelin receptor signaling is associated with Pit-1 suppression: relevance to the immune system. Brain Behav Immun 22:1138-45
Taub, Dennis D (2008) Novel connections between the neuroendocrine and immune systems: the ghrelin immunoregulatory network. Vitam Horm 77:325-46
Taub, Dennis D (2008) Neuroendocrine interactions in the immune system. Cell Immunol 252:1-6
Weeraratna, Ashani T; Taub, Dennis D (2007) Microarray data analysis: an overview of design, methodology, and analysis. Methods Mol Biol 377:1-16
Lustig, Ana; Weeraratna, Ashani T; Wood 3rd, William W et al. (2007) Transcriptome analysis of age-, gender- and diet-associated changes in murine thymus. Cell Immunol 245:42-61
Dixit, Vishwa Deep; Yang, Hyunwon; Sun, Yuxiang et al. (2007) Ghrelin promotes thymopoiesis during aging. J Clin Invest 117:2778-90
Dixit, Vishwa Deep; Weeraratna, Ashani T; Yang, Hyunwon et al. (2006) Ghrelin and the growth hormone secretagogue receptor constitute a novel autocrine pathway in astrocytoma motility. J Biol Chem 281:16681-90
Dixit, Vishwa Deep; Taub, Dennis D (2005) Ghrelin and immunity: a young player in an old field. Exp Gerontol 40:900-10
Taub, Dennis D; Longo, Dan L (2005) Insights into thymic aging and regeneration. Immunol Rev 205:72-93

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