Abstract
Recent research has proposed that GIT2 (G protein-coupled receptor kinase interacting protein 2) acts as an integrator of the aging process through regulation of ‘neurometabolic’ integrity. One of the commonly accepted hallmarks of the aging process is thymic involution. At a relatively young age, 12 months old, GIT2−/− mice present a prematurely distorted thymic structure and dysfunction compared to age-matched 12 month-old wild-type control (C57BL/6) mice. Disruption of thymic structure in GIT2−/− (GIT2KO) mice was associated with a significant reduction in the expression of the cortical thymic marker, Troma-I (cytokeratin 8). Double positive (CD4+CD8+) and single positive CD4+ T cells were also markedly reduced in 12 month-old GIT2KO mice compared to age-matched control wild-type mice. Coincident with this premature thymic disruption in GIT2KO mice was the unique generation of a novel cervical ‘organ’, i.e. ‘parathymic lobes’. These novel organs did not exhibit classical peripheral lymph node-like characteristics but expressed high levels of T cell progenitors that were reflexively reduced in GIT2KO thymi. Using signaling pathway analysis of GIT2KO thymus and parathymic lobe transcriptomic data we found that the molecular signaling functions lost in the dysfunctional GIT2KO thymus were selectively reinstated in the novel parathymic lobe – suggestive of a compensatory effect for the premature thymic disruption. Broader inspection of high-dimensionality transcriptomic data from GIT2KO lymph nodes, spleen, thymus and parathymic lobes revealed a systemic alteration of multiple proteins (Dbp, Tef, Per1, Per2, Fbxl3, Ddit4, Sin3a) involved in the multidimensional control of cell cycle clock regulation, cell senescence, cellular metabolism and DNA damage. Altered cell clock regulation across both immune and non-immune tissues therefore may be responsible for the premature ‘aging’ phenotype of GIT2KO mice.
Highlights
The thymus gland, responsible for T-cell maturation is most active during neonatal and pre-adolescent periods
Assessing age-related survival of male and female homozygous GIT2 knockout (GIT2KO) mice we found that GIT2KO males and females possessed a significantly shorter total lifespan compared to wildtype (WT) controls (Figure 1A)
We have previously demonstrated that the GPCRinteracting protein GIT2 is strongly implicated in somatic regulation of the aging process, via the management of stress response systems linked to pathological aging, oxidative stress, metabolic disruption and eventual DNA damage [5, 31,32,33,34]
Summary
The thymus gland, responsible for T-cell maturation is most active during neonatal and pre-adolescent periods. Diminution in thymic size and function is a hallmark of normal aging and immunosenescence [1,2,3,4], in which the thymus begins to atrophy with gradual stromal adipose infiltration. This natural process of aging-related degeneration of the immune system exerts a significant impact upon quality of life in aged populations and increases the propensity for autoimmune diseases and cancers [5]. In this respect the structural and functional degradation of the thymus is considered as one of the hallmarks of the natural aging process [6]
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