Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption
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.
Introduction
The thymus gland, responsible for T-cell maturation is most active during neonatal and pre-adolescent periods. Hematopoietic precursors originating from bone marrow translocate to the thymus and eventually these cells undergo a process of expansion, maturation and TcR (T-cell receptor) repertoire selection, and finally migrate to the periphery as mature T cells. Diminution in thymic size and function is a hallmark of normal aging and immunosenescence [1–4], 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]. It is estimated that approximately 80% of aged individuals are afflicted with at least one chronic disease as a result of a declination of immune function [6]. In this respect the structural and functional degradation of the thymus is considered as one of the hallmarks of the natural aging process [6].
The thymus comprises a peripheral cortex and the central medulla that control separate maturational steps in the differentiation process from precursor cells to mature T cells. Loss of medullary and cortical definition and a disorganization of the corticomedullary junction are characteristic of the aged thymus [7,8]. Age-related thymic involution results in the reduction of thymopoiesis which precedes T-cell related immuno-incompetence in an advanced age. Age-related thymic involution is classically associated with loss of gross structural integrity as well as disruption of multiple pathways involved in stress responses [6]. From several decades of concerted research it has become ever more clear that the ‘rate’ of somatic aging is a complex sum of multiple interconnected and synergistic molecular pathologies including mitochondrial dysfunction, alterations in nutrient sensation and metabolism, dysfunctions in tissue and DNA repair, chronic inflammation, attenuated stress responsivity and accumulated oxidative damage [9]. The aging process appears to be effectively coordinated across the whole body and the impact of these diverse molecular disruptions appears to effectively underpin virtually every form of disease-related process [10,11]. Systemic and single cellular metabolic disruption, linked to either mitochondrial insufficiency or dysfunctional glucose uptake/transport, represents one of core features of aging as this pathophysiology can further entrain oxidative damage to lipids, nucleic acids and proteins. Given this, it is unsurprising that age-related diseases including Metabolic Syndrome/Type II diabetes mellitus (T2DM) [12], nonalcoholic steatohepatitis (NASH [13]:), cardiovascular disease [14], chronic kidney disease [15] and central neurodegenerative disorders such as Alzheimer’s and Huntington’s disease [16,17] are strongly influenced by aberrant glucose metabolism. https://www.aging-us.com/article/101185/text
When general population discuss contemporary medicine, precision plays one of the most significant roles and human lives are literally dependent on it. Hence, any researches pertaining to medicine are required to comply with the top standards. The challenge nowadays is that any recommendations of researches can be shared online and used as a reference without being properly checked and validated. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this issue and tried to create an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been founded back in 2010. The major principle of this journal is related to Altmetric scores that are used as a quality indicator. That helps both readers and authors to verify publications with Altmetric Article Reports that provide “real-time feedback containing data summary related to a particular publication.” Oncotarget website has a full publications list with corresponding scores above 100 as well as reports discussed above. Mikhail (Misha) Blagosklonny proud to share his new approach and hopes it provides the required assistance to anyone, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This study was released back in 2018 by Oncotarget and completed by several experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study discusses “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The article has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that most of readers are willing to understand the very meaning of it. Based on the Altmetric website, the score indicates “how many people have been exposed to and engaged with a scholarly output.” Likewise, the article about melanoma, was used for citations in different news articles 69 times. Moreover, it was quoted in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their news on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study
Another Oncotarget’s research with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This research has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have seen a short overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do receive useful scientific facts. Oncotarget is proud to have the chance to share with online viewers this highly appreciated and high-quality information, that is trustworthy and reliable.
When people speak of modern medicine, accuracy plays one of the most significant roles and human lives are literally dependent on it. Likewise, any researches pertaining to medicine are necessary to comply with the highest standards. The problem nowadays is that any conclusions of researches can be published online and used as a reference without being properly verified and approved. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this challenge and attempted to come up with an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been established back in 2010. The main principle of this journal is based on Altmetric scores that are used as a quality indicator. That allows both readers and authors to verify publications with Altmetric Article Reports that provide “real-time feedback containing data summary related to a particular publication.” Oncotarget website provides a complete publications list with corresponding scores above 100 as well as reports discussed previously. Mikhail (Misha) Blagosklonny proud to share his new approach and hopes it provides the required help to anybody, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This study was released back in 2018 by Oncotarget and written by various experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study mentions that “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The paper has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that most of readers are willing to understand the very meaning of it. Based on the Altmetric website, the score indicates “how many people have been exposed to and engaged with a scholarly output.” Likewise, the publication about melanoma, was used for citations in different news articles 69 times. Besides that, it was referred to in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their report on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study
Another Oncotarget’s study with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This publication has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have seen a concise overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do get useful scientific facts. Oncotarget is glad to have the chance to share with online customers this highly appreciated and top-quality information, that is trustworthy and reliable.
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