MTOR inhibition by INK128 extends ovarian functions in aging and premature aging mice following germline stem cell transplantation
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PROVIDER: PRJNA660943 | ENA |
REPOSITORIES: ENA
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Project description:Germline stem cell transplantation in combination with mTOR inhibition by INK128 can improve and extend ovarian and endocrine functions of aging and particularly premature aging mice.
2020-09-08 | GSE157325 | GEO
Project description:Stem cell transplantation has been generally considered as promising therapeutics in preserving or recovering functions of lost, damaged, or aging tissues. Transplantation of primordial germ cells (PGCs) or oogonia stem cells (OSCs) can reconstitute ovarian functions that yet sustain for only short period of time, limiting potential application of stem cells in preservation of fertility and endocrine function. Here, we show that mTOR inhibition by INK128 extends the follicular and endocrine functions of the reconstituted ovaries in aging and premature aging mice following transplantation of PGCs/OSCs. Follicular development and endocrine functions of the reconstituted ovaries by transplanting PGCs into kidney capsule of the recipient mice were maintained by INK128 treatment for more than 12 weeks, in contrast to the controls for only about 4 weeks without receiving the mTOR inhibitors. Comparatively, rapamycin also can prolong the ovarian functions but for limited time. Furthermore, our data reveal that INK128 promotes mitochondrial function in addition to its known function in suppression of immune response and inflammation. Taken together, germline stem cell transplantation in combination with mTOR inhibition by INK128 improves and extends the reconstituted ovarian and endocrine functions in reproductive aging and premature aging mice.
| S-EPMC7884035 | biostudies-literature
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal human premature aging disease1-5, characterized by premature atherosclerosis and degeneration of vascular smooth muscle cells (SMCs)6-8. HGPS is caused by a single-point mutation in the LMNA gene, resulting in the generation of progerin, a truncated mutant of lamin A. Accumulation of progerin leads to various aging-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin9-12. Here, we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature aging. Upon differentiation of HGPS-iPSCs, progerin and its associated aging consequences are restored. In particular, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescent SMC phenotypes associated with vascular aging. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs) as a component of the progerin-containing protein complex. The absence of nuclear DNAPKcs correlates with premature as well as physiological aging. Since progerin also accumulates during physiological aging6,12,13, our results provide an in vitro iPSC-based model with an acceleration progerin accumulation to study the pathogenesis of human premature and physiological vascular aging. Microarray gene expression profiling was done to: (1) Compare differences between WT fibroblasts and fibroblasts from patients suffering of the Hutchinson-Gilford progeria syndrome (2) Check that iPSC originating from WT and patients are in fact similar to ESC
2011-03-14 | E-GEOD-24487 | biostudies-arrayexpress
Project description:Rapamycin extends life span in mice, but it remains unclear if this compound also delays mammalian aging. Here, we present results from a comprehensive large-scale assessment of a wide rage of structural and functional aging phenotypes in mice. Rapamycin extended life span but showed few effects on a large number of systemic aging phenotypes, suggesting that rapamycin's effects on aging are largely limited to the regulation of age-related mortality and carcinogenesis. Total RNA obtained from 2-4 male mice of each analysed group (25 weeks old controls, 25 month old controls, 25 month old rapamycin treated)
2013-07-29 | E-GEOD-41018 | biostudies-arrayexpress
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal human premature aging disease1-5, characterized by premature atherosclerosis and degeneration of vascular smooth muscle cells (SMCs)6-8. HGPS is caused by a single-point mutation in the LMNA gene, resulting in the generation of progerin, a truncated mutant of lamin A. Accumulation of progerin leads to various aging-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin9-12. Here, we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature aging. Upon differentiation of HGPS-iPSCs, progerin and its associated aging consequences are restored. In particular, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescent SMC phenotypes associated with vascular aging. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs) as a component of the progerin-containing protein complex. The absence of nuclear DNAPKcs correlates with premature as well as physiological aging. Since progerin also accumulates during physiological aging6,12,13, our results provide an in vitro iPSC-based model with an acceleration progerin accumulation to study the pathogenesis of human premature and physiological vascular aging.
2011-03-14 | GSE24487 | GEO
Project description:Rapamycin extends life span in mice, but it remains unclear if this compound also delays mammalian aging. Here, we present results from a comprehensive large-scale assessment of a wide rage of structural and functional aging phenotypes in mice. Rapamycin extended life span but showed few effects on a large number of systemic aging phenotypes, suggesting that rapamycin's effects on aging are largely limited to the regulation of age-related mortality and carcinogenesis.
2013-07-29 | GSE41018 | GEO
Project description:Cx3cr1-deficient microglia exhibit a premature aging transcriptome
| PRJNA545148 | ENA
Project description:Cx3cr1-deficient microglia exhibit a premature aging transcriptome
| PRJNA542087 | ENA
Project description:Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understand the aging process. Using a model that carries a proofreading defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging including anemia, lymphopenia and myeloid lineage skewing. However, in contrast to physiologic stem cell aging, rapidly accumulating mitochondrial DNA mutations displayed little involvement of the hematopoietic stem cell pool but rather with distinct differentiation blocks and/or disappearance of downstream progenitors. Hematopoietic stem cells (HSC) has been sorted out from midaged wildtype and mutator mice and compared with stem cells sorted from young and and old wt mice
2011-05-06 | E-GEOD-27686 | biostudies-arrayexpress
Project description:Aging increases the vulnerability to various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a nature product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate targets were identified and quercetin was further investigated due to its leading effects. Mechanistic studies revealed that in WS hMSCs, quercetin alleviated senescence via the enhancement of cell proliferation and the restoration and differentiation of heterochromatin architecture. RNA-seq analysis uncovered that quercetin and Vitamin C exerted geroprotective effects through different mechanisms. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS), physiological-aging and replicative-senescent hMSCs. More importantly, quercetin significantly improved the exercise endurance of old C57Bl/6 mice. Taken together, our study identifies quercetin as a geroprotective agent against premature and physiological aging, providing a novel therapeutic intervention for treating premature aging and promoting healthy aging.
2018-06-23 | GSE116166 | GEO