4E-BP1 counteracts human mesenchymal stem cell senescence via maintaining mitochondrial homeostasis

Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders, the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown. Here, we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem cells (hMSCs). Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration, increases mitochondrial reactive oxygen species (ROS) production, and accelerates cellular senescence. Mechanistically, the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes, especially several key subunits of complex III including UQCRC2. Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs. These f indings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis, particularly for the mitochondrial respiration complex III, thus providing a new potential target to counteract human stem cell senescence.

SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer

SIRT7, a sirtuin family member implicated in aging and disease, is a regulator of metabolism and stress responses. It remains elusive how human somatic stem cell populations might be impacted by SIRT7. Here, we found that SIRT7 expression declines during human mesenchymal stem cell (hMSC) aging and that SIRT7 deficiency accelerates senescence. Mechanistically, SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins, thus maintaining the repressive state of heterochromatin at nuclear periphery. Accordingly, deficiency of SIRT7 results in loss of heterochromatin, de-repression of the LINE1 retrotransposon (LINE1), and activation of innate immune signaling via the cGAS-STING pathway. These aging-associated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor. Together, these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.

SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer

SIRT7, a sirtuin family member implicated in aging and disease, is a regulator of metabolism and stress responses. It remains elusive how human somatic stem cell populations might be impacted by SIRT7. Here, we found that SIRT7 expression declines during human mesenchymal stem cell (hMSC) aging and that SIRT7 deficiency accelerates senescence. Mechanistically, SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins, thus maintaining the repressive state of heterochromatin at nuclear periphery. Accordingly, deficiency of SIRT7 results in loss of heterochromatin, de-repression of the LINE1 retrotransposon (LINE1), and activation of innate immune signaling via the cGAS-STING pathway. These aging-associated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor. Together, these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.

Chemical screen identifies a geroprotective role of quercetin in premature aging

Aging increases the risk of 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 natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.

Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome

Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.

The effects of shade and light irradiation on the polymerization of composite resin core materials / 实用口腔医学杂志

Objective:To evaluate the effects of shade and light irradiation condition on the polymerization of composite resin core material.Methods:The light-proof silicon rubber cuboid mold with one end open were stringed and filled by dual-cured flowable composite resin core material with the shade of dentine and white(Paracore) respectively,then the open end of mold was irradiated directly by a light unit at 1 000 mW/cm2 ×20 s and 3 200 mW/cm2 ×6 s respectively.And all specimens of 4 groups(n =5) were stored in the light-proof box.1 h and 24 h after irradiation,Knoop microhardness was measured along the vertical surfaces of the specimens at the depth of 1,2 and 3 mm respectively.Data were analyzed by One-way ANOVA.Results:At all light irradiation conditions,the hardness of all specimens decreased with the increase of measurement depth.24 h after irradiation,the hardness of dentine shade specimens at each measurement depth showed no difference between 1 000 mW/cm2 × 20 s and 3 200 mW/cm2 × 6 s irradiation,while the white shade specimens irradiated by 1 000 mW/cm2 × 20 s showed higher hardness than those by 3 200 mW/cm2 × 6 s.Conclusion:To obtain sufficient polymerization of composite core material with different shade optimal light irradiation condition should be selected.

Effect of Shuxuening Injection on NO, NOS, SOD and MDA of Angina Pectoris Patients / 中国中医药信息杂志

Objective To observe the effect of Shuxuening Injection NO, NOS, SOD and MDA on of angina pectoris patients. Methods 100 patients with angina pectoris were randomly divided into two groups. 50 patients in treatment group were treated with Shuxuening Injection, 5 mL once, drop into 250 mL 5% glucose injection (it change into 250 mL 0.9% sodium chloride injection if the patient have diabetes), one time a day. 50 patients in control group were treated with isosorbide mononitrate injection, 60 mg once, drop into 250 mL 5% glucose injection (it change into 250 mL 0.9% sodium chloride injection if the patient have diabetes), 15 gtt one minute, one time a day. Results NO, NOS and SOD of the treatment group were objective improved, and MDA objective reduced. NO improved from (47.61?8.76)?mol/L to (71.84? 13.26)?mol/L, NOS improved from (1.64?0.23)U/mL to (2.31?0.29)U/mL, SOD improved from (46.34? 5.62)U/mL to (64.54?9.10)U/mL, and MDA reduced from (8.96?1.76)U/mL to (6.71?1.43)U/mL. Total effective rate in improving angina pectoris was 96%, and ECG was 76%. The time (ischemic ST-T changes) of holter ECG was reduced from (130.45?18.61)min to (32.33?5.32)min, there was a significant difference between the two groups (P