Редактирование: BCL2

Apoptosis regulator Bcl-2

==Publications==

{{medline-entry
|title=Aberrant mitochondrial morphology and function associated with impaired mitophagy and [[DNM1L]]-MAPK/ERK signaling are found in aged mutant Parkinsonian [[LRRK2]]  mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33300446
|abstract=Mitochondrial dysfunction causes energy deficiency and nigrostriatal neurodegeneration which is integral to the pathogenesis of Parkinson disease (PD). Clearance of defective mitochondria involves fission and ubiquitin-dependent degradation via mitophagy to maintain energy homeostasis. We hypothesize that [[LRRK2]] (leucine-rich repeat kinase 2) mutation disrupts mitochondrial turnover causing accumulation of defective mitochondria in aging brain. We found more ubiquitinated mitochondria with aberrant morphology associated with impaired function in aged (but not young) [[LRRK2]]  knockin mutant mouse striatum compared to wild-type (WT) controls. [[LRRK2]]  mutant mouse embryonic fibroblasts (MEFs) exhibited reduced MAP1LC3/LC3 activation indicating impaired macroautophagy/autophagy. Mutant MEFs under FCCP-induced (mitochondrial uncoupler) stress showed increased LC3-aggregates demonstrating impaired mitophagy. Using a novel flow cytometry assay to quantify mitophagic rates in MEFs expressing photoactivatable [i]mito[/i]-PAmCherry, we found significantly slower mitochondria clearance in mutant cells. Specific [[LRRK2]] kinase inhibition using [[GNE]]-7915 did not alleviate impaired mitochondrial clearance suggesting a lack of direct relationship to increased kinase activity alone. [[DNM1L]]/Drp1 knockdown in MEFs slowed mitochondrial clearance indicating that [[DNM1L]] is a prerequisite for mitophagy. [[DNM1L]] knockdown in slowing mitochondrial clearance was less pronounced in mutant MEFs, indicating preexisting impaired [[DNM1L]] activation. [[DNM1L]] knockdown disrupted mitochondrial network which was more evident in mutant MEFs. [[DNM1L]]-Ser616 and MAPK/ERK phosphorylation which mediate mitochondrial fission and downstream mitophagic processes was apparent in WT using FCCP-induced stress but not mutant MEFs, despite similar total MAPK/ERK and [[DNM1L]] levels. In conclusion, aberrant mitochondria morphology and dysfunction associated with impaired mitophagy and [[DNM1L]]-MAPK/ERK signaling are found in mutant [[LRRK2]] MEFs and mouse brain.   ATP: adenosine triphosphate; BAX: [[BCL2]]-associated X protein; CDK1: cyclin-dependent kinase 1; CDK5: cyclin-dependent kinase 5; CQ: chloroquine; CSF: cerebrospinal fluid; [[DNM1L]]/DRP1: dynamin 1-like; ELISA: enzyme-linked immunosorbent assay; FACS: fluorescence-activated cell sorting; FCCP: carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; LAMP2A: lysosomal-associated membrane protein 2A; [[LRRK2]]: leucine-rich repeat kinase 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK1/ERK2: mitogen-activated protein kinase 1; MEF: mouse embryonic fibroblast; MFN1: mitofusin 1; MMP: mitochondrial membrane potential; PAmCherry: photoactivatable-mCherry; PD: Parkinson disease; PINK1: [[PTEN]] induced putative kinase 1; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; [[RAB10]]: [[RAB10]], member RAS oncogene family; RAF: v-raf-leukemia oncogene; SNCA: synuclein, alpha; TEM: transmission electron microscopy; VDAC: voltage-dependent anion channel; WT: wild type; SQSTM1/p62: sequestosome 1.

|keywords=* Aging
* Dnm1l/DRP1
* SQSTM1/p62
* knockin mice
* macroautophagy
* mitochondria dysfunction
* mitochondrial fission
* mitophagy
* parkinson disease
* ubiquitination
|full-text-url=https://sci-hub.do/10.1080/15548627.2020.1850008
}}
{{medline-entry
|title=[[CISD2]] Attenuates Inflammation and Regulates Microglia Polarization in EOC Microglial Cells-As a Potential Therapeutic Target for Neurodegenerative Dementia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33005144
|abstract=: Accumulating evidence has demonstrated a significant association between microglia-driven inflammation in the brain and neurodegenerative dementia. We previously showed a significant decline in [[CISD2]] expression in mice models with advanced age. Moreover, we observed that the knockdown of [[CISD2]] led to remarkable inflammation and mitochondrial dysfunction in neural cells. In the present study, we investigated whether [[CISD2]] attenuation influences anti-inflammatory effects and M1-M2 polarization in microglia.  : The knockdown of [[CISD2]] expression by siRNA (si[[CISD2]]) in EOC microglial cells was performed to mimic the age-driven decline of [[CISD2]] expression. The extent of the inflammatory reaction, polarization in the M1/M2 spectrum, and NFκB activation were verified in EOC microglial cells exhibiting [[CISD2]] deficiency.  : In the cellular model of microglia, loss of [[CISD2]] function mediated by si[[CISD2]] exhibited a significant augmentation of proinflammatory signaling, as well as reduced expression levels of Arg-1, Ym1, IL-10, and [[BCL2]]. Attenuation of [[CISD2]] expression led to a decrease in the proportion of the M2 phenotype of microglia (compared to M1). Enhanced DNA-binding activity of the NFκB p65 subunit was confirmed in cells transfected with si[[CISD2]], as demonstrated by enzyme-linked immunosorbent assay (ELISA).  : To the best of our knowledge, this is the first report examining the following phenomena: (1) anti-inflammatory effects of [[CISD2]] in microglia [i]via[/i] NFκB regulation; and (2) microglial [[CISD2]] assistance in the restoration of M2 microglia phenotype. The anti-inflammatory effects of [[CISD2]] in microglia eventually augment anti-apoptotic effects, which provides a rationale for the development of potential therapeutic target for neurodegenerative diseases and neurodegenerative dementia.

|keywords=* CISD2
* M1/M2 microglia polarization
* aging
* anti-inflammatory effects
* neurodegenerative disease and dementia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479185
}}
{{medline-entry
|title=miR-155 inhibits mitophagy through suppression of [[BAG5]], a partner protein of [[PINK1]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31948758
|abstract=Removal of dysfunctional mitochondria is essential step to maintain normal cell physiology, and selective autophagy in mitochondria, called mitophagy, plays a critical role in quality control of mitochondria. While in several diseases and aging, disturbed mitophagy has been observed. In stem cells, accumulation of damaged mitochondria can lead to deterioration of stem cell properties. Here, we focused on miR-155-5p (miR-155), one of the most prominent miRNAs in inflammatory and aged tissues, and found that miR-155 disturbed mitophagy in mesenchymal stem cells (MSCs). As a molecular mechanism of miR-155-mediated mitophagy suppression, we found that [[BCL2]] associated athanogene 5 ([[BAG5]]) is a direct target of miR-155. Reduction of [[BAG5]] resulted in destabilization of [[PTEN]]-induced kinase ([[PINK1]]) and consequently disrupted mitophagy. Our study suggests a novel mechanism connecting aging and aging-associated inflammation with mitochondrial dysfunction in stem cells through a miRNA-mediated mechanism.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Aging
* Animals
* Cell Line
* Cells, Cultured
* Down-Regulation
* Humans
* Male
* Mesenchymal Stem Cells
* Mice, Inbred C57BL
* MicroRNAs
* Mitophagy
* Protein Interaction Maps
* Protein Kinases
* Up-Regulation
|keywords=* Aging
* Bone marrow MSCs
* Mitophagy
* miR-155
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2020.01.022
}}
{{medline-entry
|title=The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31908069
|abstract=Aging-related organ degeneration is driven by multiple factors including the cell maintenance mechanisms of autophagy, the cytoprotective protein αKlotho, and the lesser known effects of excess phosphate (Pi), or phosphotoxicity. To examine the interplay between Pi, autophagy, and αKlotho, we used the BK/BK mouse (homozygous for mutant Becn1  ) with increased autophagic flux, and αKlotho-hypomorphic mouse (kl/kl) with impaired urinary Pi excretion, low autophagy, and premature organ dysfunction. BK/BK mice live longer than WT littermates, and have heightened phosphaturia from downregulation of two key NaPi cotransporters in the kidney. The multi-organ failure in kl/kl mice was rescued in the double-mutant BK/BK;kl/kl mice exhibiting lower plasma Pi, improved weight gain, restored plasma and renal αKlotho levels, decreased pathology of multiple organs, and improved fertility compared to kl/kl mice. The beneficial effects of heightened autophagy from Becn1  was abolished by chronic high-Pi diet which also shortened life span in the BK/BK;kl/kl mice. Pi promoted beclin 1 binding to its negative regulator [[BCL2]], which impairs autophagy flux. Pi downregulated αKlotho, which also independently impaired autophagy. In conclusion, Pi, αKlotho, and autophagy interact intricately to affect each other. Both autophagy and αKlotho antagonizes phosphotoxicity. In concert, this tripartite system jointly determines longevity and life span.
|mesh-terms=* Aging
* Animals
* Autophagy
* Beclin-1
* Female
* Glucuronidase
* HEK293 Cells
* Humans
* Kidney
* Male
* Mice
* Phosphates
* Protein Binding
* Proto-Oncogene Proteins c-bcl-2
|keywords=* BCL2
* NaPi cotransporter
* aging
* autophagy
* beclin 1
* fertility
* longevity
* phosphorus
* phosphotoxicity
* αKlotho
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286356
}}
{{medline-entry
|title=The transcription factor [[ETS1]] promotes apoptosis resistance of senescent cholangiocytes by epigenetically up-regulating the apoptosis suppressor [[BCL2]]L1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31659122
|abstract=Primary sclerosing cholangitis (PSC) is an idiopathic, progressive cholangiopathy. Cholangiocyte senescence is important in PSC pathogenesis, and we have previously reported that senescence is regulated by the transcription factor ETS proto-oncogene 1 ([[ETS1]]) and associated with overexpression of [[BCL2]] like 1 ([[BCL2]]L1 or BCL-xL), an anti-apoptotic [[BCL2]]-family member. Here, we further explored the mechanisms regulating BCL-xL-mediated, apoptosis resistance in senescent cholangiocytes and uncovered that [[ETS1]] and the histone acetyltransferase E1A-binding protein P300 (EP300 or p300) both promote [i]BCL-xL[/i] transcription. Using immunofluorescence, we found that BCL-xL protein expression is increased both in cholangiocytes of livers from individuals with PSC and a mouse model of PSC. Using an [i]in vitro[/i] model of lipopolysaccharide-induced senescence in normal human cholangiocytes (NHCs), we found increased BCL-xL mRNA and protein levels, and ChIP-PCRs indicated increased occupancy of [[ETS1]], p300, and histone 3 Lys-27 acetylation (H3K27Ac) at the [i]BCL-xL[/i] promoter. Using co-immunoprecipitation and proximity ligation assays, we further demonstrate that [[ETS1]] and p300 physically interact in senescent but not control NHCs. Additionally, mutagenesis of predicted [[ETS1]]-binding sites within the [i]BCL-xL[/i] promoter blocked luciferase reporter activity, and CRISPR/Cas9-mediated genetic deletion of [i][[ETS1]][/i] reduced senescence-associated BCL-xL expression. In senescent NHCs, TRAIL-mediated apoptosis was reduced ∼70%, and [[ETS1]] deletion or RNAi-mediated BCL-xL suppression increased apoptosis. Overall, our results suggest that [[ETS1]] and p300 promote senescent cholangiocyte resistance to apoptosis by modifying chromatin and inducing BCL-xL expression. These findings reveal [[ETS1]] as a central regulator of both cholangiocyte senescence and the associated apoptosis-resistant phenotype.
|mesh-terms=* ATP Binding Cassette Transporter, Subfamily B
* Animals
* Apoptosis
* Cellular Senescence
* Hepatocytes
* Humans
* Lipopolysaccharides
* Liver
* Mice
* Proto-Oncogene Protein c-ets-1
* Transcription Factors
* bcl-X Protein
|keywords=* BCL2 like 1 (BCL2L1)
* apoptosis
* cholangiocyte
* chromatin modification
* epigenetics
* gene expression
* primary sclerosing cholangitis (PSC)
* senescence
* transcription factor
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901313
}}
{{medline-entry
|title=Vitamin D3 treatment regulates apoptosis, antioxidant defense system, and DNA integrity in the epididymal sperm of an aged rat model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31566824
|abstract=The present study aimed to investigate the effects of vitamin D3 in the epididymal sperm cells of D-gal-induced aged rats. It is well known that during aging sperm quality and quantity declines and leads to age-related infertility problems in males. The results of the present study showed that there were elevated levels of oxidative stress and poor DNA integrity of sperm of aged rats. The expression of [[BCL2]] also showed a significant decline in the sperm of aged rats, however, the expression of [[BAX]] and active caspase-3 did not show significant change compared with the control group. The treatment of vitamin D3 at lower doses to aged rats showed increased expression of [[BAX]] and active caspase-3 in the sperm, this finding suggests that increased apoptosis may be responsible for removal of poor quality sperm during aging. Vitamin D3 treatment at both doses showed improvement in the oxidative stress and DNA integrity in the sperm of aged rats. We also investigated the expression of [[AGER]], visfatin, and [[HSPA1A]] in the epididymal sperm. It has been found that expression of [[AGER]], visfatin, and [[HSPA1A]] increased in the sperm aged rats and vitamin D3 treatments at both doses decreased its expression. Thus, it might be suggested that during aging vitamin D3 treatment would be important for managing the sperm quality by regulating the apoptosis, antioxidant system and DNA integrity via modulation of visfatin and [[HSPA1A]].
|mesh-terms=* Aging
* Animals
* Antioxidants
* Apoptosis
* Cholecalciferol
* Epididymis
* Male
* Rats
* Rats, Wistar
* Spermatozoa
|keywords=* aging
* apoptosis
* oxidative stress
* sperm
|full-text-url=https://sci-hub.do/10.1002/mrd.23280
}}
{{medline-entry
|title=Soy isoflavones protect against oxidative stress and diminish apoptosis in ovary of middle-aged female rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30784335
|abstract=Ovarian aging is characterized by declines in follicular reserve and oocyte quality due, in part, to increased oxidative stress and apoptosis. Soy isoflavones (ISOs) have been shown to improve ovarian lifespan by acting as antioxidant and antiapoptotic agents. We aimed at evaluating whether ISOs could modulate oxidative stress and reduce apoptosis and improve ovarian follicle survival in middle-aged female rats. Twelve ovary-intact female Wistar rats (12-month-old) were divided into groups: control ([[CTRL]]) and ISO, daily treated by gavage with vehicle or soy-ISO extract (150 mg/kg b.w), respectively. After 8 weeks, rats were euthanized and their ovaries removed for histomorphometric (% follicles) and apoptosis (cleaved-caspase-3/[[BCL2]] immunostaining) evaluations, or subjected to biochemical assays to survey reactive oxygen species (ROS) and lipid peroxidation levels and total antioxidant capacity (TAC). The frequency of atretic follicles and number of cleaved-caspase-3-positive cells, as well as the ROS and lipid peroxidation levels, were significantly lower in ISO group compared to [[CTRL]]. A significantly higher number of [[BCL2]]-positive cells and TAC levels were also observed in ISO group. In conclusion, soy ISOs could decrease follicular atresia, apoptosis and oxidative stress, as well as increase the TAC in ovaries of female rats.
|mesh-terms=* Animals
* Apoptosis
* Caspase 3
* Female
* Isoflavones
* Ovary
* Oxidative Stress
* Protective Agents
* Rats
* Rats, Wistar
* Reactive Oxygen Species
|keywords=* apoptosis
* ovarian aging
* oxidative stress
* rats
* soy isoflavones
|full-text-url=https://sci-hub.do/10.1080/09513590.2018.1559287
}}
{{medline-entry
|title=Nrdp1 is involved in hippocampus apoptosis in cardiopulmonary bypass-induced cognitive dysfunction via the regulation of ErbB3 protein levels.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30720051
|abstract=The cardiopulmonary bypass (CPB) is an important risk factor for the development of postoperative cognitive dysfunction (POCD). The pathological mechanism of the neuro‑modulation receptor degradation protein ring finger protein 41 (Nrdp1) in CPB‑induced cognitive dysfunction remains unclear. In the present study, aged Sprague‑Dawley male rats and CPB treatment were selected to duplicate the POCD model. A hypoxia/reoxygeneration (H/R) model was established to evaluate the effect of Nrdp1 in vitro. Apoptosis in the hippocampus regions were measured using a terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labelling assay, the viability and apoptosis level of the cells were measured via an MTT assay and flow cytometry, respectively, and the expression levels of Nrdp1, erb‑b2 receptor tyrosine kinase 3 (ErbB3), phosphorylated‑protein kinase B (p‑AKT) and cleaved (c‑) caspase‑3 were detected using western blot analysis. Then, Nrdp1 was upregulated and downregulated in vitro and in vivo through lentivirus infection to further investigate the effect of Nrdp1 in the rats following CPB. The results revealed that Nrdp1 is associated with hippocampus neuronal apoptosis and POCD following CPB in rats. The overexpression of Nrdp1 altered the cognitive function of the rats which was inhibited by CPB, and additionally inhibited the viability and increased the apoptosis of primary hippocampus neuron cells under H/R treatment. Furthermore, knockdown of Nrdp1 promoted the viability of primary hippocampus neuron cells and decreased the apoptosis of cells under H/R treatment. Further study indicated that Nrdp1 regulates the protein expression of ErbB3, p‑AKT, cytochrome c, [[BCL2]]-associated X, apoptosis regulator, [[BCL2]], apoptosis regulator and c‑caspase‑3. The results of the present study suggested that CPB may induce apoptosis in the hippocampus of aged rats. Nrdp1 serves an important role in regulating the apoptosis induced by CPB in vivo and in vitro through regulating ErbB3 and p‑AKT protein levels.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Cardiopulmonary Bypass
* Carrier Proteins
* Cell Survival
* Cognition
* Cognitive Dysfunction
* Hippocampus
* Male
* Neurons
* Phosphorylation
* Proto-Oncogene Proteins c-akt
* Rats, Sprague-Dawley
* Receptor, ErbB-3
* Ubiquitin-Protein Ligases

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414174
}}
{{medline-entry
|title=Self-Digestion for Lifespan Extension: Enhanced Autophagy Delays Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30118677
|abstract=By systemically boosting autophagy with a knockin mutation that prevents binding of beclin 1 to [[BCL2]], Fernández et al. (2018) demonstrate that enhanced autophagy prolongs lifespan in mammals.
|mesh-terms=* Animals
* Autophagy
* Beclin-1
* Longevity
* Mice
* Mutation
* Proto-Oncogene Proteins c-bcl-2

|full-text-url=https://sci-hub.do/10.1016/j.molcel.2018.08.002
}}
{{medline-entry
|title=Disruption of the beclin 1-[[BCL2]] autophagy regulatory complex promotes longevity in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29849149
|abstract=Autophagy increases the lifespan of model organisms; however, its role in promoting mammalian longevity is less well-established . Here we report lifespan and healthspan extension in a mouse model with increased basal autophagy. To determine the effects of constitutively increased autophagy on mammalian health, we generated targeted mutant mice with a Phe121Ala mutation in beclin 1 (Becn1 ) that decreases its interaction with the negative regulator [[BCL2]]. We demonstrate that the interaction between beclin 1 and [[BCL2]] is disrupted in several tissues in Becn1   knock-in mice in association with higher levels of basal autophagic flux. Compared to wild-type littermates, the lifespan of both male and female knock-in mice is significantly increased. The healthspan of the knock-in mice also improves, as phenotypes such as age-related renal and cardiac pathological changes and spontaneous tumorigenesis are diminished. Moreover, mice deficient in the anti-ageing protein klotho   have increased beclin 1 and [[BCL2]] interaction and decreased autophagy. These phenotypes, along with premature lethality and infertility, are rescued by the beclin 1(F121A) mutation. Together, our data demonstrate that disruption of the beclin 1-[[BCL2]] complex is an effective mechanism to increase autophagy, prevent premature ageing, improve healthspan and promote longevity in mammals.
|mesh-terms=* Aging
* Animals
* Autophagosomes
* Autophagy
* Beclin-1
* Cells, Cultured
* Female
* Fibroblasts
* Gene Knock-In Techniques
* Glucuronidase
* HeLa Cells
* Health
* Humans
* Longevity
* Male
* Mice
* Mice, Inbred C57BL
* Mutation
* Proto-Oncogene Proteins c-bcl-2

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992097
}}
{{medline-entry
|title=Sestrins are differentially expressed with age in the skeletal muscle of men: A cross-sectional analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29751091
|abstract=A gradual loss of skeletal muscle mass is a common feature of aging, leading to impaired insulin sensitivity and mobility. Sestrin1, 2, 3 are multifunctional proteins that regulate the mammalian target of rapamycin complex (mTORC1), autophagy and redox homeostasis. It is unclear how aging affects Sestrins and their downstream targets in human, therefore this study examined the basal expression of Sestrins in three age groups, young, middle-aged and older men and explored the mTORC1 pathway, autophagy markers and antioxidant regulation. Older men had less Sestrin1 and 3 protein and a different pattern of Sestrin2 electrophoretic mobility. The mRNA expression of [[SESN1]] was upregulated in older men, but the discrepancy was not by microRNA expression. Although protein expressions of Sestrins were downregulated with aging, phosphorylation of AMP-dependent protein kinase (AMPKα ) and read-outs of mTORC1 activation, ribosomal protein S6 kinase 1 (p70S6K1 ) and 4E-binding protein 1 (4E-BP1) mobility shift were unaltered. However, total p70S6K1 and 4E-BP1 were reduced in middle-aged and older men. The mRNA expressions of autophagic markers including microtubule-associated protein 1 light chain 3 (LC3) and [[BCL2]] interacting protein 3 (BNIP3) were upregulated in middle-aged and older men. Although nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was upregulated in older men, the protein and mRNA expressions of its downstream antioxidants were either increased, decreased or unaltered. No clear relationship was observed between Sestrins and their downstream targets, yet it can be concluded that Sestrins proteins are clearly downregulated with aging.
|mesh-terms=* AMP-Activated Protein Kinases
* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Aging
* Animals
* Antioxidants
* Autophagy
* Cross-Sectional Studies
* Heat-Shock Proteins
* Humans
* Male
* Membrane Proteins
* Microtubule-Associated Proteins
* Middle Aged
* Muscle, Skeletal
* NF-E2-Related Factor 2
* Nuclear Proteins
* Protein Processing, Post-Translational
* Proto-Oncogene Proteins
* RNA, Messenger
* TOR Serine-Threonine Kinases
* Young Adult
|keywords=* Aging
* Antioxidant
* Autophagy
* Sarcopenia
* Sestrins
* mTORC1
|full-text-url=https://sci-hub.do/10.1016/j.exger.2018.05.006
}}
{{medline-entry
|title=Autophagy regulates the degeneration of the auditory cortex through the AMPK-mTOR-[[ULK1]] signaling pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29344647
|abstract=Presbycusis is the most common sensory impairment associated with aging; however, the underlying molecular mechanism remains unclear. Autophagy has been demonstrated to serve a key role in diverse diseases; however, no studies have examined its function in central presbycusis. The aim of the present study was to investigate the changes of autophagy in the physiological processes of the auditory cortex and its role in the degeneration of the auditory cortex, as well as the related mechanisms using naturally aging rats and a D‑galactose (D‑gal)‑induced mimetic rat model of aging. The present study demonstrated that autophagy increased from 3 months to 15 months in the normal saline (NS) control group, while it decreased in the D‑gal group. Compared with the age‑matched NS group, the D‑gal group demonstrated significantly increased levels of the autophagy‑related proteins, LC3 and Beclin 1 ([[BECN1]]) and the anti‑apoptotic proteins B‑cell lymphoma (BCL)2 and BCL‑extra large (BCL‑xL) at 3 months, with no obvious changes in cell apoptosis level and neuron ultrastructural morphology. However, LC3, [[BECN1]], [[BCL2]] and BCL‑xL were decreased at 15 months in the D-gal group, with cell apoptosis significantly increased and substantial neuron degeneration. Additionally, 5' AMP‑activated protein kinase (AMPK) activity was enhanced, and mechanistic target of rapamycin (mTOR) and [[ULK1]] phosphorylation (Ser 757) activities were inhibited at 3 months compared with those of the NS group, while the opposite was observed at 9 and 15 months. The present results suggested that autophagy increases from young to adult and decreases at old age in the physiological processes of the auditory cortex, and has anti‑apoptotic as well as anti‑aging functions in the degeneration of the auditory cortex. Additionally, autophagy was regulated through AMPK activation and mTOR suppression, and impairment of autophagy may serve a key role in the degeneration of the auditory cortex, even in the pathogenesis of central presbycusis.
|mesh-terms=* AMP-Activated Protein Kinases
* Aging
* Animals
* Apoptosis
* Auditory Cortex
* Autophagy
* Autophagy-Related Protein-1 Homolog
* Male
* Rats, Sprague-Dawley
* Signal Transduction
* TOR Serine-Threonine Kinases

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810242
}}
{{medline-entry
|title=The effect of [[ARC]] ablation on skeletal muscle morphology, function, and apoptotic signaling during aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29056555
|abstract=Augmented apoptotic signaling can result in degradation of skeletal muscle proteins and loss of myonuclei, ultimately contributing to muscle atrophy and contractile dysfunction. Apoptosis repressor with caspase recruitment domain ([[ARC]]) is an anti-apoptotic protein highly expressed in skeletal muscle. Here we examined the role of [[ARC]] on age-related skeletal muscle apoptosis and wasting by utilizing an [[ARC]]-deficient mouse model. Aged mice displayed a number of morphological, phenotypic, and contractile alterations in both soleus and plantaris muscle with aging. Although no differences were found in proteolytic enzyme activity, [[ARC]] protein decreased while several anti-apoptotic proteins (e.g., [[BCL2]], BCLXL, HSP70, and XIAP) and the release of mitochondrial housed protein (i.e., SMAC, AIF) increased in aged muscle. Importantly, [[ARC]] KO mice had low muscle weights and fewer fibers in soleus, with 2-year-old [[ARC]] KO mice displaying lower mitochondrial [[BCL2]] protein along with augmented release of CYTC and SMAC in red/oxidative muscle. Overall, these results indicate that aged skeletal muscle undergoes atrophy as well as contractile and fiber type composition alterations despite an increase in anti-apoptotic protein expression. Although some mitochondrial-specific apoptotic alterations occurred in skeletal muscle due to [[ARC]] ablation over the lifespan, our data suggest that [[ARC]] may not have a large influence during skeletal muscle aging.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Apoptosis Regulatory Proteins
* Caspase Activation and Recruitment Domain
* Caspases
* Cellular Senescence
* Mice
* Muscle Proteins
* Muscle, Skeletal
* Signal Transduction

|full-text-url=https://sci-hub.do/10.1016/j.exger.2017.10.018
}}
{{medline-entry
|title=High-Throughput Functional Genetic and Compound Screens Identify Targets for Senescence Induction in Cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29045843
|abstract=Senescence is a proliferation arrest that can result from a variety of stresses. Cancer cells can also undergo senescence, but the stresses that provoke cancer cells to undergo senescence are unclear. Here, we use both functional genetic and compound screens in cancer cells harboring a reporter that is activated during senescence to find targets that induce senescence. We show that suppression of the SWI/SNF component [[SMARCB1]] induces senescence in melanoma through strong activation of the MAP kinase pathway. From the compound screen, we identified multiple aurora kinase inhibitors as potent inducers of senescence in RAS mutant lung cancer. Senescent melanoma and lung cancer cells acquire sensitivity to the [[BCL2]] family inhibitor ABT263. We propose a one-two punch approach for the treatment of cancer in which a drug is first used to induce senescence in cancer cells and a second drug is then used to kill senescent cancer cells.
|mesh-terms=* Aurora Kinases
* CRISPR-Cas Systems
* Cell Line, Tumor
* Cellular Senescence
* Down-Regulation
* ErbB Receptors
* Gene Knockout Techniques
* Genes, Reporter
* Genetic Testing
* Green Fluorescent Proteins
* High-Throughput Screening Assays
* Humans
* Melanoma
* Neoplasms
* Oncogenes
* Protein Kinase Inhibitors
* SMARCB1 Protein
* SOXE Transcription Factors
|keywords=* SWI/SNF
* aurora kinase
* compound screen
* genetic screens
* miR146
* senescence
* senolysis
|full-text-url=https://sci-hub.do/10.1016/j.celrep.2017.09.085
}}
{{medline-entry
|title=Detecting Markers of Therapy-Induced Senescence in Cancer Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27812866
|abstract=Therapy-induced senescence (TIS), a lasting chemotherapy-evoked proliferative arrest of tumor cells, has gained increasing attention by cancer researchers because of its' profound biological implications, and by clinical oncologists due to its potential contribution to the long-term outcome of cancer patients post-treatment. Although both apoptosis and senescence represent therapy-inducible, ultimate cell-cycle exit programs, mediated via DNA damage response signaling, apoptotic cell death as the faster and often quantitatively more prominent tumor response has been in the scientific focus for decades. The more recently recognized TIS as another "safeguard" response of cancer cells that were never primed for or failed to execute apoptosis, not only reflects a more complex "arrest-plus-other features" cell-autonomous condition but produces non-cell-autonomous phenotypes at the tumor site, collectively impinging on tumor control and clinical outcome. Hence, TIS research is gaining pivotal interest from both a tumor biological and a therapeutic perspective, and the development of non-DNA damaging, senescence-evoking therapeutics is about to become a major research objective. In this chapter, we describe a well-characterized, genetically controlled TIS model system based on primary [[BCL2]]-expressing Eμ-myc transgenic lymphoma cells harboring defined genetic lesions and provide protocols for co-staining of either senescence-associated β-galactosidase (SA-β-gal) activity or trimethylated lysine 9 of histone H3 (H3K9me3) together with Ki67 to detect the senescent status of therapy-exposed cancer cells.
|mesh-terms=* Antineoplastic Agents
* Biomarkers
* Cell Line, Tumor
* Cellular Senescence
* Chromatin Assembly and Disassembly
* DNA Damage
* Gene Expression Regulation
* Gene Knock-In Techniques
* Heterochromatin
* Histones
* Humans
* Immunohistochemistry
* Ki-67 Antigen
* beta-Galactosidase
|keywords=* Cancer
* Chemotherapy
* DNA damage response
* H3K9me3
* Heterochromatin
* Ki67
* SA-β-gal
* Senescence markers
* Senescence-associated β-galactosidase
* TIS model system
* Therapy-induced senescence (TIS)
|full-text-url=https://sci-hub.do/10.1007/978-1-4939-6670-7_4
}}
{{medline-entry
|title=Sperm-associated antigen 9 ([[SPAG9]]) promotes the survival and tumor growth of triple-negative breast cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27449044
|abstract=Recently, we demonstrated the association of sperm-associated antigen 9 ([[SPAG9]]) expression with breast cancer. Among breast cancer, 15 % of the cancers are diagnosed as triple-negative breast cancers (TNBC) based on hormone receptor status and represent an important clinical challenge because of lack of effective available targeted therapy. Therefore, in the present investigation, plasmid-based small hairpin (small hairpin RNA (shRNA)) approach was used to ablate [[SPAG9]] in aggressive breast cancer cell line model (MDA-[[MB]]-231) in order to understand the role of [[SPAG9]] at molecular level in apoptosis, cell cycle, and epithelial-to-mesenchymal transition (EMT) signaling. Our data in MDA-[[MB]]-231 cells showed that ablation of [[SPAG9]] resulted in membrane blebbing, increased mitochondrial membrane potential, DNA fragmentation, phosphatidyl serine surface expression, and caspase activation. [[SPAG9]] depletion also resulted in cell cycle arrest in G0-G1 phase and induced cellular senescence. In addition, in in vitro and in vivo xenograft studies, ablation of [[SPAG9]] resulted in upregulation of p21 along with pro-apoptotic molecules such as BAK, [[BAX]], BIM, [[BID]], NOXA, AIF, Cyto-C, [[PARP1]], [[APAF1]], Caspase 3, and Caspase 9 and epithelial marker, E-cadherin. Also, [[SPAG9]]-depleted cells showed downregulation of cyclin B1, cyclin D1, cyclin E, [[CDK1]], [[CDK4]], [[CDK6]], [[BCL2]], Bcl-xL, [[XIAP]], cIAP2, [[MCL1]], GRP78, SLUG, SNAIL, TWIST, vimentin, N-cadherin, [[MMP2]], [[MMP3]], [[MMP9]], SMA, and β-catenin. Collectively, our data suggests that [[SPAG9]] promotes tumor growth by inhibiting apoptosis, altering cell cycle, and enhancing EMT signaling in in vitro cells and in vivo mouse model. Hence, [[SPAG9]] may be a potential novel target for therapeutic use in TNBC treatment.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Animals
* Apoptosis
* Blotting, Western
* Cell Proliferation
* Fluorescent Antibody Technique, Indirect
* Humans
* Immunoenzyme Techniques
* Membrane Potential, Mitochondrial
* Mice
* RNA, Small Interfering
* Triple Negative Breast Neoplasms
* Tumor Cells, Cultured
|keywords=* Apoptosis
* Cell growth
* Cellular motility
* SPAG9
* Senescence
* Triple-negative breast cancer
* Tumor growth
|full-text-url=https://sci-hub.do/10.1007/s13277-016-5240-6
}}
{{medline-entry
|title=Methylation of CpG sites in [[BCL2]] major breakpoint region and the increase of [[BCL2]]/JH translocation with aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26335622
|abstract=The [[BCL2]] breakage mechanism has been shown to be highly dependent on DNA methylation at the major breakpoint region (MBR) CpG sites. We recently described an increased frequency of [[BCL2]]/ JH translocation with aging. It is known that methylation levels change with aging. The present study aimed to determine whether methylation alterations at CpG sites of [[BCL2]] MBR were the cause of increased breakages with aging. We analyzed the methylation levels of three CpG sites on the region by pyrosequencing and studied if methylation levels and/or polymorphisms affecting CpG sites were associated with an increase of translocations. We observed that although the methylation levels of MBR CpG sites were higher in individuals with [[BCL2]]/JH translocation, in contrast to our expectations, these levels decreased with the age. Moreover, we show that polymorphisms at those CpG sites leading to absence of methylation seem to be a protective factor for the apparition of translocations. 
|mesh-terms=* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Aging
* Child
* Child, Preschool
* CpG Islands
* DNA Methylation
* Female
* Gene Frequency
* Humans
* Infant
* Male
* Middle Aged
* Polymerase Chain Reaction
* Polymorphism, Genetic
* Proto-Oncogene Proteins c-bcl-2
* Reference Values
* Retrospective Studies
* Translocation, Genetic
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005837
}}
{{medline-entry
|title=Combined inhibitory effects of low temperature and N-acetyl-l-cysteine on the postovulatory aging of mouse oocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25801325
|abstract=The postovulatory aging of oocytes eventually affects the development of oocytes and embryos. Oxidative stress is known to accelerate the onset of apoptosis in oocytes and influence their capacity for fertilisation. This study aimed to reveal the roles of temperature and the antioxidant N-acetyl-l-cysteine in preventing the aging of postovulatory mouse oocytes. First, newly ovulated mouse oocytes were cultured at various temperature and time combinations in HCZB medium with varying concentrations of N-acetyl-l-cysteine to assess signs of aging and developmental potential. When cultured in HCZB with 300 μM N-acetyl-l-cysteine at different temperature and incubation time combinations (namely 25°C for 12 h, 15°C for 24 h and 5°C for 12 h), the increase in the susceptibility of oocytes to activating stimuli was efficiently prevented, and the developmental potential was maintained following Sr2  activation or in vitro fertilisation. After incubation at either 15°C for 36 h or 5°C for 24 h, oocytes that had decreased blastocyst rates displayed unrecoverable abnormal cortical granule distribution together with decreased [[BCL2]] levels, total glutathione concentrations and glutathione/glutathione disulphide (GSH/GSSG) ratios. In conclusion, postovulatory oocyte aging could be effectively inhibited by appropriate N-acetyl-l-cysteine addition at low temperatures. In addition, a simple method for the temporary culture of mature oocytes was established. 
|mesh-terms=* Acetylcysteine
* Animals
* Blastocyst
* Cells, Cultured
* Cellular Senescence
* Cold Temperature
* Female
* Fertilization in Vitro
* Free Radical Scavengers
* Glutathione
* Glutathione Disulfide
* Male
* Mice
* Microscopy, Confocal
* Oocytes
* Ovulation
* Proto-Oncogene Proteins c-bcl-2
* Time Factors
|keywords=* Aging
* Antioxidant
* Low temperature
* N-acetyl-l-cysteine
* Oxidative stress
|full-text-url=https://sci-hub.do/10.1017/S0967199415000039
}}
{{medline-entry
|title=Methylation of the nonhomologous end joining repair pathway genes does not explain the increase of translocations with aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25399073
|abstract=Chromosome translocations are especially frequent in human lymphomas and leukemias but are insufficient to drive carcinogenesis. Indeed, several of the so-called tumor specific translocations have been detected in peripheral blood of healthy individuals, finding a higher frequency of some of them with aging. The inappropriate repair of DNA double strand breaks by the nonhomologous end joining (NHEJ) pathway is one of the reasons for a translocation to occur. Moreover, fidelity of this pathway has been shown to decline with age. Although the mechanism underlying this inefficacy is unknown, other repair pathways are inactivated by methylation with aging. In this study, we analyzed the implication of NHEJ genes methylation in the increase of translocations with the age. To this aim, we determined the relationship between translocations and aging in 565 Spanish healthy individuals and correlated these data with the methylation status of 11 NHEJ genes. We found higher frequency of [[BCL2]]-JH and BCR-ABL (major) translocations with aging. In addition, we detected that two NHEJ genes (LIG4 and XRCC6) presented age-dependent promoter methylation changes. However, we did not observe a correlation between the increase of translocations and methylation, indicating that other molecular mechanisms are involved in the loss of NHEJ fidelity with aging. 
|mesh-terms=* Adolescent
* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Chi-Square Distribution
* Child
* Child, Preschool
* Cohort Studies
* Confidence Intervals
* DNA Breaks, Double-Stranded
* DNA End-Joining Repair
* DNA Methylation
* Female
* Humans
* Infant
* Male
* Middle Aged
* Odds Ratio
* Polymerase Chain Reaction
* Sensitivity and Specificity
* Signal Transduction
* Translocation, Genetic
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233023
}}
{{medline-entry
|title=Age-associated changes in gene expression of goat oocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23746875
|abstract=Oocyte aging severely decreases the quality of oocytes, which hampers fertilization and subsequent embryo development. In the present study, age-dependent molecular changes in goat oocytes were investigated. First, the quality of goat oocytes with various in vitro culture times (24, 30, 36, 48, and 60 hours) was evaluated on the basis of developmental rates of parthenogenetically activated embryos and apoptosis of cumulus cells (CCs). Second, relative gene expression of six genes (mitochondrial genes: [[PGC]]-1α and NRF-1; epigenetic modification genes: [[SNRPN]] and [[HAT1]]; mitotic spindle checkpoint protein: [[SMAD2]]; and hyaluronan synthase gene: [[HAS3]]) were analyzed during oocyte aging. Third, we further studied the changes of seven genes ([[PGC]]-1α and NRF-1; apoptotic-related genes: [[BAX]] and [[BCL2]]; hyaluronan synthase gene: [[HAS2]]; metabolism-related gene: STAR; and superoxide dismutase gene: [[SOD1]]) in CCs during oocyte aging. In these studies, the blastocyst rate gradually decreased and the number of apoptotic cells significantly increased as the culture time increased (P < 0.05). Moreover, relative gene expressions of [[PGC]]-1α, NRF-1 and [[SMAD2]] significantly decreased from 24 to 36 hours (P < 0.05), whereas the levels of [[HAT1]] and [[HAS3]] slowly increased as culture was prolonged. Furthermore, the levels of [[PGC]]-1α, [[BCL2]], [[HAS2]] and [[SOD1]] quickly reduced, and [[BAX]] significantly increased from 24 to 36 hours in aged CCs (P < 0.05). In conclusion, goat oocytes started to age at 30 hours in vitro culture, and gene expression patterns of oocytes and CCs significantly changed as the oocytes aged. Gene expression pattern changes in CCs may provide a convenient and effective way to detect oocyte aging without compromising oocyte integrity.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Cells, Cultured
* Cellular Senescence
* Female
* Gene Expression
* Goats
* Oocytes
* Parthenogenesis
* Time Factors
|keywords=* Aging
* Apoptosis
* Cumulus cells
* Gene expression
* Goat
* Oocytes
|full-text-url=https://sci-hub.do/10.1016/j.theriogenology.2013.04.019
}}
{{medline-entry
|title=[Association of polymorphic markers of [[CASP8]], [[BCL2]] and [[BAX]] genes with aging and longevity].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23289213
|abstract=We performed the analysis of genotype frequency dynamics of [[CASP8]], [[BCL2]] and [[BAX]] genes polymorphic markers between 21 and 109 years in the group of Ethnic Tatars from Bashkortostan. Genotyping was carried out using PCR and PCR-RFLP. We found associations between age and -652(6N)I/D polymorphism of [[CASP8]] gene (rs3834129), 140016C>T polymorphism of [[BCL2]] gene (rs12454712) and 919A>G polymorphism of [[BAX]] gene (rs1805419). An increase of genotype frequency of [[BCL2]]*C/*C and decrease of genotype frequency of [[CASP8]]*I/*D was observed in male of senile age; and also decrease of genotype frequency of [[BAX]]*G/*G among long-livers. In female of longevity age, the number of [[CASP8]]*I/*D, [[BCL2]]*T/*T and [[BAX]]*A/*A genotype carriers was higher and number of [[CASP8]]*DI/*D, [[BCL2]]*C/*C, [[BAX]]*A/*G and [[BAX]] *G/*G genotype carriers was reduced.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Alleles
* Bashkiria
* Caspase 8
* Female
* Gene Frequency
* Genes, bcl-2
* Genotype
* Humans
* Longevity
* Male
* Middle Aged
* Polymerase Chain Reaction
* Polymorphism, Genetic
* Young Adult
* bcl-2-Associated X Protein


}}
{{medline-entry
|title=The apoptotic transcriptome of the human MII oocyte: characterization and age-related changes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23179180
|abstract=Fully competent oocytes represent the final outcome of a highly selective process. The decline of oocyte competence with ageing, coupled to quantitative decrease of ovarian follicles has been well established; on the contrary, its molecular bases are still poorly understood. Through quantitative high throughput PCR, we investigated the role of apoptotic machinery (AM) in this process. To this aim, we determined AM transcriptome in mature MII oocyte pools from women aged more than 38 years (cohort A), and compared to women aged up to 35 years (cohort B). Subsequently, 10 representative AM genes were selected and analyzed in 33 single oocytes (15 from cohort A and 18 from cohort B). These investigations led us to identify: (1) the significant upregulation of proapoptotic genes such us [[CD40]], [[TNFRSF10A]], [[TNFRSF21]] and the downregulation of antiapoptotic genes such as [[BCL2]] and [[CFLAR]] in cohort A respect to cohort B; (2) AM transcripts that have not previously been reported in human oocytes (BAG3, [[CD40]], [[CFLAR]], [[TNFRSF21]], [[TRAF2]], TRAF3). Our results demonstrated that during maturation the oocytes from older women selectively accumulate mRNAs that are able to trigger the extrinsic apoptotic pathway. These data contribute to clarify the molecular mechanisms of AM involvement in the natural selection strategy of removing low quality oocytes and preventing unfit or poorly fit embryos.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Adult
* Aging
* Apoptosis
* Apoptosis Regulatory Proteins
* CASP8 and FADD-Like Apoptosis Regulating Protein
* CD40 Antigens
* Down-Regulation
* Female
* Humans
* Maternal Age
* Oocytes
* Proto-Oncogene Proteins c-bcl-2
* Receptors, TNF-Related Apoptosis-Inducing Ligand
* Receptors, Tumor Necrosis Factor
* Transcriptome
* Up-Regulation

|full-text-url=https://sci-hub.do/10.1007/s10495-012-0783-5
}}
{{medline-entry
|title=Validation of the aging hen (Gallus gallus domesticus) as an animal model for uterine leiomyomas.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22811571
|abstract=Uterine leiomyomas, or fibroids, are the most frequent gynecological tumors in premenopausal women with as many as 65% of women becoming clinically symptomatic. Uterine fibroids are benign myometrial tumors that produce large quantities of extracellular matrix proteins. Despite its high morbidity, the molecular basis underlying the development of uterine leiomyomas is not well understood. Domestic hens of Gallus gallus domesticus develop oviductal leiomyomas similar to those found in humans. We investigated the natural history of chicken leiomyomas, in vivo expression of protein biomarkers, and in vitro expression of ovarian steroid receptors. Based on the analysis of 263 hens, tumor prevalence, tumor number per hen, and tumor size increased as the hens aged. Immunohistochemistry for alpha-smooth muscle actin (SMA) and desmin confirmed the smooth muscle phenotype of the chicken leiomyomas. Intense collagen expression was detected in these oviductal leiomyomas by Mason's trichrome, and the tumors also showed increased expression of [[TGFB3]] and collagen type I mRNAs. Consistent with human leiomyomas, chicken fibroids displayed increased [[BCL2]] and estrogen (E) and progesterone (P) receptor expression. Chicken leiomyomas were dissociated for in vitro culture. Cells from explants were positive for SMA, desmin, and E and P receptors until the fourth passage. These cells also displayed a response similar to human cells when challenged with halofuginone, an antifibrotic agent. Our findings indicate that the chicken is an excellent complementary model for studies involving the pathophysiology of human uterine leiomyomas.
|mesh-terms=* Aging
* Animals
* Antineoplastic Agents
* Chickens
* Disease Models, Animal
* Drug Evaluation, Preclinical
* Female
* Humans
* Leiomyoma
* Oviducts
* Piperidines
* Poultry Diseases
* Prevalence
* Primary Cell Culture
* Quinazolinones
* Tumor Cells, Cultured
* Uterine Neoplasms

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434995
}}
{{medline-entry
|title=Transcriptomic biomarkers of the response of hospitalized geriatric patients admitted with heart failure. Comparison to hospitalized geriatric patients with infectious diseases or hip fracture.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/21335025
|abstract=The abundance of a preselection of transcripts involved in inflammation, immunosenescence and stress response was compared between PBMC of healthy aged donors and aged patients in acute phase of heart failure and at recovery. This study identified 22 transcripts differentially abundant in acute phase of heart failure versus healthy aged subjects. Transcripts involved in inflammation and oxidative stress were more abundant. Those associated with T-cell functions were less abundant. The results were compared to two other major acute geriatric issues: infectious diseases and hip fracture. In acute phase, compared to healthy aged subjects, the abundance of 15/22 transcripts was also altered in both geriatric infectious diseases and hip fracture. Many variations had not vanished at the recovery phase. The abundance of [[CD28]], [[CD69]], [[LCK]], [[HMOX1]], [[TNFRSF1A]] transcripts, known to be altered in healthy aged versus healthy young subjects, was further affected in acute phase of the three geriatric diseases considered. The transcript levels of [[BCL2]], [[CASP8]], [[CCL5]], [[[[DDIT3]]]], [[EGR3]], [[IL10RB]], [[IL1R2]], [[SERPINB2]] and [[TIMP1]] were affected in all three pathological conditions compared to healthy aged, but not versus healthy young subjects. In conclusion, this work provides critical targets for therapeutic research on geriatric heart failure, infectious diseases and hip fracture.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Biomarkers
* Communicable Diseases
* Female
* Heart Failure
* Hip Fractures
* Hospitalization
* Humans
* Male
* Neutrophils
* Transcription, Genetic

|full-text-url=https://sci-hub.do/10.1016/j.mad.2011.02.002
}}
{{medline-entry
|title=Age-related transcription levels of KU70, [[MGST1]] and [[BIK]] in CD34  hematopoietic stem and progenitor cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/17714764
|abstract=Despite the known longevity of human hematopoietic stem and progenitor cells (HSC), numerous functional impairments of these cells can be observed in an age-dependent manner. However, the molecular alterations associated with aging of HSC are largely unknown. Therefore, we scrutinized gene expression patterns of HSC from newborn, young and old healthy donors. CD34  HSC were isolated via immuno-magnetic separation and evaluated by FACS analysis. We performed cDNA macroarray analyses on a first set of CD34  samples (n=13). We found the genes encoding KU-antigen 70 kD (KU70), microsomal glutathione S-transferase 1 ([[MGST1]]) and [[BCL2]]-interacting killer ([[BIK]]) to possess age-related mRNA expression levels. KU70 is a DNA repair gene and part of the DNA-dependent protein kinase (DNA-PK) complex. Its expression was negatively correlated with donor age showing highest expression levels in newborn, 2.6-fold lower levels in young and 6.3-fold lower levels in old donors. The transcription levels of [[MGST1]], a gene protecting against oxidative stress, progressively increased with age. Expression was lowest in newborn, 2.6-fold higher in young and 4.3-fold higher in old donors. [[BIK]] is a proapoptotic gene and its expression was positively correlated with donor age: lowest in newborn, 1.8-fold higher in young and 4.1-fold higher in old donors. These findings were confirmed with an independent, second set of CD34  samples (n=16) by means of quantitative real-time RT-PCR. Elucidation of age-dependent molecular alterations in healthy HSC facilitate a better understanding of functional impairments in hematopoiesis and may become valuable for anti-aging drug development and the emerging field of regenerative medicine.
|mesh-terms=* Adult
* Adult Stem Cells
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Antigens, CD34
* Antigens, Nuclear
* Apoptosis Regulatory Proteins
* Cellular Senescence
* Cluster Analysis
* DNA-Binding Proteins
* Fetal Blood
* Gene Expression Profiling
* Glutathione Transferase
* Hematopoietic Stem Cells
* Humans
* Infant, Newborn
* Ku Autoantigen
* Membrane Proteins
* Middle Aged
* Mitochondrial Proteins
* Oligonucleotide Array Sequence Analysis
* Polymerase Chain Reaction
* RNA, Messenger
* Reproducibility of Results
* Transcription, Genetic

|full-text-url=https://sci-hub.do/10.1016/j.mad.2007.06.008
}}
{{medline-entry
|title=Degeneration of human oncogenes and mitochondrial genes occurs in cells that exhibit age-related pathology.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/8706795
|abstract=The development of a new class of assays to determine in vivo mutation frequencies has provided new perspectives on the timing, location, and distribution of somatic mutagenesis in mitochondrial genes and in oncogenes of the aging human body. This descriptive information has led to the inference of new models for age-related pathophysiology and oncogenesis. Mutations of mitochondrial genes rise rapidly with age to frequencies a thousand-fold higher than those of nuclear genes. Genotypic selection analysis has revealed that mitochondrial mutations accumulate predominantly in nonmitotic cells whose age-dependent loss is associated with pathology. Random mitochondrial mutation is most likely to inactivate Complex I, deficiency of which induces mitochondrial superoxide formation and cell death. Genotypic selection of oncogenic mutations at the [[BCL2]] and p53 loci has revealed that the cell specificity of oncogenic mutations in persons without cancer correlates well with sites of tumor origin, indicating that cells bearing such mutations are the likely precursors of future tumors. Quantitative variation in human [[BCL2]] mutation frequency is extensive, and [[BCL2]] mutation frequency rises with age, concordant with increased risk for lymphoma. The clonality and persistence of [[BCL2]] mutations suggests two specific testable mechanisms of lymphomagenesis. [[BCL2]] mutation frequency rises in persons exposed to cigarette smoke, and more p53 mutations occur in skin exposed to sunlight than in unexposed skin. Thus, in addition to their likely relevance to future cancer risk, the dose-response relationship between exposure and oncogenic mutations indicates promise for their future use as in vivo biodosimeters of human exposure to carcinogens.
|mesh-terms=* Aging
* DNA, Mitochondrial
* Genotype
* Humans
* Models, Biological
* Mutation
* Oncogenes
* Proto-Oncogene Proteins
* Proto-Oncogene Proteins c-bcl-2

|full-text-url=https://sci-hub.do/10.1016/0531-5565(95)00021-6
}}
{{medline-entry
|title=Genotypic selection of mitochondrial and oncogenic mutations in human tissue suggests mechanisms of age-related pathophysiology.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/7565870
|abstract=The invention of the polymerase chain reaction (PCR) has facilitated the development of a new class of assays to quantify human somatic mutations in vivo, based on genotypic selection of mutants at the DNA level rather than phenotypic selection of mutants at the cell level. Use of these assays has provided new perspectives on the timing, location and distribution of somatic mutagenesis in mitochondrial genes and in oncogenes of the aging human body. This descriptive information has led to the inference and development of new models for age-related pathophysiology and oncogenesis. Mutations of mitochondrial genes rise rapidly with age to frequencies a thousand fold higher than those of nuclear genes. Genotypic selection analysis has revealed that mitochondrial mutations accumulate predominantly in non-mitotic cells whose age-dependent loss is associated with pathology. Random mitochondrial mutation is most likely to inactive Complex I, a deficiency of which induces mitochondrial superoxide formation and cell death. Genotypic selection of oncogenic mutations at the [[BCL2]] and p53 loci has revealed that the cell specificity of oncogenic mutations in persons without cancer correlates well with sites of tumor origin, indicating that cells bearing such mutations are the likely precursors of future tumors. Quantitative variation in human [[BCL2]] mutation frequency is extensive, and [[BCL2]] mutation frequency rises with age, concordant with increased risk for lymphoma. The clonality and persistence of [[BCL2]] mutations suggests two specific testable mechanisms of lymphomagenesis. [[BCL2]] mutation frequency rises in persons exposed to cigarette smoke, and more p53 mutations occur in skin exposed to sunlight than in unexposed skin. Thus, in addition to their likely relevance to future cancer risk, the dose-response relationship between exposure and oncogenic mutations indicates promise for their future use as in vivo biodosimeters of human exposure to carcinogens.
|mesh-terms=* Aging
* Apoptosis
* Brain
* Chromosomes, Human
* DNA, Mitochondrial
* Genotype
* Humans
* Mutation
* Neoplasms
* Oncogenes
* Parkinson Disease

|full-text-url=https://sci-hub.do/10.1016/0921-8734(95)00020-7
}}