Редактирование: HSF1

Heat shock factor protein 1 (HSF 1) (Heat shock transcription factor 1) (HSTF 1) [HSTF1]

==Publications==

{{medline-entry
|title=Cellular proteostasis decline in human senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33257563
|abstract=Proteostasis collapse, the diminished ability to maintain protein homeostasis, has been established as a hallmark of nematode aging. However, whether proteostasis collapse occurs in humans has remained unclear. Here, we demonstrate that proteostasis decline is intrinsic to human senescence. Using transcriptome-wide characterization of gene expression, splicing, and translation, we found a significant deterioration in the transcriptional activation of the heat shock response in stressed senescent cells. Furthermore, phosphorylated [[HSF1]] nuclear localization and distribution were impaired in senescence. Interestingly, alternative splicing regulation was also dampened. Surprisingly, we found a decoupling between different unfolded protein response (UPR) branches in stressed senescent cells. While young cells initiated UPR-related translational and transcriptional regulatory responses, senescent cells showed enhanced translational regulation and endoplasmic reticulum (ER) stress sensing; however, they were unable to trigger UPR-related transcriptional responses. This was accompanied by diminished [[ATF6]] nuclear localization in stressed senescent cells. Finally, we found that proteasome function was impaired following heat stress in senescent cells, and did not recover upon return to normal temperature. Together, our data unraveled a deterioration in the ability to mount dynamic stress transcriptional programs upon human senescence with broad implications on proteostasis control and connected proteostasis decline to human aging.

|keywords=* UPR
* chaperones
* heat shock response
* protein homeostasis
* senescence
|full-text-url=https://sci-hub.do/10.1073/pnas.2018138117
}}
{{medline-entry
|title=A Mitochondrial Stress-Specific Form of [[HSF1]] Protects against Age-Related Proteostasis Collapse.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32735771
|abstract=The loss of protein homeostasis (proteostasis) is a primary driver of age-related tissue dysfunction. Recent studies have revealed that the failure of proteostasis with age is triggered by developmental and reproductive cues that repress the activity of proteostasis-related pathways in early adulthood. In Caenorhabditis elegans, reduced mitochondrial electron transport chain (ETC) function during development can override signals that promote proteostasis collapse in aged tissues. However, it is unclear precisely how these beneficial effects are mediated. Here, we reveal that in response to ETC impairment, the PP2A complex generates a dephosphorylated, mitochondrial stress-specific variant of the transcription factor HSF-1. This results in the selective induction of small heat shock proteins in adulthood, thereby protecting against age-related proteostasis collapse. We propose that mitochondrial signals early in life can protect the aging cytosolic proteome by tailoring HSF-1 activity to preferentially drive the expression of non-ATP-dependent chaperones.

|keywords=* HSF1
* PP2A
* aging
* mitochondria
* molecular chaperones
* protein aggregation
* proteostasis
* stress responses
|full-text-url=https://sci-hub.do/10.1016/j.devcel.2020.06.038
}}
{{medline-entry
|title=Heat shock factor 1-mediated transcription activation of Omi/HtrA2 induces myocardial mitochondrial apoptosis in the aging heart.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31627188
|abstract=Increased cardiac apoptosis is a hallmark of the elderly, which in turn increases the risk for developing cardiac disease. The overexpression of Omi/HtrA2 mRNA and protein contributes to apoptosis in the aged heart. Heat shock factor 1 ([[HSF1]]) is a transcription factor that binds to the promoter of Omi/HtrA2 in the aging myocardium. However, whether [[HSF1]] participates in cardiomyocyte apoptosis via transcriptional regulation of Omi/HtrA2 remains unclear. The present study was designed to investigate whether [[HSF1]] plays a role in Omi/HtrA2 transcriptional regulation and myocardial apoptosis. Assessment of the hearts of mice of different ages was performed, which indicated a decrease in cardiac function reserve and an increase in mitochondrial apoptosis. Omi/HtrA2 overexpression in the elderly was negatively correlated with left ventricular function after exercise overload and positively correlated with myocardial Caspase-9 apoptosis. Chromatin immunoprecipitation (ChIP) of aging hearts and plasmid transfection/RNA interference of H9C2 cells revealed that enhancement of [[HSF1]] expression promotes Omi/HtrA2 expression by inducing the promoter activity of Omi/HtrA2 while also increasing mitochondrial apoptosis by upregulating Omi/HtrA2 expression. [[HSF1]] acts as a transcriptional factor that induces Omi/HtrA2 expression and Caspase-9 apoptosis in aged cardiomyocytes, while also decreasing cardiac function reserve.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Heat Shock Transcription Factors
* High-Temperature Requirement A Serine Peptidase 2
* Male
* Mice
* Mice, Inbred C57BL
* Mitochondria, Heart
* Myocytes, Cardiac
* NIH 3T3 Cells
* Transcriptional Activation
* Up-Regulation
|keywords=* Omi/HtrA2
* age-related pathology
* cardiovascular
* mitochondria
* transcriptional regulation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834417
}}
{{medline-entry
|title=Multifactorial Attenuation of the Murine Heat Shock Response With Age.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31612204
|abstract=Age-dependent perturbation of the cellular stress response affects proteostasis and other key functions relevant to cellular action and survival. Central to age-related changes in the stress response is loss of heat shock factor 1 ([[HSF1]])-DNA binding and transactivation properties. This report elucidates how age alters different checkpoints of [[HSF1]] activation related to posttranslational modification and protein interactions. When comparing liver extracts from middle aged (12 M) and old (24 M) mice, significant differences are found in [[HSF1]] phosphorylation and acetylation. [[HSF1]] protein levels and messenger RNA decline with age, but its protein levels are stress-inducible and exempt from age-dependent changes. This surprising adaptive change in the stress response has additional implications for aging and chronic physiological stress that might explain an age-dependent dichotomy of [[HSF1]] protein levels that are low in neurodegeneration and elevated in cancer.

|keywords=* Aging
* HSF1
* Stress
|full-text-url=https://sci-hub.do/10.1093/gerona/glz204
}}
{{medline-entry
|title=Nutrition and water temperature regulate the expression of heat-shock proteins in golden pompano larvae (Trachinotus ovata, Limmaeus 1758).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30397841
|abstract=Understanding fish larval development is of a great interest for aquaculture production efficiency. Identifying possible indicators of fish larvae stress could improve the production and limit the mortality rate that larval stage is subjected to. Heat-shock proteins (HSPs) and heat-shock factors (HSFs) are well known as indicators of response to many kinds of stressor (e.g., environmental, morphological, or pathological changes). In this study, golden pompano larvae were raised at different temperatures (23 °C, 26 °C, and 29 °C), as well as three different diets (Artemia nauplii unenriched, Artemia nauplii enriched with Nannochloropsis sp., and Artemia nauplii enriched with Algamac 3080), and the expression of HSP60, HSP70, [[HSF1]], HSP2, and GRP94 were monitored. While stress genes were widely expressed in the larval tissues, HSP60 and HSP70 were principally from the gills and heart; [[HSF1]] principally from the muscle, brain, and heart; and GRP94 principally from the head kidney and spleen. Golden pompano larvae were found to be more sensitive to thermal changes at later larval stage, and 29 °C was showed to likely be the best condition for golden pompano larval development. Nannochloropsis sp.-enriched Artemia nauplii treatment was found to be the most appropriate feed type with moderate relative expressions of HSP60, HSP70, [[HSF1]], [[HSF2]], and GRP94.
|mesh-terms=* Adaptation, Physiological
* Aging
* Animal Feed
* Animal Nutritional Physiological Phenomena
* Animals
* Cloning, Molecular
* Diet
* Fishes
* Gene Expression Regulation
* Heat-Shock Proteins
* Larva
* Temperature
|keywords=* Fish larvae
* Gene expression
* Heat-shock protein
* Nutrition
* Temperature
|full-text-url=https://sci-hub.do/10.1007/s10695-018-0578-x
}}
{{medline-entry
|title=CCAR-1 is a negative regulator of the heat-shock response in Caenorhabditis elegans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30003683
|abstract=Defects in protein quality control during aging are central to many human diseases, and strategies are needed to better understand mechanisms of controlling the quality of the proteome. The heat-shock response (HSR) is a conserved survival mechanism mediated by the transcription factor [[HSF1]] which functions to maintain proteostasis. In mammalian cells, [[HSF1]] is regulated by a variety of factors including the prolongevity factor [[SIRT1]]. [[SIRT1]] promotes the DNA-bound state of [[HSF1]] through deacetylation of the DNA-binding domain of [[HSF1]], thereby enhancing the HSR. [[SIRT1]] is also regulated by various factors, including negative regulation by the cell-cycle and apoptosis regulator [[CCAR2]]. [[CCAR2]] negatively regulates the HSR, possibly through its inhibitory interaction with [[SIRT1]]. We were interested in studying conservation of the [[SIRT1]]/[[CCAR2]] regulatory interaction in Caenorhabditis elegans, and in utilizing this model organism to observe the effects of modulating sirtuin activity on the HSR, longevity, and proteostasis. The HSR is highly conserved in C. elegans and is mediated by the [[HSF1]] homolog, HSF-1. We have uncovered that negative regulation of the HSR by [[CCAR2]] is conserved in C. elegans and is mediated by the [[CCAR2]] ortholog, CCAR-1. This negative regulation requires the [[SIRT1]] homolog SIR-2.1. In addition, knockdown of CCAR-1 via ccar-1 RNAi works through SIR-2.1 to enhance stress resistance, motility, longevity, and proteostasis. This work therefore highlights the benefits of enhancing sirtuin activity to promote the HSR at the level of the whole organism.
|mesh-terms=* Acetylation
* Animals
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Disease Models, Animal
* Heat-Shock Response
* Huntington Disease
* Longevity
* Peptides
* Promoter Regions, Genetic
* Protein Binding
* RNA Interference
* RNA, Messenger
* Sirtuins
* Stress, Physiological
* Temperature
* Transcription Factors
|keywords=*  C. elegans 
* CCAR-1
* HSF-1
* SIR-2.1
* heat-shock response
* longevity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156500
}}
{{medline-entry
|title=Modulation of Heat Shock Factor 1 Activity through Silencing of Ser303/Ser307 Phosphorylation Supports a Metabolic Program Leading to Age-Related Obesity and Insulin Resistance.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29941492
|abstract=Activation of the adaptive response to cellular stress orchestrated by heat shock factor 1 ([[HSF1]]), which is an evolutionarily conserved transcriptional regulator of chaperone response and cellular bioenergetics in diverse model systems, is a central feature of organismal defense from environmental and cellular stress. [[HSF1]] activity, induced by proteostatic, metabolic, and growth factor signals, is regulated by posttranscriptional modifications, yet the mechanisms that regulate [[HSF1]] and particularly the functional significance of these modifications in modulating its biological activity [i]in vivo[/i] remain unknown. [[HSF1]] phosphorylation at both Ser303 (S303) and Ser307 (S307) has been shown to repress [[HSF1]] transcriptional activity under normal physiological growth conditions. To determine the biological relevance of these [[HSF1]] phosphorylation events, we generated a knock-in mouse model in which S303 and S307 were replaced with alanine ([[HSF1]] ). Our results confirmed that loss of phosphorylation in [[HSF1]]  cells and tissues increases protein stability but also markedly sensitizes [[HSF1]] activation under normal and heat- or nutrient-induced stress conditions. Interestingly, the enhanced [[HSF1]] activation in [[HSF1]]  mice activates a supportive metabolic program that aggravates the development of age-dependent obesity, fatty liver diseases, and insulin resistance. Thus, these findings highlight the importance of a posttranslational mechanism (through phosphorylation at S303 and S307 sites) of regulation of the [[HSF1]]-mediated transcriptional program that moderates the severity of nutrient-induced metabolic diseases.
|mesh-terms=* Aging
* Amino Acid Substitution
* Animals
* Cells, Cultured
* Disease Models, Animal
* Female
* Gene Knock-In Techniques
* Heat Shock Transcription Factors
* Heat-Shock Response
* Humans
* Insulin Resistance
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Obesity
* Phosphorylation
* Protein Stability
* Recombinant Proteins
* Serine
|keywords=* insulin resistance
* knock-in mouse model
* obesity
* phosphorylation of HSF1 (Ser303A/Ser307A)
* posttranslational HSF1 regulation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113599
}}
{{medline-entry
|title=The longevity SNP rs2802292 uncovered: [[HSF1]] activates stress-dependent expression of [[FOXO3]] through an intronic enhancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29733381
|abstract=The HSF and FOXO families of transcription factors play evolutionarily conserved roles in stress resistance and lifespan. In humans, the rs2802292 G-allele at [[FOXO3]] locus has been associated with longevity in all human populations tested; moreover, its copy number correlated with reduced frequency of age-related diseases in centenarians. At the molecular level, the intronic rs2802292 G-allele correlated with increased expression of [[FOXO3]], suggesting that [[FOXO3]] intron 2 may represent a regulatory region. Here we show that the 90-bp sequence around the intronic single nucleotide polymorphism rs2802292 has enhancer functions, and that the rs2802292 G-allele creates a novel HSE binding site for [[HSF1]], which induces [[FOXO3]] expression in response to diverse stress stimuli. At the molecular level, [[HSF1]] mediates the occurrence of a promoter-enhancer interaction at [[FOXO3]] locus involving the 5'UTR and the rs2802292 region. These data were confirmed in various cellular models including human [[HAP1]] isogenic cell lines (G/T). Our functional studies highlighted the importance of the [[HSF1]]-[[FOXO3]]-SOD2/CAT/GADD45A cascade in cellular stress response and survival by promoting ROS detoxification, redox balance and DNA repair. Our findings suggest the existence of an [[HSF1]]-[[FOXO3]] axis in human cells that could be involved in stress response pathways functionally regulating lifespan and disease susceptibility.
|mesh-terms=* 5' Untranslated Regions
* Alleles
* Binding Sites
* Cell Line
* Cell Survival
* Cells, Cultured
* Enhancer Elements, Genetic
* Forkhead Box Protein O3
* Heat Shock Transcription Factors
* Humans
* Introns
* Longevity
* Polymorphism, Single Nucleotide
* Promoter Regions, Genetic
* Stress, Physiological
* Transcriptional Activation

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009585
}}
{{medline-entry
|title=Acute [[HSF1]] depletion induces cellular senescence through the [[MDM2]]-p53-p21 pathway in human diploid fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29632240
|abstract=Heat shock transcription factor 1 ([[HSF1]]) regulates the expression of a wide array of genes, controls the expression of heat shock proteins (HSPs) as well as cell growth. Although acute depletion of [[HSF1]] induces cellular senescence, the underlying mechanisms are poorly understood. Here, we report that [[HSF1]] depletion-induced senescence (HDIS) of human diploid fibroblasts (HDFs) was independent of HSP-mediated proteostasis but dependent on activation of the p53-p21 pathway, partly because of the increased expression of dehydrogenase/reductase 2 ([[DHRS2]]), a putative [[MDM2]] inhibitor. We observed that HDIS occurred without decreased levels of major HSPs or increased proteotoxic stress in HDFs. Additionally, VER155008, an inhibitor of HSP70 family proteins, increased proteotoxicity and suppressed cell growth but failed to induce senescence. Importantly, we found that activation of the p53-p21 pathway resulting from reduced [[MDM2]]-dependent p53 degradation was required for HDIS. Furthermore, we provide evidence that increased [[DHRS2]] expression contributes to p53 stabilization and HDIS. Collectively, our observations uncovered a molecular pathway in which [[HSF1]] depletion-induced [[DHRS2]] expression leads to activation of the [[MDM2]]-p53-p21 pathway required for HDIS.
|mesh-terms=* Cell Line
* Cell Proliferation
* Cellular Senescence
* Diploidy
* Fibroblasts
* HEK293 Cells
* HSP70 Heat-Shock Proteins
* Heat Shock Transcription Factors
* Humans
* Proto-Oncogene Proteins c-mdm2
* Tumor Suppressor Protein p53
|keywords=* Cellular senescence
* DHRS2
* HSF1
* MDM2
* p53 (TP53)
|full-text-url=https://sci-hub.do/10.1242/jcs.210724
}}
{{medline-entry
|title=Azadiradione Restores Protein Quality Control and Ameliorates the Disease Pathogenesis in a Mouse Model of Huntington's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29294248
|abstract=Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by expansion of CAG repeats in the coding area of huntingtin gene. In the HD brain, mutant huntingtin protein goes through proteolysis, and its amino-terminal portion consisting of polyglutamine repeats accumulate as inclusions that result in progressive impairment of cellular protein quality control system. Here, we demonstrate that partial rescue of the defective protein quality control in HD model mouse by azadiradione (a bioactive limonoids found in the seed of Azadirachta indica) could potentially improve the disease pathology. Prolonged treatment of azadiradione to HD mice significantly improved the progressive deterioration in body weight, motor functioning along with extension of lifespan. Azadiradione-treated HD mice brain also exhibited considerable decrease in mutant huntingtin aggregates load and improvement of striatal pathology in comparison with age-matched saline-treated HD controls. Biochemical analysis further revealed upregulation and activation of not only [[HSF1]] (master regulator of protein folding) but also Ube3a (an ubiquitin ligase involved in the clearance of mutant huntingtin) in azadiradione-treated mice. Our results indicate that azadiradione-mediated enhanced folding and clearance of mutant huntingtin might underlie improved disease pathology in HD mice and suggests that it could be a potential therapeutic molecule to delay the progression of HD.
|mesh-terms=* Animals
* Atrophy
* Disease Models, Animal
* Disease Progression
* Dopamine and cAMP-Regulated Phosphoprotein 32
* Heat Shock Transcription Factors
* Huntingtin Protein
* Huntington Disease
* Limonins
* Longevity
* Mice, Transgenic
* Models, Biological
* Motor Activity
* Mutant Proteins
* Neostriatum
* Protein Aggregates
* Quality Control
* Ubiquitin-Protein Ligases
* Up-Regulation
|keywords=* Azadiradione
* HSF1
* Huntington’s disease
* Proteostasis
* Ube3a
|full-text-url=https://sci-hub.do/10.1007/s12035-017-0853-3
}}
{{medline-entry
|title=Structural and Functional Recovery of Sensory Cilia in C. elegans IFT Mutants upon Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27906968
|abstract=The majority of cilia are formed and maintained by the highly conserved process of intraflagellar transport (IFT). Mutations in IFT genes lead to ciliary structural defects and systemic disorders termed ciliopathies. Here we show that the severely truncated sensory cilia of hypomorphic IFT mutants in C. elegans transiently elongate during a discrete period of adult aging leading to markedly improved sensory behaviors. Age-dependent restoration of cilia morphology occurs in structurally diverse cilia types and requires IFT. We demonstrate that while DAF-16/FOXO is dispensable, the age-dependent suppression of cilia phenotypes in IFT mutants requires cell-autonomous functions of the [[HSF1]] heat shock factor and the Hsp90 chaperone. Our results describe an unexpected role of early aging and protein quality control mechanisms in suppressing ciliary phenotypes of IFT mutants, and suggest possible strategies for targeting subsets of ciliopathies.
|mesh-terms=* Aging
* Animals
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Cilia
* Ciliopathies
* Forkhead Transcription Factors
* HSP90 Heat-Shock Proteins
* Humans
* Microtubules
* Molecular Chaperones
* Mutation
* Sensory Receptor Cells
* Transcription Factors

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131903
}}
{{medline-entry
|title=Effects of intrinsic aerobic capacity, aging and voluntary running on skeletal muscle sirtuins and heat shock proteins.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27038700
|abstract=Sirtuins are proteins that connect energy metabolism, oxidative stress and aging. Expression of heat shock proteins (Hsps) is regulated by heat shock factors (HSFs) in response to various environmental and physiological stresses, such as oxidative stress. Oxidative stress accumulates during aging which makes cells more prone to DNA damage. Although many experimental animal models have been designed to study the effects of knockdown or overexpression of sirtuins, HSFs and Hsps, little is known about how aging per se affects their expression. Here we study the impact of intrinsic aerobic capacity, aging and voluntary exercise on the levels of sirtuins, HSFs and Hsps in skeletal muscle. We studied the protein levels of sirtuins (SIRT1, [[SIRT2]], [[SIRT3]], [[SIRT4]], [[SIRT5]], [[SIRT6]] and SIRT7), [[HSF1]], [[HSF2]], Hsp10, Hsp27 and Hsp70 before and after one-year of voluntary running intervention of rat strains selectively bred for intrinsic aerobic exercise capacity; high capacity runners (HCR) and low capacity runners (LCR) differ by more than 30% for median lifespan. This setup enabled us to discern the effects of inborn aerobic capacity, aging and exercise activity on the protein levels of sirtuins, HSFs and Hsps in skeletal muscle. Our results revealed that the longer lived HCR rats had higher [[SIRT3]], [[HSF1]] and [[HSF2]] contents in skeletal muscle (gastrocnemius, p < 0.05) than LCRs. Neither aging nor voluntary running had a significant effect on the studied sirtuin proteins. Aging significantly increased the protein levels of [[HSF1]], [[HSF2]] and Hsp27 (p < 0.05). Our finding of elevated [[SIRT3]] levels in HCR rats is in line with previous studies; [[SIRT3]] in general is linked to elevated fatty acid oxidation and oxidative phosphorylation, which previously have been associated with metabolic profile of HCRs. [[HSF1]], [[HSF2]] and Hsp27 levels increased with aging, showing that aged muscles responded to aging-related stress. Our study shows for the first time that [[SIRT3]] protein level is linked to high inborn aerobic capacity, and may be directly interconnected to longevity.
|mesh-terms=* Aging
* Animals
* Body Weight
* Citrate (si)-Synthase
* Energy Intake
* Female
* Heat-Shock Proteins
* Muscle, Skeletal
* Oxidative Stress
* Physical Conditioning, Animal
* Rats, Inbred Strains
* Running
* Sirtuins
|keywords=* aging
* oxidative stress
* physical activity
* sirtuin
* skeletal muscle
|full-text-url=https://sci-hub.do/10.1016/j.exger.2016.03.015
}}
{{medline-entry
|title=Determinants of rodent longevity in the chaperone-protein degradation network.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26894765
|abstract=Proteostasis is an integral component of healthy aging, ensuring maintenance of protein structural and functional integrity with concomitant impact upon health span and longevity. In most metazoans, increasing age is accompanied by a decline in protein quality control resulting in the accrual of damaged, self-aggregating cytotoxic proteins. A notable exception to this trend is observed in the longest-lived rodent, the naked mole-rat (NMR, Heterocephalus glaber) which maintains proteostasis and proteasome-mediated degradation and autophagy during aging. We hypothesized that high levels of the proteolytic degradation may enable better maintenance of proteostasis during aging contributing to enhanced species maximum lifespan potential (MLSP). We test this by examining proteasome activity, proteasome-related HSPs, the heat-shock factor 1 ([[HSF1]]) transcription factor, and several markers of autophagy in the liver and quadriceps muscles of eight rodent species with divergent MLSP. All subterranean-dwelling species had higher levels of proteasome activity and autophagy, possibly linked to having to dig in soils rich in heavy metals and where underground atmospheres have reduced oxygen availability. Even after correcting for phylogenetic relatedness, a significant (p < 0.02) positive correlation between MLSP, HSP25, [[HSF1]], proteasome activity, and autophagy-related protein 12 (ATG12) was observed, suggesting that the proteolytic degradation machinery and maintenance of protein quality play a pivotal role in species longevity among rodents.
|mesh-terms=* Aging
* Animals
* Autophagy
* Autophagy-Related Protein 12
* DNA-Binding Proteins
* Heat Shock Transcription Factors
* Liver
* Longevity
* Mice
* Mole Rats
* Molecular Chaperones
* Oxidative Stress
* Phylogeny
* Proteasome Endopeptidase Complex
* Proteolysis
* Quadriceps Muscle
* Rats
* Rodentia
* Transcription Factors
|keywords=* Aging
* Chaperones
* Naked mole rat
* Proteasome
* Proteostasis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837185
}}
{{medline-entry
|title=SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via [[HSF1]]/HSP70i chaperone system.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25167838
|abstract=Dominant mutations in superoxide dismutase 1 (SOD1) cause degeneration of motor neurons in a subset of inherited amyotrophic lateral sclerosis (ALS). The pathogenetic process mediated by misfolded and/or aggregated mutant SOD1 polypeptides is hypothesized to be suppressed by protein refolding. This genetic study is aimed to test whether mutant SOD1-mediated ALS pathology recapitulated in mice could be alleviated by overexpressing a longevity-related deacetylase SIRT1 whose substrates include a transcription factor heat shock factor 1 ([[HSF1]]), the master regulator of the chaperone system. We established a line of transgenic mice that chronically overexpress SIRT1 in the brain and spinal cord. While inducible HSP70 (HSP70i) was upregulated in the spinal cord of SIRT1 transgenic mice (PrP-Sirt1), no neurological and behavioral alterations were detected. To test hypothetical benefits of SIRT1 overexpression, we crossbred PrP-Sirt1 mice with two lines of ALS model mice: A high expression line that exhibits a severe phenotype (SOD1G93A-H) or a low expression line with a milder phenotype (SOD1G93A-L). The Sirt1 transgene conferred longer lifespan without altering the time of symptomatic onset in SOD1G93A-L. Biochemical analysis of the spinal cord revealed that SIRT1 induced HSP70i expression through deacetylation of [[HSF1]] and that SOD1G93A-L/PrP-Sirt1 double transgenic mice contained less insoluble SOD1 than SOD1G93A-L mice. Parallel experiments showed that Sirt1 transgene could not rescue a more severe phenotype of SOD1G93A-H transgenic mice partly because their HSP70i level had peaked out. The genetic supplementation of SIRT1 can ameliorate a mutant SOD1-linked ALS mouse model partly through the activation of the [[HSF1]]/HSP70i chaperone system. Future studies shall include testing potential benefits of pharmacological enhancement of the deacetylation activity of SIRT1 after the onset of the symptom.
|mesh-terms=* Acetylation
* Amyotrophic Lateral Sclerosis
* Animals
* Behavior, Animal
* DNA-Binding Proteins
* Disease Models, Animal
* Gene Dosage
* HSP70 Heat-Shock Proteins
* Heat Shock Transcription Factors
* Humans
* Longevity
* Mice, Inbred C57BL
* Mice, Transgenic
* Mutation
* Promoter Regions, Genetic
* Protein Folding
* Sirtuin 1
* Spinal Cord
* Superoxide Dismutase
* Superoxide Dismutase-1
* Transcription Factors
* Up-Regulation

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237944
}}
{{medline-entry
|title=Contesting the dogma of an age-related heat shock response impairment: implications for cardiac-specific age-related disorders.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24556212
|abstract=Ageing is associated with the reduced performance of physiological processes and has been proposed as a major risk factor for disease. An age-related decline in stress response pathways has been widely documented in lower organisms. In particular, the heat shock response (HSR) becomes severely compromised with age in Caenorhabditis elegans. However, a comprehensive analysis of the consequences of ageing on the HSR in higher organisms has not been documented. We used both HS and inhibition of HSP90 to induce the HSR in wild-type mice at 3 and 22 months of age to investigate the extent to which different brain regions, and peripheral tissues can sustain [[HSF1]] activity and HS protein (HSP) expression with age. Using chromatin immunoprecipitation, quantitative reverse transcription polymerase chain reaction, western blotting and enzyme linked immunosorbent assay (ELISA), we were unable to detect a difference in the level or kinetics of HSP expression between young and old mice in all brain regions. In contrast, we did observe an age-related reduction in chaperone levels and HSR-related proteins in the heart. This could result in a decrease in the protein folding capacity of old hearts with implications for age-related cardiac disorders. 
|mesh-terms=* Aging
* Animals
* Brain
* DNA-Binding Proteins
* Female
* Gene Expression Regulation, Developmental
* Heart
* Heat Shock Transcription Factors
* Heat-Shock Proteins
* Heat-Shock Response
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Inbred CBA
* Myocardium
* Protein Folding
* Pyridones
* Pyrimidines
* Transcription Factors

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065144
}}
{{medline-entry
|title=Late-onset Alzheimer's disease, heating up and foxed by several proteins: pathomolecular effects of the aging process.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24326519
|abstract=Late-onset Alzheimer's disease (LOAD) is the most common neurodegenerative disorder in older adults, affecting over 50% of those over age 85. Aging is the most important risk factor for the development of LOAD. Aging is associated with the decrease in the ability of cells to cope with cellular stress, especially protein aggregation. Here we describe how the process of aging affects pathways that control the processing and degradation of abnormal proteins including amyloid-β (Aβ). Genetic association studies in LOAD have successfully identified a large number of genetic variants involved in the development of the disease. However, there is a gap in understanding the interconnections between these pathomolecular events that prevent us from discovering therapeutic targets. We propose novel, pertinent links to elucidate how the biology of aging affects the sequence of events in the development of LOAD. Furthermore we analyze and synthesize the molecular-pathologic-clinical correlations of the aging process, involving the [[HSF1]] and FOXO family pathways, Aβ metabolic pathway, and the different clinical stages of LOAD. Our new model postulates that the aging process would precede Aβ accumulation, and attenuation of [[HSF1]] is an "upstream" event in the cascade that results in excess Aβ and synaptic dysfunction, which may lead to cognitive impairment and/or trigger "downstream" neurodegeneration and synaptic loss. Specific host factors, such as the activity of FOXO family pathways, would mediate the response to Aβ toxicity and the pace of progression toward the clinical manifestations of AD. 
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* DNA-Binding Proteins
* Forkhead Transcription Factors
* Heat Shock Transcription Factors
* Heat-Shock Proteins
* Humans
* Transcription Factors
|keywords=* Amyloid
* autophagy
* cognition
* dementia
* heat-shock
* neurodegeneration
* protein aggregation
* protein degradation
* stress
* transcription factor
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126605
}}
{{medline-entry
|title=Characterization of global gene expression during assurance of lifespan extension by caloric restriction in budding yeast.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24126084
|abstract=Caloric restriction (CR) is the best-studied intervention known to delay aging and extend lifespan in evolutionarily distant organisms ranging from yeast to mammals in the laboratory. Although the effect of CR on lifespan extension has been investigated for nearly 80years, the molecular mechanisms of CR are still elusive. Consequently, it is important to understand the fundamental mechanisms of when and how lifespan is affected by CR. In this study, we first identified the time-windows during which CR assured cellular longevity by switching cells from culture media containing 2% or 0.5% glucose to water, which allows us to observe CR and non-calorically-restricted cells under the same conditions. We also constructed time-dependent gene expression profiles and selected 646 genes that showed significant changes and correlations with the lifespan-extending effect of CR. The positively correlated genes participated in transcriptional regulation, ribosomal RNA processing and nuclear genome stability, while the negatively correlated genes were involved in the regulation of several metabolic pathways, endoplasmic reticulum function, stress response and cell cycle progression. Furthermore, we discovered major upstream regulators of those significantly changed genes, including AZF1 (YOR113W), [[HSF1]] (YGL073W) and [[XBP1]] (YIL101C). Deletions of two genes, AZF1 and [[XBP1]] ([[HSF1]] is essential and was thus not tested), were confirmed to lessen the lifespan extension mediated by CR. The absence of these genes in the tor1Δ and ras2Δ backgrounds did show non-overlapping effects with regard to CLS, suggesting differences between the CR mechanism for Tor and Ras signaling. 
|mesh-terms=* Caloric Restriction
* DNA-Binding Proteins
* Gene Deletion
* Gene Expression Profiling
* Gene Expression Regulation, Fungal
* Glucose
* Heat-Shock Proteins
* Longevity
* Mutation
* RNA, Fungal
* RNA, Ribosomal
* Repressor Proteins
* Ribosomes
* Saccharomyces cerevisiae
* Saccharomyces cerevisiae Proteins
* Time Factors
* Transcription Factors
* Transcription, Genetic
|keywords=* Budding yeast
* CR
* Caloric restriction
* LGS
* Longevity assurance
* Transcription factor
* Transcriptome
* caloric restriction
* longevity-related gene set
|full-text-url=https://sci-hub.do/10.1016/j.exger.2013.10.001
}}