JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age A hallmark of aging is chronic sterile inflammation, which is closely associated with frailty and age-related diseases. We found that senescent fat progenitor cells accumulate in adipose tissue with aging and acquire a senescence-associated secretory phenotype (SASP), with increased production of proinflammatory cytokines compared with nonsenescent cells. These cells provoked inflammation in adipose tissue and induced macrophage migration. The JAK pathway is activated in adipose tissue with aging, and the SASP can be suppressed by inhibiting the JAK pathway in senescent cells. JAK1/2 inhibitors reduced inflammation and alleviated frailty in aged mice. One possible mechanism contributing to reduced frailty is SASP inhibition. Our study points to the JAK pathway as a potential target for countering age-related dysfunction. A hallmark of aging is chronic, low-grade, “sterile” inflammation (1–3). Elevated proinflammatory cytokines and chemokines are closely associated with mortality (4, 5) and with a variety of age-related diseases, including atherosclerosis (6), depression (7), cancers (8), diabetes (9), and neurodegenerative diseases (10, 11). Inflammation also is associated with frailty, a geriatric syndrome characterized by decreased strength and incapacity to respond to stress (2). The underlying mechanisms of age-related chronic inflammation, tissue dysfunction, and frailty remain elusive. Cellular senescence, stable arrest of cell growth in replication-competent cells, is a plausible contributor. Senescence can be induced by a number of stimuli and stresses, including telomere dysfunction, genomic instability, oncogenic and metabolic insults, and epigenetic changes (12). Senescent cells accumulate with aging in the skin (13, 14), liver (15, 16), kidney (17), the cardiovascular system (18), and other tissues in various species (16). The senescence-associated secretory phenotype (SASP), largely comprised of proinflammatory cytokines and chemokines (19, 20), links senescent cells to age-related inflammation and diseases. We found that elimination of senescent cells delayed the onset of age-related phenotypes and enhanced healthspan (21, 22). Therefore, senescent cells and the SASP could play a role in age-related pathologies, particularly those that involve systemic inflammation. The JAK/STAT pathway plays an important role in regulating cytokine production (23, 24). We hypothesized that it may directly affect the SASP. The JAK family has four members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). JAK1 and 2 are involved in inflammatory signaling and in the action of growth hormone and other endocrine and paracrine signals (25). JAK3 is expressed primarily in blood cells and mediates erythropoietin signaling and immune cell generation (26–29). TYK2 plays an important role in white blood cell function and host defenses (30, 31). A number of inhibitors that target different JAKs have been approved or are in phase I–III studies for treating myelofibrosis (23, 32–34), acute myeloid leukemia (23), lymphoma (23), and rheumatoid arthritis (23, 35, 36). JAK inhibitors recently have been found to reprogram the SASP in senescent tumor cells, contributing to improved antitumor response (37). Therefore, we investigated the role of the JAK pathway in age-related inflammation and dysfunction. We demonstrate here that senescent preadipocytes, fat cell progenitors, accumulate in adipose tissue with aging and can contribute to adipose tissue inflammation. We found that
”Senescence is more than merely a cell division clock that regulates the proliferative lifespan of normal cells. “Premature” senescence is an active cytostaticprogram that is triggered in response to proliferative or genotoxic stress, such as the expression of strong oncogenes, tumor suppressor loss, exposure to DNA damage, and reactivation of tumor suppressor pathways. Unlike replicative senescence, premature senescence can be induced irrespective of the replicative “age” of cells, is independent of telomere attrition, and cannot be overridden by restoration of telomerase activity.24 The first example of oncogene-induced senescencewas described in 1997, where forced expression of an oncogenic allele of Ras induced a senescence response in primary human and rodent cells that was accompanied by the induction of p53 and p16INK4A.25 Inactivation of p53 or p16INK4A was sufficient to enable the proliferation of Ras-expressing rodent cells, and co-expression of adenoviral protein E1A and Ras was sufficient to enable senescence bypass in human cells. Of note, this study implied that oncogene-induced senescence acted as an important barrier to uncontrolled proliferation during multistep tumorigenesis and also provided a biological mechanism for the observed cooperation between Ras and immortalizing oncogenes (such as viral oncoproteins) alluded to earlier. The Ras proteins are master regulators of pathways that cooperate to drive cell proliferation, growth, and survival. Dissection of Ras signaling through the use of engineered Ras mutants and activated forms of downstream signaling components identified the Raf/MEK/MAPK cascade as the major arm of Ras signaling that triggered senescence.26,27Hence, activation of the very same pathways that promote cellular transformation can also drive senescence when tumor suppressor genes are intact, thus implying that senescence can serve as an antiproliferative response to aberrant mitogenic cues. Oncogene-induced senescence is not the only form of premature senescence that has been described. In fact, many forms of cellular damage, including exposure to ionizing radiation, cytotoxic drugs, and oxidative stress, can induce a cytostatic program that is phenotypically indistinguishable from senescence. Gene expression profiling studies support the notion that these senescence programs are related and demonstrate a strong similarity to the canonical replicative senescence program triggered by telomere erosion. Cellular senescencethus appears to represent a common response to cellular stress. Interestingly, virtually all of the known stimuli that induce senescence—including telomere malfunction and hyperproliferation—can activate a DNA damage response (DDR), suggesting that some aspects of DDR signaling are crucial triggers of senescence. Accordingly, abrogation of DNA damage signaling through mutation/deletion of key regulators such as ATM, NBS1, CHK2, and ATR suppresses senescence, largely due to a failure to activate the p53 pathway.7,28 Furthermore, DDR signaling can trigger generation of the SASP29 and the global chromatin changes that are observed in senescent cells.30 Generally, it appears that a substantial damage “threshold” must be reached before replicative or premature senescence responses can be triggered. For example, cells with minor DNA damage may arrest only transiently, providing an opportunity for the repair of genetic lesions. However, when DNA damage is extensive, cells may opt to undergo cell death or enter senescence. This notion of dose dependence
A branching process model of telomere shortening A continuous correlation between oxidative stress and telomere shortening in fibroblasts A Critical Role for Pin2/TRF1 in ATM-dependent Regulation INHIBITION OF Pin2/TRF1 FUNCTION COMPLEMENTS telomere shortening, RADIOSENSITIVITY, AND THE G2/M CHECKPOINT DEFECT OF ATAXIA-TELANGIECTASIA CELLS A G-quadruplex-interactive agent, telomestatin (SOT-095), induces telomere shortening with apoptosis and enhances chemosensitivity in acute myeloid leukemia A Home Use Study in Healthy Volunteers to Assess Effectiveness of a Dietary Supplement to Halt the Shortening of telomere Length as Demonstrated by the “ … A kinetic model of telomere shortening in infants and adults A protein array screen for Kaposi's sarcoma-associated herpesvirus LANA interactors links LANA to TIP60, PP2A activity, and telomere shortening A randomized-controlled clinical study of Telos95®, a novel antioxidative dietary supplement, on the shortening of telomere length in healthy volunteers A stochastic model of cell replicative senescence based on telomere shortening, oxidative stress, and somatic mutations in nuclear and mitochondrial DNA A tel2 Mutation That Destabilizes the Tel2-Tti1-Tti2 Complex Eliminates Rad3ATR Kinase Signaling in the DNA Replication Checkpoint and Leads to telomere shortening in Fission Yeast A TIN2 dyskeratosis congenita mutation causes telomerase-independent telomere shortening in mice A15812 Angiotensin Converting Enzyme Inhibitors Epigenetically Atenuate telomere shortening A7. 9 Does telomere shortening in Women with Rheumatoid Arthritis Predict X Chromosome Inactivation Bias? AB181. telomere shortening is associated with genetic anticipation in Chinese Von Hippel-Lindau disease families Abnormal telomere shortening in leucocytes of children with Shwachman–Diamond syndrome Abnormal telomere shortening of peripheral blood mononuclear cells and granulocytes in patients with chronic idiopathic neutropenia Abrogation of miR-195 Improves Function in Aged Heart by Preventing telomere shortening and Mitochondrial Dysfunction Abrupt telomere shortening in cell aging and cancer Abrupt telomere shortening in normal human fibroblasts Absence of telomere shortening and oxidative DNA damage in the young adult offspring of women with pre-gestational type 1 diabetes Abstract A63: Rsf-1, a chromatin remodeling protein, interacts with shelterin protein hRap1 and induces telomere shortening Abstract# 3036: telomere length shortening in individuals with sporadic compared with familial breast cancer Abstract# 3482: telomere shortening in human tumor cells in vitro and in vivo following treatment with telomerase inhibitor, GRN163L Abstract# 4505: Peripheral telomere shortening is most closely associated with young age of onset for pancreatic cancer Abstract# 5139: The inflammatory cytokine TNF-\# 945; induces rapid, reversible telomere shortening in breast cancer cell lines Accelerated aging as evidenced by increased telomere shortening and mitochondrial DNA depletion in patients with type 2 diabetes Accelerated telomere length shortening in granulocytes: a diagnostic marker for myeloproliferative diseases Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A Accelerated telomere shortening and senescence in human pancreatic islet cells stimulated to divide in vitro Accelerated telomere shortening and telomerase activation in Fanconi's anaemia Accelerated telomere shortening and telomere abnormalities in radiosensitive cell lines Accelerated telomere shortening following allogeneic transplantation is independent of the cell source and occurs within the first year post transplant Accelerated telomere shortening in acromegaly; IGF-I induces telomere shortening and cellular senescence
Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, which is why Hsp90 inhibitors are investigated as anti-cancer drugs. Heat shock proteins, as a class, are among the most highly expressed cellular proteins across all species.[3] As their name implies, heat shock proteins protect cells when stressed by elevated temperatures. They account for 1–2% of total protein in unstressed cells. However, when cells are heated, the fraction of heat shock proteins increases to 4–6% of cellular proteins.[4] Heat shock protein 90 (Hsp90) is one of the most common of the heat-related proteins. The "90" comes from the fact that it weighs roughly 90 kiloDaltons. A 90 kDa protein is considered fairly large for a non-fibrous protein. Hsp90 is found in bacteria and all branches of eukarya, but it is apparently absent in archaea.[5] Whereas cytoplasmic Hsp90 is essential for viability under all conditions in eukaryotes, the bacterial homologue HtpG is dispensable under non-heat stress conditions.[6] This protein was first isolated by extracting proteins from cells stressed by heating, dehydrating or by other means, all of which caused the cell’s proteins to begin to denature.[7] However it was later discovered that Hsp90 also has essential functions in unstressed cells. -wiki Identification of HSP90 inhibitors as a novel class of senolytics Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues is a major contributor to aging and age-related diseases. Recently, a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging. To identify novel and more optimal senotherapeutic drugs and combinations, we established a senescence associated β-galactosidase assay as a screening platform to rapidly identify drugs that specifically affect senescent cells. We used primary Ercc1 −/− murine embryonic fibroblasts with reduced DNA repair capacity, which senesce rapidly if grown at atmospheric oxygen. This platform was used to screen a small library of compounds that regulate autophagy, identifying two inhibitors of the HSP90 chaperone family as having significant senolytic activity in mouse and human cells. Treatment of Ercc1 −/∆ mice, a mouse model of a human progeroid syndrome, with the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several age-related symptoms and reduced p16INK4a expression. These results demonstrate the utility of our screening platform to identify senotherapeutic agents as well as identified HSP90 inhibitors as a promising new class of senolytic drugs. SCIENTIFIC STUDIES Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone Inhibiting the Hsp90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression Inhibiting Hsp90 to treat cancer: a strategy in evolution Molecular simulation of HER2/neu degradation by inhibiting HSP90 Inhibiting the Hsp90 chaperone slows cyst growth in a mouse model of autosomal dominant polycystic kidney disease Black tea polyphenols induce human leukemic cell cycle arrest by inhibiting Akt signaling: Possible involvement of Hsp90, Wnt/β‐catenin signaling and FOXO1 Microparticles from patients with the acute coronary
Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis Human SIR2 deacetylates p53 and antagonizes PML/p53‐induced cellular senescence Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a PML regulates p53 acetylation and premature senescence induced by oncogenic Ras Regulation of cellular senescence by p53 Reversal of human cellular senescence: roles of the p53 and p16 pathways Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor A role for both RB and p53 in the regulation of human cellular senescence Senescence and aging: the critical roles of p53 A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy Paradoxical suppression of cellular senescence by p53 Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling Oncogenic ras and p53 cooperate to induce cellular senescence Escape from senescence in human diploid fibroblasts induced directly by mutant p53. Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53 Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence JunD protects cells from p53-dependent senescence and apoptosis Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer p53, ROS and senescence in the control of aging Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction Pathways connecting telomeres and p53 in senescence, apoptosis, and cancer Reversal of senescence in mouse fibroblasts through lentiviral suppression of p53 p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC SIRT1 and p53, effect on cancer, senescence and beyond Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence Weak p53 permits senescence during cell cycle arrest The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence Significant role for p16INK4a in p53-independent telomere-directed senescence Tumour suppression by p53: the importance of apoptosis and cellular senescence Evidence that transcriptional activation by p53 plays a direct role in the induction of cellular senescence. Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53‐dependent cellular senescence p53 isoforms Δ133p53 and p53β are endogenous regulators of replicative cellular senescence DNA damage signaling and p53-dependent senescence after prolonged β-interferon stimulation Suppression of p53-dependent senescence by the JNK signal transduction pathway A two-stage, p16INK4A-and p53-dependent keratinocyte senescence mechanism that limits replicative potential independent of telomere status Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells Senescence, aging, and malignant transformation mediated by p53 in mice lacking the Brca1 full-length isoform p53-independent regulation of p21Waf1/Cip1 expression and senescence by Chk2 ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation
Klotho is a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in ageing. Its discovery was documented in 1997 by Makoto Kuro-o et al.[9] The name of the gene comes from Klotho or Clotho, one of the Moirai, or Fates, in Greek mythology. The Klotho protein is a novel β-glucuronidase (EC number 3.2.1.31) capable of hydrolyzing steroid β-glucuronides. Genetic variants in KLOTHO have been associated with human aging,[10][11] and Klotho protein has been shown to be a circulating factor detectable in serum that declines with age.[12] The binding of certain fibroblast growth factors(FGF's) viz., FGF19, FGF21, and FGF23, to their fibroblast growth factor receptors, is promoted via their interactions as co-receptors with β-Klotho.[13][14] Klotho-deficient mice manifest a syndromeresembling accelerated human aging and display extensive and accelerated arteriosclerosis. Additionally, they exhibit impaired endotheliumdependent vasodilation and impaired angiogenesis, suggesting that Klotho protein may protect the cardiovascular system through endothelium-derived NO production. Although the vast majority of research has been based on lack of Klotho, it was demonstrated that an overexpression of Klotho in mice might extend their average life span between 19% and 31% compared to normal mice.[8] In addition, variations in the Klotho gene (SNP Rs9536314) are associated with both life extension and increased cognition in human populations.[15] The mechanism of action of klotho is not fully understood, but it changes cellular calcium homeostasis, by both increasing the expression and activity of TRPV5 and decreasing that of TRPC6.[16]Additionally, klotho increases membrane expression of the inward rectifier channel ROMK.[16] Klotho-deficient mice show increased production of vitamin D, and altered mineral-ion homeostasis is suggested to be a cause of premature aging‑like phenotypes, because the lowering of vitamin D activity by dietary restriction reverses the premature aging‑like phenotypes and prolongs survival in these mutants. These results suggest that aging‑like phenotypes were due to klotho-associated vitamin D metabolic abnormalities (hypervitaminosis).[17][18][19][20] Recently it has been found that the decreased Klotho expression may be due to DNA hypermethylation, which may have been induced by the overexpression of DNMT3a.[21] Klotho may be a reliable gene for early detection of methylation changes in oral tissues, and can be used as a target for therapeutic modification in oral cancer during the early stages. Suppression of Aging in Mice by the Hormone Klotho A defect in Klotho gene expression in mice accelerates the degeneration of multiple age-sensitive traits. Here, we show that overexpression of Klotho in mice extends life span. Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and insulin-like growth factor 1 (IGF1), an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in Klotho-deficient mice was observed by perturbing insulin and IGF1 signaling, suggesting that Klotho-mediated inhibition of insulin and IGF1 signaling contributes to its anti-aging properties. Klotho protein may function as an anti-aging hormone in mammals. Life Extension Factor Klotho Prevents Mortality and Enhances Cognition Aging is the principal
Regulation of longevity by FGF21: Interaction between energy metabolism and stress responses. Fibroblast growth factor 21 (FGF21) is a hormone-like member of FGF family which controls metabolic multiorgan crosstalk enhancing energy expenditure through glucose and lipid metabolism. In addition, FGF21 acts as a stress hormone induced by endoplasmic reticulum stress and dysfunctions of mitochondria and autophagy in several tissues. FGF21 also controls stress responses and metabolism by modulating the functions of somatotropic axis and hypothalamic-pituitary-adrenal (HPA) pathway. FGF21 is a potent longevity factor coordinating interactions between energy metabolism and stress responses. Recent studies have revealed that FGF21 treatment can alleviate many age-related metabolic disorders, e.g. atherosclerosis, obesity, type 2 diabetes, and some cardiovascular diseases. In addition, transgenic mice overexpressing FGF21 have an extended lifespan. However, chronic metabolic and stress-related disorders involving inflammatory responses can provoke FGF21 resistance and thus disturb healthy aging process. First, we will describe the role of FGF21 in interorgan energy metabolism and explain how its functions as a stress hormone can improve healthspan. Next, we will examine both the induction of FGF21 expression via the integrated stress response and the molecular mechanism through which FGF21 enhances healthy aging. Finally, we postulate that FGF21 resistance, similarly to insulin resistance, jeopardizes human healthspan and accelerates the aging process The starvation hormone, fibroblast growth factor-21, extends lifespan in mice Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity, blocks somatic growth and causes bone loss. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting markers of NAD+ metabolism or AMP kinase and mTOR signaling. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used to extend lifespan in other species. Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution Liver-derived metabolic hormone fibroblast growth factor 21 (FGF21) improves insulin sensitivity and extends lifespan in mice. Aging also compromises the adaptive immune system by reducing T-cell production from the thymus. In this paper, we describe a new immunological function of FGF21 as a regulator of T-cell production from thymus in aging. The overexpression of FGF21 prevents thymic lipoatrophy, which protects the mice from age-induced loss of naïve T cells. FGF21 expression in thymic epithelial cells and signaling in thymic stromal cells support thymic function in aging. Loss of FGF21 in mice increases lethality postirradiation and delays the reconstitution of thymus. Hence, we highlight FGF21 as an immunometabolic regulator that can be harnessed to delay immune senescence. Irisin and FGF21 Are Cold-Induced Endocrine Activators of Brown Fat Function in Humans •Shivering stimulates irisin secretion in humans •Nonshivering cold exposure increases FGF21, which may be a brown adipokine •Irisin and/or FGF21 upregulates brown-fat-like program in human adipocytes •Exercise may be a shivering mimic exemplifying
FOXO3 belongs to the O subclass of the forkhead family of transcription factorswhich are characterized by a distinct fork head DNA-binding domain. There are three other FoxO family members in humans, FOXO1, FOXO4 and FOXO6. These transcription factors share the ability to be inhibited and translocated out of the nucleus on phosphorylation by proteins such as Akt/PKB in the PI3Ksignaling pathway (aside from FOXO6, which may be constitutively nuclear).[6]Other post-translational modifications including acetylation and methylation are seen and can result in increased or altered FOXO3a activity. This protein likely functions as a trigger for apoptosis through upregulation of genes necessary for cell death, such as Bim and PUMA,[7] or downregulation of anti-apoptotic proteins such as FLIP.[8] Gopinath et al.(2014)[9] demonstrate a functional requirement for FOXO3 as a regulator of Notch signaling pathway (an essential regulator of quiescence in adult stem cells) in the self-renewal of stem cells during muscle regeneration. It is thought that FOXO3a is also involved in protection from oxidative stress by upregulating antioxidants such as catalase and MnSOD. Ron DePinho's group generated Foxo3 knockout mice, and showed that female exhibit a dramatic age-dependent infertility, due to premature ovarian failure. Clinical significance Deregulation of FOXO3a is involved in tumorigenesis,[10] for example translocation of this gene with the MLLgene is associated with secondary acute leukemia. Downregulation of FOXO3a activity is often seen in cancer (e.g. by increase in Akt activity resulting from loss of PTEN). FOXO3 is known as a tumour suppressor. Alternatively spliced transcript variants encoding the same protein have been observed.[11] Association with longevity A variant of FOXO3 has been shown to be associated with longevity in humans. It is found in most centenarians across a variety of ethnic groups around the world.[12][13] The homologous genes daf-16 in the nematode C. elegans and dFOXO in the fruit fly are also associated with longevity in those organisms. FoxO3 Controls Autophagy in Skeletal Muscle In Vivo FoxO3 Regulates Neural Stem Cell Homeostasis FoxO3 Coordinately Activates Protein Degradation by the Autophagic/Lysosomal and Proteasomal Pathways in Atrophying Muscle Cells PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription The Energy Sensor AMP-activated Protein Kinase Directly Regulates the Mammalian FOXO3 Transcription Factor Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor Foxo3 is required for the regulation of oxidative stress in erythropoiesis Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2 Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation Foxo3 is a PI3K-dependent molecular switch controlling the initiation of oocyte growth SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice Foxo3 activity promoted by non-coding effects of circular RNA and Foxo3 pseudogene in the inhibition of tumor growth and angiogenesis GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy The Transcription of FOXO
SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae), referring to the fact that its sirtuinhomolog (biological equivalent across species) in yeast (S. cerevisiae) is Sir2. SIRT1 is an enzyme that deacetylates proteins that contribute to cellular regulation (reaction to stressors, longevity).[8] Sirtuin 1 is a member of the sirtuin family of proteins, homologs of the Sir2 gene in S. cerevisiae. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class I of the sirtuin family.[6] Sirtuin 1 is downregulated in cells that have high insulin resistance and inducing its expression increases insulin sensitivity, suggesting the molecule is associated with improving insulin sensitivity.[9]Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.[10][11][12][13][14][15] In mammals, SIRT1 has been shown to deacetylate and thereby deactivate the p53 protein.[16] SIRT1 also stimulates autophagy by preventing acetylation of proteins (via deacetylation) required for autophagy as demonstrated in cultured cells and embryonic and neonatal tissues. This function provides a link between sirtuin expression and the cellular response to limited nutrients due to caloric restriction.[17] Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.[10][11][12][13][14][15] Human aging is characterized by a chronic, low-grade inflammation level[18] and NF-κB is the main transcriptional regulator of genes related to inflammation.[19] SIRT1 inhibits NF-κB-regulated gene expression by deacetylating the RelA/p65 subunit of NF-κB at lysine 310.[20][21] Increased expression of SIRT1 protein extended both the mean and maximal lifespan of mice.[53] In these mice health was also improved as well as bone and muscle mass. Another SIRT1 activator (SRT1720) also extended lifespan and improved the health of mice.[54] A Remarkable Age-Related Increase in SIRT1 Protein Expression against Oxidative Stress in Elderly: SIRT1 Gene Variants and Longevity in Human Aging is defined as the accumulation of progressive organ dysfunction. Controlling the rate of aging by clarifying the complex pathways has a significant clinical importance. Nowadays, sirtuins have become famous molecules for slowing aging and decreasing age-related disorders. In the present study, we analyzed the SIRT1 gene polymorphisms (rs7895833 A>G, rs7069102 C>G and rs2273773 C>T) and its relation with levels of SIRT1, eNOS, PON-1, cholesterol, TAS, TOS, and OSI to demonstrate the association between genetic variation in SIRT1 and phenotype at different ages in humans. We observed a significant increase in the SIRT1 level in older people and found a significant positive correlation between SIRT1 level and age in the overall studied population. The oldest people carrying AG genotypes for rs7895833 have the highest SIRT1 level suggesting an association between rs7895833 SNP
“5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryoticprotein family and its orthologues are SNF1 and SnRK1 in yeast and plants, respectively. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, activation of adipocyte lipolysis, and modulation of insulin secretion by pancreatic beta-cells.[1]” AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 TSC2 Integrates Wnt and Energy Signals via a Coordinated Phosphorylation by AMPK and GSK3 to Regulate Cell Growth AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity AMPK: a nutrient and energy sensor that maintains energy5 homeostasis AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α The AMPK signalling pathway coordinates cell growth, autophagy and metabolism LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1 AMPK and PPARδ Agonists Are Exercise Mimetics The LKB1–AMPK pathway: metabolism and growth control in tumour suppression TSC2 Integrates Wnt and Energy Signals via a Coordinated Phosphorylation by AMPK and GSK3 to Regulate Cell Growth The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2–dependent mechanisms AMPK in Health and Disease PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure AMPK Regulates the Circadian Clock by Cryptochrome Phosphorylation and Degradation Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-Induced Insulin-Resistant Mice AMPK: An Emerging Drug Target for Diabetes and the Metabolic Syndrome The energy sensing LKB1–AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia SIRT1 Is Required for AMPK Activation and the Beneficial Effects of Resveratrol on Mitochondrial Function Structure of mammalian AMPK and its regulation by ADP Interdependence of AMPK and SIRT1 for Metabolic Adaptation to Fasting and Exercise in Skeletal Muscle Role of AMPK-mTOR-Ulk1/2 in the Regulation of Autophagy: Cross Talk, Shortcuts, and Feedbacks AMPK β Subunit Targets Metabolic Stress Sensing to Glycogen Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1 AMPK: a key regulator of energy balance in the single cell and the whole organism Identification and characterization of a