FNDC5
Fibronectin type III domain-containing protein 5 precursor (Fibronectin type III repeat-containing protein 2) [Contains: Irisin] [FRCP2]
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Irisin is a myokine produced by skeletal muscle during exercise in both mice and humans. We previously showed that irisin treatment ameliorates immobility-induced osteoporosis and muscular atrophy in mice. Data in humans showed a positive association between irisin and bone mineral density (BMD) in athletes and a population of healthy children. However, the role of this myokine regarding the state of muscle and bone in the same population remained to be determined. For this purpose, 62 patients (age 68.71 ± 12.31 years) undergoing total hip or knee replacement were recruited. Our results showed that irisin serum levels negatively correlated with age (R = -0.515; p = .000018) and positively correlated with femoral BMD (R = 0.619; p = .001) and vertebral BMD (R = 0.201; p = .0001). Irisin was also positively associated with Fndc5 mRNA in muscle biopsies (R = 0.248; p = .016), as well as with Osteocalcin (Ocn) mRNA in bone biopsies (R = 0.708; p = .006). In skeletal muscle, FNDC5 positive fibers positively correlate with BMD of total femur (R = 0.765; p = .0014) and BMD of femoral neck (R = 0.575; p = .031), Interestingly, by analyzing patients divided by their T-score, we found lower irisin levels (p = .0011) in patients with osteopenia/osteoporosis (OP) compared to healthy controls matched for age and sex. By analyzing the senescence marker p21, we found a significant increase of its mRNA expression in the bone biopsies of OP patients compared to control ones. Therefore, we investigated in vitro whether rec-irisin had a direct effect on this senescence marker, showing that p21 mRNA expression was significantly downregulated in osteoblasts by the treatment with irisin. Overall, these results indicate that higher irisin levels are associated with a lower rate of age-related osteoporosis and that irisin could be effective in delaying the osteoblast aging process, suggesting a potential senolytic action of this myokine. © 2020 American Society for Bone and Mineral Research (ASBMR).
Keywords
- BONE-MUSCLE INTERACTIONS
- IRISIN
- OSTEOPOROSIS
- SARCOPENIA
- SENESCENCE
Altered adipose tissue may contribute to the longevity of Snell dwarf and growth hormone receptor (GHR) knock-out mice. We report here that white (WAT) and brown (BAT) fat have elevated UCP1 in both kinds of mice, and that adipocytes in WAT depots turn beige/brown. These imply increased thermogenesis and are expected to lead to improved glucose control. Both kinds of long-lived mice show lower levels of inflammatory M1 macrophages and higher levels of anti-inflammatory M2 macrophages in BAT and WAT, with correspondingly lower levels of TNFα, IL-6, and MCP1. Experiments with mice with tissue-specific disruption of GHR showed that these adipocyte and macrophage changes were not due to hepatic IGF1 production nor to direct GH effects on adipocytes, but instead reflect GH effects on muscle. Muscles deprived of GH signals, either globally (GKO) or in muscle only (MKO), produce higher levels of circulating irisin and its precursor FNDC5. The data thus suggest that the changes in adipose tissue differentiation and inflammatory status seen in long-lived mutant mice reflect interruption of GH-dependent irisin inhibition, with consequential effects on metabolism and thermogenesis.
Keywords
- adipose tissue
- aging
- growth hormone
- inflammation
- uncoupling protein 1 (UCP1)
Among the diseases of the cardiovascular system in elderly people, ischemic heart disease and myocardial infarction (MI) occupy the first place in the structure of mortality. One of the main causes of disability and death from MI is late diagnosis. In this regard, the search for new, highly informative and non-invasive methods for diagnosing MI is an important task of molecular gerontology. An enzyme immunoassay showed that the concentration of TNF-α, IL-8 cytokines and p16 aging marker in saliva in elderly people without cardiovascular pathologies (CP) increases in 2,1-4,8 times as compared with middle-aged people. At the same time, in elderly people without CP the concentration in the saliva of the hormone irisin (FNDC5) decreases by 1,8 times as compared with middle-aged people. In middle-aged patients with MI the concentration of IL-8, TNF-α, MMP8, MMP9 in saliva increases 4,3-15,3 times, and FNDC5 decreases 1,8 times compared with those parameters without CP in this age group. In elderly people with MI the concentration of IL-8, TNF-α, MMP8 and MMP9 in saliva increases 4,3-7,1 times as compared with elderly people without CP. Thus, the study of the concentration of signaling molecules IL-8, TNF-α, MMP8, MMP9 in saliva can be used as a non-invasive method for diagnosing MI in people of middle and elderly age. To assess the rate of aging of the organism in middle-aged and elderly people without CP, a study of the concentration of p16 and FNDC5 molecules in saliva is recommended.
MeSH Terms
- Aged
- Aging
- Biomarkers
- Cytokines
- Humans
- Middle Aged
- Myocardial Infarction
- Saliva
- Tumor Necrosis Factor-alpha
Keywords
- aging
- diagnosis
- myocardial infarction
- saliva
- signaling molecules
- Alzheimer's disease (AD), the primary cause of dementia in the elderly, is one of the leading age-related neurodegenerative diseases worldwide. While AD is notorious for destroying memory and cognition, dementia patients also experience greater incidence of bone loss and skeletal fracture than age-matched neurotypical individuals, greatly impacting their quality of life. Despite the significance of this comorbidity, there is no solid understanding of the mechanisms driving early bone loss in AD. Here, we review studies that have evaluated many of the obvious risk factors shared by dementia and osteoporosis, and illuminate emerging work investigating covert pathophysiological mechanisms shared between the disorders that may have potential as new risk biomarkers or therapeutic targets in AD. : Skeletal deficits emerge very early in clinical Alzheimer's progression, and cannot be explained by coincident factors such as aging, female sex, mobility status, falls, or genetics. While research in this area is still in its infancy, studies implicate several potential mechanisms in disrupting skeletal homeostasis that include direct effects of amyloid-beta pathology on bone cells, neurofibrillary tau-induced damage to neural centers regulating skeletal remodeling, and/or systemic Wnt/Beta-catenin signaling deficits. Data from an increasing number of studies substantiate a role for the newly discovered "exercise hormone" irisin and its protein precursor FNDC5 in bone loss and AD-associated neurodegeneration. We conclude that the current status of research on bone loss in AD is insufficient and merits critical attention because this work could uncover novel diagnostic and therapeutic opportunities desperately needed to address AD.
Keywords
- Aging
- Alzheimer’s
- bone density
- dementia
- osteoporosis
Use of the frailty index to measure an accumulation of deficits has been proven a valuable method for identifying elderly people at risk for increased vulnerability, disease, injury, and mortality. However, complementary molecular frailty biomarkers or ideally biomarker panels have not yet been identified. We conducted a systematic search to identify biomarker candidates for a frailty biomarker panel. Gene expression databases were searched (http://genomics.senescence.info/genes including GenAge, AnAge, LongevityMap, CellAge, DrugAge, Digital Aging Atlas) to identify genes regulated in aging, longevity, and age-related diseases with a focus on secreted factors or molecules detectable in body fluids as potential frailty biomarkers. Factors broadly expressed, related to several "hallmark of aging" pathways as well as used or predicted as biomarkers in other disease settings, particularly age-related pathologies, were identified. This set of biomarkers was further expanded according to the expertise and experience of the authors. In the next step, biomarkers were assigned to six "hallmark of aging" pathways, namely (1) inflammation, (2) mitochondria and apoptosis, (3) calcium homeostasis, (4) fibrosis, (5) NMJ (neuromuscular junction) and neurons, (6) cytoskeleton and hormones, or (7) other principles and an extensive literature search was performed for each candidate to explore their potential and priority as frailty biomarkers. A total of 44 markers were evaluated in the seven categories listed above, and 19 were awarded a high priority score, 22 identified as medium priority and three were low priority. In each category high and medium priority markers were identified. Biomarker panels for frailty would be of high value and better than single markers. Based on our search we would propose a core panel of frailty biomarkers consisting of (1) CXCL10 (C-X-C motif chemokine ligand 10), IL-6 (interleukin 6), CX3CL1 (C-X3-C motif chemokine ligand 1), (2) GDF15 (growth differentiation factor 15), FNDC5 (fibronectin type III domain containing 5), vimentin (VIM), (3) regucalcin (RGN/SMP30), calreticulin, (4) PLAU (plasminogen activator, urokinase), AGT (angiotensinogen), (5) BDNF (brain derived neurotrophic factor), progranulin (PGRN), (6) α-klotho (KL), FGF23 (fibroblast growth factor 23), FGF21, leptin (LEP), (7) miRNA (micro Ribonucleic acid) panel (to be further defined), AHCY (adenosylhomocysteinase) and KRT18 (keratin 18). An expanded panel would also include (1) pentraxin (PTX3), sVCAM/ICAM (soluble vascular cell adhesion molecule 1/Intercellular adhesion molecule 1), defensin α, (2) APP (amyloid beta precursor protein), LDH (lactate dehydrogenase), (3) S100B (S100 calcium binding protein B), (4) TGFβ (transforming growth factor beta), PAI-1 (plasminogen activator inhibitor 1), TGM2 (transglutaminase 2), (5) sRAGE (soluble receptor for advanced glycosylation end products), HMGB1 (high mobility group box 1), C3/C1Q (complement factor 3/1Q), ST2 (Interleukin 1 receptor like 1), agrin (AGRN), (6) IGF-1 (insulin-like growth factor 1), resistin (RETN), adiponectin (ADIPOQ), ghrelin (GHRL), growth hormone (GH), (7) microparticle panel (to be further defined), GpnmB (glycoprotein nonmetastatic melanoma protein B) and lactoferrin (LTF). We believe that these predicted panels need to be experimentally explored in animal models and frail cohorts in order to ascertain their diagnostic, prognostic and therapeutic potential.
MeSH Terms
- Aged
- Aging
- Amyloid beta-Peptides
- Amyloid beta-Protein Precursor
- Animals
- Apoptosis
- Biomarkers
- Fibronectins
- Frailty
- Genetic Association Studies
- Growth Differentiation Factor 15
- Humans
- Insulin-Like Growth Factor I
- Interleukin-1 Receptor-Like 1 Protein
- Membrane Glycoproteins
- MicroRNAs
- Signal Transduction
Keywords
- Age-related diseases
- Biomarker panel
- Frailty
- Hallmark of aging pathways
This study aimed to determine the effect of exercise training on cognitive functioning, and hippocampal PGC-1α, FNDC5, BDNF, and other cognition-related gene and protein expression in rats. Rats were divided into 4 groups based on age [3 months (young) vs. 20 months (aged)] and training status (control vs. exercise training). The rats that exercised voluntarily performed exercise training for 90 days, and then all the rats underwent several methods of behavioral assessment. Locomotor activity and spatial memory were lower but anxiety scores were higher in the aged control rats, than in the young control, young exercised, and aged exercised rats (P < 0.05). Hippocampal BDNF, FNDC5, PGC-1α, mTOR, ARC, cF-OS, ERK, SIRT, and FOXO expressions were lower, but NF-κB expressions were higher in the aged control rats than in the young control, young exercised, and aged exercised rats (P < 0.05). Similarly, hippocampal BDNF and FNDC5 protein expression were lower in the aged control rats than in the young control, young exercised, and aged exercised rats (P < 0.05). These findings show that aging-induced cognitive dysfunction is associated with a decrease in hippocampal expression of PGC-1α, FNDC5, and BDNF, and that exercise training might improve cognitive functioning via activation of these genes and proteins.
MeSH Terms
- Accessory Atrioventricular Bundle
- Aging
- Animals
- Anxiety
- Body Weight
- Brain-Derived Neurotrophic Factor
- Cognitive Dysfunction
- Exploratory Behavior
- Female
- Fibronectins
- Hippocampus
- Locomotion
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- Physical Conditioning, Animal
- Rats
- Signal Transduction
- Spatial Memory
Keywords
- Aging
- BDNF
- Cognition
- Exercise
- FNDC5
- Irisin
Forkhead box O3A (FOXOA3) and apolipoprotein E (APOE) are arguably the strongest gene candidates to influence human exceptional longevity (EL, i.e., being a centenarian), but inconsistency exists among cohorts. Epistasis, defined as the effect of one locus being dependent on the presence of 'modifier genes', may contribute to explain the missing heritability of complex phenotypes such as EL. We assessed the potential association of epistasis among candidate polymorphisms related to physical capacity, as well as antioxidant defense and cardiometabolic traits, and EL in the Japanese population. A total of 1565 individuals were studied, subdivided into 822 middle-aged controls and 743 centenarians. We found a FOXOA3 rs2802292 T-allele-dependent association of fibronectin type III domain-containing 5 (FDNC5) rs16835198 with EL: the frequency of carriers of the FOXOA3 rs2802292 T-allele among individuals with the rs16835198 GG genotype was significantly higher in cases than in controls (P < 0.05). On the other hand, among non-carriers of the APOE 'risk' ε4-allele, the frequency of the FDNC5 rs16835198 G-allele was higher in cases than in controls (48.4% vs. 43.6%, P < 0.05). Among carriers of the 'non-risk' APOE ε2-allele, the frequency of the rs16835198 G-allele was higher in cases than in controls (49% vs. 37.3%, P < 0.05). The association of FDNC5 rs16835198 with EL seems to depend on the presence of the FOXOA3 rs2802292 T-allele and we report a novel association between FNDC5 rs16835198 stratified by the presence of the APOE ε2/ε4-allele and EL. More research on 'gene*gene' and 'gene*environment' effects is needed in the field of EL.
MeSH Terms
- Adult
- Apolipoproteins E
- Epistasis, Genetic
- Exercise
- Female
- Fibronectins
- Forkhead Box Protein O3
- Gene Frequency
- Genotype
- Humans
- Longevity
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Young Adult
Keywords
- APOE
- Ageing
- Centenarians
- Exceptional longevity
- FNDC5
- FOXO3A
Exercise is known to have numerous beneficial effects. Recent studies indicate that exercise improves mitochondrial energetics not only in skeletal muscle but also in other tissues. While exercise elicits positive effects on memory, neurogenesis, and synaptic plasticity, the effects of exercise on brain mitochondrial energetics remain relatively unknown. Herein, we studied the effects of exercise training in old and young mice on brain mitochondrial energetics, in comparison to known effects on peripheral tissues that utilize fatty acid oxidation. Exercise improved the capacity for muscle and liver to oxidize palmitate in old mice, but not young mice. In the brain, exercise increased rates of respiration and reactive oxygen species (ROS) production in the old group only while utilizing complex I substrates, effects that were not seen in the young group. Coupled complex I to III enzymatic activity was significantly increased in old trained versus untrained mice with no effect on coupled II to III enzymatic activity. Mitochondrial protein content and markers of mitochondrial biogenesis (PGC-1α and TFAM) were not affected by exercise training in the brain, in contrast to the skeletal muscle of old mice. Brain levels of the autophagy marker LC3-II and protein levels of other signaling proteins that regulate metabolism or transport (BDNF, HSP60, phosphorylated mTOR, FNDC5, SIRT3) were not significantly altered. Old exercised mice showed a significant increase in DRP1 protein levels in the brain without changes in phosphorylation, while MFN2 and OPA1 protein levels were unchanged. Our results suggest that exercise training in old mice can improve brain mitochondrial function through effects on electron transport chain function and mitochondrial dynamics without increasing mitochondrial biogenesis.
MeSH Terms
- Aging
- Animals
- Cerebellar Cortex
- Dynamins
- Electron Transport Complex I
- Male
- Mice
- Mice, Inbred C57BL
- Mitochondria, Muscle
- Mitochondrial Dynamics
- Mitochondrial Proteins
- Organelle Biogenesis
- Physical Conditioning, Animal
- Reactive Oxygen Species
- Signal Transduction
Keywords
- Brain
- Complex I
- Cortex
- DRP1
- Exercise
- Mitochondria
Irisin has recently been described as a novel myokine, which reduces visceral obesity and improves glucose metabolism in mice. Thus, polymorphisms in the gene encoding irisin, fibronectin type III domain containing 5 (FNDC5), may be associated with type 2 diabetes mellitus (T2DM) and related disorders. However, to date, no study has investigated the association between FNDC5 polymorphisms and susceptibility to T2DM. To investigate the association of FNDC5 rs3480 (A/G) and rs1746661 (G/T) polymorphisms, alone or in combination, with T2DM and its clinical features. We analyzed 1006 T2DM patients and 434 nondiabetic subjects. Polymorphisms were genotyped by real-time PCR using TaqMan MGB probes. Haplotypes constructed from the combination of rs1746661 and rs3480 polymorphisms were inferred using the Phase 2.1 program. Genotype, allele and haplotype frequencies of rs1746661 and rs3480 polymorphisms did not differ significantly between nondiabetic subjects and T2DM patients. Women with T2DM carrying the G allele of rs3480 showed increased HbA1c levels compared with A/A carriers, adjusted for age. The T allele of rs1746661 was associated with increased systolic blood pressure, total cholesterol and LDL-cholesterol and decreased HDL-cholesterol in women with T2DM, adjusted for covariates. Moreover, prevalence of hypercholesterolemia was higher in women carrying the T allele of rs1746661 than in G/G carriers (72.4% vs. 58.7%, OR=2.010, 95% CI=1.210-3.390), but it was not significantly different in men. These results indicate that, although not associated with T2DM, the G allele of rs3480 appears to be associated with increased HbA1c, while the T allele of rs1746661 appears to be associated with higher systolic blood pressure and dyslipidemia in women with T2DM.
MeSH Terms
- Aging
- Blood Pressure
- Cholesterol
- Diabetes Mellitus, Type 2
- Female
- Fibronectins
- Gene Frequency
- Genotype
- Glycated Hemoglobin A
- Heterozygote
- Humans
- Linkage Disequilibrium
- Lipids
- Male
- Middle Aged
- Polymorphism, Genetic
- Sex Characteristics
Keywords
- Blood pressure
- Dyslipidemia
- FNDC5 gene
- Irisin
- Type 2 diabetes mellitus
Irisin might play an important role in reducing the risk of obesity, insulin resistance, or several related diseases, and high irisin levels may contribute to successful aging. Thus, the irisin precursor (FNDC5) gene is a candidate to influence exceptional longevity (EL), i.e., being a centenarian. It has been recently shown that two single-nucleotide polymorphisms (SNPs) in the FNDC5 gene, rs16835198 and rs726344, are associated with in vivo insulin sensitivity in adults. We determined luciferase gene reporter activity in the two above-mentioned SNPs and studied genotype distributions among centenarians (n = 175, 144 women) and healthy controls (n = 347, 142 women) from Spain. We also studied an Italian [79 healthy centenarians (40 women) and 316 healthy controls (156 women)] and a Japanese cohort [742 centenarians (623 women) and 499 healthy controls (356 women)]. The rs726344 SNP had functional significance, as shown by differences in luciferase activity between the constructs of this SNP (all P ≤ 0.05), with the variant A-allele having higher luciferase activity compared with the G-allele (P = 0.04). For the rs16835198 SNP, the variant T-allele tended to show higher luciferase activity compared with the G-allele (P = 0.07). However, we found no differences between genotype/allele frequencies of the two SNPs in centenarians versus controls in any cohort, and no significant association (using logistic regression adjusted by sex) between the two SNPs and EL. Further research is needed with different cohorts as well as with additional variants in the FNDC5 gene or in other genes involved in irisin signaling.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Cohort Studies
- Confidence Intervals
- Female
- Fibronectins
- Gene Frequency
- Genotype
- Humans
- Italy
- Japan
- Logistic Models
- Longevity
- Male
- Middle Aged
- Odds Ratio
- Polymorphism, Single Nucleotide
- Reference Values
- Spain
- Young Adult