FGF21
Fibroblast growth factor 21 precursor (FGF-21) [UNQ3115/PRO10196]
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Diet can affect health and longevity by altering the gut microbiome profile. Sulfur amino acid restriction (SAAR), like caloric restriction, extends lifespan. But, its effect on the gut microbiome profile and functional significance of such effects are understudied. We investigated whether SAAR alters the gut microbiome profile and bile acid composition, an index of microbial metabolism. We also compared these changes with those induced by a 12% low-calorie diet (LCD). Male 21-week-old C57BL6/J mice were fed CD (0.86% methionine), SAAR (0.12% methionine), and LCD diets (0.86% methionine). After ten weeks on the diet, plasma markers and fecal microbial profiles were determined. SAAR mice had lower body weights and IGF-1, and higher food intake and FGF21 than CD mice. Compared to SAAR mice, LCD mice had higher body weights, lower FGF-21 and food intake, but similar IGF-1. β-Diversity indices were different between SAAR and LCD, LCD and CD, but not between CD and SAAR. In group-wise comparisons of individual taxa, differences were more discernable between SAAR and LCD than between other groups. Abundances of firmicutes, clostridiaceae, and turicibacteraceae were higher, but verrucomicrobia was lower in SAAR than in LCD. Secondary bile acids and the ratio of secondary to primary bile acids were lower in SAAR than in LCD. SAAR favored bile acid conjugation with glycine at the expense of taurine. Overall, SAAR and LCD diets induced distinct changes in the gut microbiome and bile acid profiles. Additional studies on the role of these changes in improving health and lifespan are warranted.
Keywords
- Clostridales
- firmicutes
- lifespan
- methionine restriction
- sulfur metabolism
Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF15), and Humanin (HN) are mitochondrial stress-related mitokines, whose role in health and disease is still debated. In this study, we confirmed that their plasma levels are positively correlated with age in healthy subjects. However, when looking at patients with type 2 diabetes (T2D) or Alzheimer's disease (AD), two age-related diseases sharing a mitochondrial impairment, we found that GDF15 is elevated in T2D but not in AD and represents a risk factor for T2D complications, while FGF21 and HN are lower in AD but not in T2D. Moreover, FGF21 reaches the highest levels in centenarian' offspring, a model of successful aging. As a whole, these data indicate that (i) the adaptive mitokine response observed in healthy aging is lost in age-related diseases, (ii) a common expression pattern of mitokines does not emerge in T2D and AD, suggesting an unpredicted complexity and disease-specificity, and (iii) FGF21 emerges as a candidate marker of healthy aging.
Keywords
- AD
- Aging
- FGF21
- GDF15
- Humanin
- T2D
The cause of Alzheimer's disease (AD) is poorly understood. In 1991, the amyloid hypothesis postulated that β-amyloid (Aβ) accumulation is a key element. It follows that clearing the brain of Aβ would be beneficial, which has not been the case. Therefore, Aβ is likely a result, not a cause, of AD and may be protective rather than harmful. The apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor for AD. Klotho (KL), encoded by the KL gene, may be another AD-related protein. FGF21 is a circulating endocrine hormone, mainly secreted by the liver, mostly during fasting. FGF21 acts by binding to its receptor FGFR1 and co-receptor β-klotho. FGF21 is neuroprotective and could delay onset of AD. In the present study, the KL protein structure was examined to determine whether it may interact with Aβ. Protein data bank (pdb) entries for klotho and Aβ were searched on the RCSB Protein Data Bank for β-KL and AD amyloid β-peptide. The protein structures were superimposed and aligned on PYMOL v2.3.4 with the super command, which super aligns two protein selections. To evaluate the conservation and alignment of the Aβ and KL genomes across species, BLAT, the Blast-Like Alignment Tool of the UCSC Genome Browser, was used. The amino acid residues phe76-val96 of KL aligned closely with residues asp7-asn27 of Aβ. Cross-species comparison of KL revealed a high degree of alignment and conservation in the chimp and 27 other primates; however, less alignment and conservation were observed in the mouse, dog and elephant, even less in the chicken, western clawed frog ([i]Xenopus tropicalis[/i]), zebrafish and lamprey. The current finding of amino acid residues phe76-val96 of klotho aligning closely with residues asp7-asn27 of Aβ suggests that Aβ can enhance the ability of klotho to draw FGF21 to regions of incipient neurodegeneration in AD. The problem arises with age. Older individuals do not heal or repair tissue damage as well as younger individuals. As neurodegeneration advances in an older individual, perhaps caused by neuroinflammation related to herpes simplex virus type 1, increasing amounts of amyloid are produced, forming an adhesive web, as the brain tries to hold the pathologic process in check. Meanwhile, the damage increases and spreads. Progressive neurodegeneration and cognitive decline are the outcome.
Keywords
- Alzheimer’s disease
- HSV-1
- aging
- alignment
- klotho
- neurodegeneration
- neuroinflammation
- protein
- ubiquitin
- β-amyloid
Circulating levels of fibroblast growth factor 21 (FGF21) increase with advancing age and may lead to the development of cardiometabolic diseases via impaired lipid and glucose metabolism. While physical activity can reduce these risks of cardiometabolic dysfunction, it remains obscure whether circulation FGF21 levels are influenced by physical activity. The purpose of this study was to investigate the relations between daily physical activities and circulating FGF21 levels in middle-aged and older adults. In this cross-sectional study with 110 middle-aged and 102 older adults, circulating (serum) FGF21 levels were evaluated by enzyme-linked immunosorbent assay, and the time spent in light-intensity physical activity (LPA) and moderate-to-vigorous-intensity physical activity (MVPA) was assessed using a uniaxial accelerometer. Serum FGF21 levels in the older group (158 pg/mL) were significantly higher than those in the middle-aged group (117 pg/mL). When we examined the joint association of age (middle-aged or older) and MVPA (lower or higher than the median) groups, serum FGF21 levels in the older and higher MVPA group (116 pg/mL) were significantly lower than those in the older and lower MVPA group (176 pg/mL). However, there was no difference in serum FGF21 levels between the lower and higher MVPA groups in the middle-aged group. In multivariable liner regression analysis, serum FGF21 levels were independently determined by MVPA time after adjusting for potential covariates in older adults (β = -0.209). These cross-sectional study findings indicate that the time spent in MVPA is an independent determinant of circulating FGF21 levels, and that an age-related increase in serum FGF21 levels may be attenuated by habitually performing MVPA. (250/250 words).
Keywords
- Accelerometer
- Activity intensity
- Aging
- FGF21
- Physical activity
Exercise and dietary intervention are currently available strategies to treat nonalcoholic fatty liver disease (NAFLD), while the underlying mechanism remains controversial. Emerging evidence shows that lipophagy is involved in the inhibition of the lipid droplets accumulation. However, it is still unclear if exercise and dietary intervention improve NAFLD through regulating lipophagy, and how exercise of skeletal muscle can modulate lipid metabolism in liver. Moreover, NAFLD is associated with aging, and little is known about the effect of lipid accumulation on aging process. Here in vivo and in vitro models, we found that exercise and dietary intervention reduced lipid droplets formation, decreased hepatic triglyceride in the liver induced by high-fat diet. Exercise and dietary intervention enhanced the lipophagy by activating AMPK/ULK1 and inhibiting Akt/mTOR/ULK1 pathways respectively. Furthermore, exercise stimulated FGF21 production in the muscle, followed by secretion to the circulation to promote the lipophagy in the liver via an AMPK-dependent pathway. Importantly, for the first time, we demonstrated that lipid accumulation exacerbated liver aging, which was ameliorated by exercise and dietary intervention through inducing lipophagy. Our findings suggested a new mechanism of exercise and dietary intervention to improve NAFLD through promoting lipophagy. The study also provided evidence to support that muscle exercise is beneficial to other metabolic organs such as liver. The FGF21-mediated AMPK dependent lipophagy might be a potential drug target for NAFLD and aging caused by lipid metabolic dysfunction.
Keywords
- Aging
- Exercise
- FGF21
- Lipophagy
- Nonalcoholic fatty liver disease (NAFLD)
A global reshaping of the immune responses occurs with ageing, indicated as immunosenescence, where mitochondria and mitochondrial metabolism play an important role. However, much less is known about the role of mitochondrial stress response in this reshaping and in particular of the molecules induced by such response, collectively indicated as mitokines. In this review, we summarize the current knowledge on the role of mitokines in modulating immune response and inflammation focusing on GDF15, FGF21 and humanin and their possible involvement in the chronic age-related low-grade inflammation dubbed inflammaging. Although many aspects of their biology are still controversial, available data suggest that these mitokines have an anti-inflammatory role and increase with age. Therefore, we hypothesize that they can be considered part of an adaptive and integrated immune-metabolic mechanism activated by mitochondrial dysfunction that acts within the framework of a larger anti-inflammatory network aimed at controlling both acute inflammation and inflammaging.
Keywords
- Human ageing
- Immunosenescence
- Inflammaging
- Mitochondrial metabolism
- Mitokines
Trade-offs in life-history traits are clinically and mechanistically important. Sulfur amino acid restriction (SAAR) extends lifespan. But whether this benefit comes at the cost of other traits including stress resistance and growth is unclear. We investigated the effects of SAAR on growth markers (body weight, IGF1, and IGFBP3) and physiological stresses. Male-F344 rats were fed control (0.86% Met) and SAAR (0.17% Met) diets starting at 2, 10, and 20 months. Rats were injected with keyhole-limpet-hemocyanin (KLH) to measure immune responses (anti-KLH-IgM, anti-KLH-IgG, and delayed-type-hypersensitivity [DTH]). Markers of ER stress (FGF21 and adiponectin), detoxification capacity (glutathione [GSH] concentrations, GSH-S-transferase [GST], and cytochrome-P -reductase [CPR] activities), and low-grade inflammation (C-reactive protein [CRP]) were also determined. SAAR decreased body weight, liver weight, food intake, plasma IGF1, and IGFBP3; the effect size diminished with increasing age-at-onset. SAAR increased FGF21 and adiponectin, but stress damage markers GRP78 and Xbp1 were unchanged, suggesting that ER stress is hormetic. SAAR increased hepatic GST activity despite lower GSH, but CPR activity was unchanged, indicative of enhanced detoxification capacity. Other stress markers were either uncompromised (CRP, anti-KLH-IgM, and DTH) or slightly lower (anti-KLH-IgG). Increases in stress markers were similar across all ages-at-onset, except for adiponectin, which peaked at 2 months. Overall, SAAR did not compromise stress responses and resulted in maximal benefits with young-onset. In survival studies, median lifespan extension with initiation at 52 weeks was 7 weeks (p = .05); less than the 33.5-week extension observed in our previous study with 7-week initiation. Findings support SAAR translational studies and the need to optimize Met dose based on age-at-onset.
Keywords
- ER stress
- cysteine
- glutathione
- hormesis
- lifespan
- methionine
- trade-offs
- translational
Fibroblast growth factor 21 (FGF21), an FGF family member, is an atypical hormone and pro-longevity factor. To better understand of the effects of exogenous administration of FGF21 on lifespan and stress tolerance, and the underlying molecular basis, we used the silkworm, [i]Bombyx mori[/i], as an experimental animal model to evaluate FGF21's pharmaceutical effects. Lifespan was significantly prolonged in female silkworms with FGF21 replenishment, whereas no effect was observed in the male silkworms. FGF21 replenishment also significantly improved the activity of antioxidant systems such as glutathione-S-transferase (GST) and superoxide dismutase (SOD) and significantly decreased malondialdehyde (MDA) content. Moreover, FGF21 was found to play a critical role in enhancing stress resistance, including ultraviolet (UV) irradiation tolerance and thermotolerance. Furthermore, [i]AMPK[/i], [i]FoxO[/i], and sirtuins were activated by FGF21 and may be responsible for the prolonged lifespan and enhanced antioxidant activity observed in silkworms. Collectively, the results suggest the molecular pathways underlying of FGF21-induced longevity and stress tolerance, and support the use of silkworms as a promising experimental animal model for evaluating the pharmaceutical effects of small molecules.
Keywords
- Bombyx mori
- fibroblast growth factor 21 (FGF21)
- lifespan
- oxidation resistance
- stress tolerance
Frailty is a risk factor for cardiovascular disease (CVD). Biomarkers have the potential to detect the early stages of frailty, such as pre-frailty. Myokines may act as biomarkers of frailty-related disease progression, as a decline in muscle health is a hallmark of the frailty phenotype. This study is a secondary analysis of 104 females 55 years of age or older with no previous history of CVD. Differences in systemic myokine concentrations based on frailty status and CVD risk profile were examined using a case-control design. Propensity matching identified two sets of 26 pairs with pre-frailty as the exposure variable in low or elevated CVD risk groups for a total 104 female participants. Frailty was assessed using the Fried Criteria (FC) and CVD risk was assessed using the Framingham Risk Score (FRS). Factorial ANOVA compared the main effects of frailty, CVD risk, and their interaction on the concentrations of 15 myokines. Differences were found when comparing elevated CVD risk status with low for the concentrations of EPO (384.76 ± 1046.07 vs. 206.63 ± 284.61 pg/mL, p = .001), FABP3 (2772.61 ± 3297.86 vs. 1693.31 ± 1019.34 pg/mL, p = .017), FGF21 (193.17 ± 521.09 vs. 70.18 ± 139.51 pg/mL, p = .010), IL-6 (1.73 ± 4.97 vs. 0.52 ± 0.89 pg/mL, p = .023), and IL-15 (2.62 ± 10.56 vs. 0.92 ± 1.25 pg/mL, p = .022). Pre-frail females had lower concentrations of fractalkine compared to robust (27.04 ± 20.60 vs. 103.62 ± 315.45 pg/mL, p = .004). Interaction effects between frailty status and CVD risk for FGF21 and OSM were identified. In elevated CVD risk, pre-frail females, concentrations of FGF21 and OSM were lower than that of elevated CVD risk, robust females (69.10 ± 62.86 vs. 317.24 ± 719.69, p = .011; 1.73 ± 2.32 vs. 24.43 ± 69.21, p = .018, respectively). These data identified specific biomarkers of CVD risk and biomarkers of frailty that are exacerbated with CVD risk.
Keywords
- Aging
- Biomarkers
- Cardiovascular disease
- Females
- Frailty
- Myokines
The gut microbiota evolves as the host ages, yet the effects of these microbial changes on host physiology and energy homeostasis are poorly understood. To investigate these potential effects, we transplanted the gut microbiota of old or young mice into young germ-free recipient mice. Both groups showed similar weight gain and skeletal muscle mass, but germ-free mice receiving a gut microbiota transplant from old donor mice unexpectedly showed increased neurogenesis in the hippocampus of the brain and increased intestinal growth. Metagenomic analysis revealed age-sensitive enrichment in butyrate-producing microbes in young germ-free mice transplanted with the gut microbiota of old donor mice. The higher concentration of gut microbiota-derived butyrate in these young transplanted mice was associated with an increase in the pleiotropic and prolongevity hormone fibroblast growth factor 21 (FGF21). An increase in FGF21 correlated with increased AMPK and SIRT-1 activation and reduced mTOR signaling. Young germ-free mice treated with exogenous sodium butyrate recapitulated the prolongevity phenotype observed in young germ-free mice receiving a gut microbiota transplant from old donor mice. These results suggest that gut microbiota transplants from aged hosts conferred beneficial effects in responsive young recipients.
MeSH Terms
- Animals
- Butyrates
- Fecal Microbiota Transplantation
- Fibroblast Growth Factors
- Gastrointestinal Microbiome
- Germ-Free Life
- Hippocampus
- Intestines
- Liver
- Longevity
- Male
- Metabolome
- Mice, Inbred C57BL
- Microtubule-Associated Proteins
- Neurogenesis
- Neurons
- Neuropeptides
- Phenotype
- Proton Magnetic Resonance Spectroscopy
Aging increases the prevalence of glucose intolerance, but exercise improves glucose homeostasis. The fibroblast growth factor 21 (FGF21)-adiponectin axis helps regulate glucose metabolism. However, the role of FGF21 in mediating glucose metabolism with aging and exercise remains unknown. This study examined whether FGF21 responses to a glucose challenge are associated with habitual exercise, aging and glucose regulation. Eighty age- and sex-matched healthy individuals were assigned to young sedentary and active (≤36 yr, n = 20 each group) and older sedentary and active (≥45 yr, n = 20 each group) groups. Fasted and postprandial blood glucose concentration and plasma concentration of insulin, FGF21, and adiponectin were determined during an oral glucose tolerance test (OGTT). During the OGTT, glucose concentrations were 9% higher (P = 0.008) and FGF21 concentrations were 58% higher (P = 0.014) in the older than the younger group, independent of activity status. Active participants had 40% lower insulin concentration and 53% lower FGF21 concentration than sedentary participants, independent of age (all P < 0.001). Adiponectin concentration during the OGTT did not differ by age (P = 0.448) or activity status (P = 0.611). Within the younger group, postprandial glucose, insulin and FGF21 concentrations during the OGTT were lower in active than in sedentary participants. In the older group, only postprandial insulin and FGF21 concentrations were lower in active participants. FGF21, but not adiponectin, response during the OGTT is higher in older than younger adults and lower in active than sedentary individuals. Exercise-associated reduction in OGTT glucose concentrations was observed in younger but not older adults.
MeSH Terms
- Adiponectin
- Adult
- Aging
- Blood Glucose
- Blood Pressure
- Body Mass Index
- Diabetes Mellitus, Type 2
- Exercise
- Female
- Fibroblast Growth Factors
- Glucose Tolerance Test
- Humans
- Insulin
- Lipids
- Male
- Middle Aged
- Risk Factors
Ageing is a major risk factor for the development of metabolic disorders linked to dyslipidemia, usually accompanied by increased adiposity. The goal of this work was to investigate whether avoiding an excessive increase in adiposity with ageing, via moderate chronic food restriction (FR), ameliorates postprandial dyslipidemia in a rat model of metabolic syndrome associated with ageing. Accordingly, we performed an oral lipid loading test (OLLT) in mature middle-aged (7 months) and middle-old-aged (24 months) Wistar rats fed ad libitum (AL) or under moderate FR for 3 months. Briefly, overnight fasted rats were orally administered a bolus of extra-virgin olive oil (1 mL/Kg of body weight) and blood samples were taken from the tail vein before fat load (t = 0) and 30, 60, 90, 120, 180, and 240 min after fat administration. Changes in serum lipids, glucose, insulin, and glucagon levels were measured at different time-points. Expression of liver and adipose tissue metabolic genes were also determined before (t = 0) and after the fat load (t = 240 min). Postprandial dyslipidemia progressively increased with ageing and this could be associated with hepatic ChREBP activity. Interestingly, moderate chronic FR reduced adiposity and avoided excessive postprandial hypertriglyceridemia in 7- and 24-month-old Wistar rats, strengthening the association between postprandial triglyceride levels and adiposity. The 24-month-old rats needed more insulin to maintain postprandial normoglycemia; nevertheless, hyperglycemia occurred at 240 min after fat administration. FR did not alter the fasted serum glucose levels but it markedly decreased glucagon excursion during the OLLT and the postprandial rise of glycemia in the 24-month-old rats, and FGF21 in the 7-month-old Wistar rats. Hence, our results pointed to an important role of FR in postprandial energy metabolism and insulin resistance in ageing. Lastly, our data support the idea that the vWAT might function as an ectopic site for fat deposition in 7-month-old and in 24-month-old Wistar rats that could increase their browning capacity in response to an acute fat load.
MeSH Terms
- Adiposity
- Aging
- Animals
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
- Blood Glucose
- Diet, Fat-Restricted
- Dietary Fats
- Disease Models, Animal
- Dyslipidemias
- Glucagon
- Insulin
- Lipids
- Liver
- Metabolic Syndrome
- Postprandial Period
- Rats
- Rats, Wistar
- Triglycerides
Keywords
- ChREBP
- adipose tissue
- ageing
- oral lipid loading test
- postprandial hypertrigliceridemia
- postprandial thermogenesis
The maintenance of muscle mass and its ability to function relies on a bioenergetic efficient mitochondrial network. This network is highly impacted by fusion and fission events. We have recently shown that the acute deletion of the fusion protein Opa1 induces muscle atrophy, systemic inflammatory response, precocious epithelial senescence, and premature death that are caused by muscle-dependent secretion of FGF21. However, both fusion and fission machinery are suppressed in aging sarcopenia, cancer cachexia, and chemotherapy-induced muscle wasting. We generated inducible muscle-specific Opa1 and Drp1 double-knockout mice to address the physiological relevance of the concomitant impairment of fusion and fission machinery in skeletal muscle. Here we show that acute ablation of Opa1 and Drp1 in adult muscle causes the accumulation of abnormal and dysfunctional mitochondria, as well as the inhibition of autophagy and mitophagy pathways. This ultimately results in ER stress, muscle loss, and the reduction of force generation. However, the simultaneous inhibition of the fission protein Drp1 when Opa1 is absent alleviates FGF21 induction, oxidative stress, denervation, and inflammation rescuing the lethal phenotype of Opa1 knockout mice, despite the presence of any muscle weakness. Thus, the simultaneous inhibition of fusion and fission processes mitigates the detrimental effects of unbalanced mitochondrial fusion and prevents the secretion of pro-senescence factors.
MeSH Terms
- Aging
- Animals
- Autophagy
- Dynamins
- Endoplasmic Reticulum Stress
- Fibroblast Growth Factors
- GTP Phosphohydrolases
- Mice, Knockout
- Mitochondria
- Mitochondrial Dynamics
- Mitophagy
- Muscle Weakness
- Muscle, Skeletal
- Muscular Atrophy
- Oxidative Stress
- Proteasome Endopeptidase Complex
- Proteolysis
- Ubiquitin
Keywords
- FGF21
- fission
- mitochondrial fusion
- mitophagy
- muscle dystrophy
- muscle wasting
Fibroblast growth factor (FGF)21 is promptly induced by short fasting in animal models to regulate glucose and fat metabolism. Data on FGF21 in humans are inconsistent and FGF21 has not yet been investigated in old patients with cachexia, a complex syndrome characterized by inflammation and weight loss. The aim of this study was to explore the association of FGF21 with cachexia in old patients compared with their healthy counterparts. Serum FGF21 and its inactivating enzyme fibroblast activation protein (FAP)-α were measured with enzyme-linked immunoassays. Cachexia was defined as ≥5% weight loss in the previous 3 mo and concurrent anorexia (Council on Nutrition appetite questionnaire). We included 103 patients with and without cachexia (76.9 ± 5.2 y of age) and 56 healthy controls (72.9 ± 5.9 y of age). Cachexia was present in 16.5% of patients. These patients had significantly higher total FGF21 levels than controls (952.1 ± 821.3 versus 525.2 ± 560.3 pg/mL; P = 0.012) and the lowest FGF21 levels (293.3 ± 150.9 pg/mL) were found in the control group (global P < 0.001). Although FAP-α did not differ between the three groups (global P = 0.082), bioactive FGF21 was significantly higher in patients with cachexia (global P = 0.002). Risk factor-adjusted regression analyses revealed a significant association between cachexia and total (β = 649.745 pg/mL; P < 0.001) and bioactive FGF21 (β = 393.200 pg/mL; P <0.001), independent of sex, age, and body mass index. Patients with cachexia exhibited the highest FGF21 levels. Clarification is needed to determine whether this is an adaptive response to nutrient deprivation in disease-related cachexia or whether the increased FGF21 values contribute to the catabolic state.
MeSH Terms
- Aged
- Aged, 80 and over
- Cachexia
- Cross-Sectional Studies
- Female
- Fibroblast Growth Factors
- Gelatinases
- Humans
- Male
- Membrane Proteins
- Pilot Projects
- Prospective Studies
- Serine Endopeptidases
- Weight Loss
Keywords
- Aging
- Anorexia
- Biomarker
- Cachexia
- Fibroblast growth factor 21
Caloric restriction (CR) suppresses age-related pathophysiology and extends lifespan. We recently reported that metabolic remodeling of white adipose tissue (WAT) plays an important role in the beneficial actions of CR; however, the detailed molecular mechanisms of this remodeling remain to be established. In the present study, we aimed to identify CR-induced alterations in the expression of fibroblast growth factor 21 (FGF21), a regulator of lipid and glucose metabolism, and of its downstream signaling mediators in liver and WAT, across the lifespan of rats. We evaluated groups of rats that had been either fed ad libitum or calorie restricted from 3 months of age and were euthanized at 3.5, 9, or 24 months of age, under fed and fasted conditions. The expression of FGF21 mRNA and/or protein increased with age in liver and WAT. Interestingly, in the WAT of 9-month-old fed rats, CR further upregulated FGF21 expression and eliminated the aging-associated reductions in the expression of FGFR1 and beta-klotho (KLB; FGF21 receptor complex). It also enhanced the expression of FGF21 targets, including glucose transporter 1 and peroxisome proliferator-activated receptor (PPAR)γ coactivator-1α. The analysis of transcriptional regulators of Fgf21 suggested that aging and CR might upregulate Fgf21 expression via different mechanisms. In adipocytes in vitro, constitutive FGF21 overexpression upregulated the FGF21 receptor complex and FGF21 targets at the mRNA or protein level. Thus, both aging and CR induced FGF21 expression in rat WAT; however, only CR activated FGF21 signaling. Our results suggest that FGF21 signaling contributes to the CR-induced metabolic remodeling of WAT, likely activating glucose uptake and mitochondrial biogenesis.
MeSH Terms
- 3T3-L1 Cells
- Adipose Tissue, White
- Aging
- Animals
- Caloric Restriction
- Fibroblast Growth Factors
- Glucose Transporter Type 1
- Male
- Mice
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- Rats
- Rats, Wistar
- Signal Transduction
Keywords
- Caloric restriction
- Fibroblast growth factor 21
- Glucose transporter 1
- White adipose tissue
- β-Klotho
Three fibroblast growth factor(FGF) members, FGF19, FGF21, and FGF23, function as endocrine factors that regulate various metabolic processes. The unique feature of these endo- crine FGFs is the fact that they require Klotho proteins to bind to their cognate FGF recep- tors. Defects in Klotho or FGF23 result in disturbed mineral metabolism and accelerated aging. The aging phenotypes can be alleviated by correcting phosphate imbalance, leading us to hypothesize that phosphate accelerates aging. In contrast, overexpression of FGF21 extends life span in mice. Thus, the FGF-Klotho endocrine axes have emerged as key regula- tors of the aging process and are regarded as potential therapeutic targets for the treatment of age-related disorders.
MeSH Terms
- Aging
- Animals
- Fibroblast Growth Factors
- Glucuronidase
- Humans
- Longevity
- Mice
The Klotho proteins, αKlotho and βKlotho, are essential components of endocrine fibroblast growth factor (FGF) receptor complexes, as they are required for the high-affinity binding of FGF19, FGF21 and FGF23 to their cognate FGF receptors (FGFRs). Collectively, these proteins form a unique endocrine system that governs multiple metabolic processes in mammals. FGF19 is a satiety hormone that is secreted from the intestine on ingestion of food and binds the βKlotho-FGFR4 complex in hepatocytes to promote metabolic responses to feeding. By contrast, under fasting conditions, the liver secretes the starvation hormone FGF21, which induces metabolic responses to fasting and stress responses through the activation of the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system following binding to the βKlotho-FGFR1c complex in adipocytes and the suprachiasmatic nucleus, respectively. Finally, FGF23 is secreted by osteocytes in response to phosphate intake and binds to αKlotho-FGFR complexes, which are expressed most abundantly in renal tubules, to regulate mineral metabolism. Growing evidence suggests that the FGF-Klotho endocrine system also has a crucial role in the pathophysiology of ageing-related disorders, including diabetes, cancer, arteriosclerosis and chronic kidney disease. Therefore, targeting the FGF-Klotho endocrine axes might have therapeutic benefit in multiple systems; investigation of the crystal structures of FGF-Klotho-FGFR complexes is paving the way for the development of drugs that can regulate these axes.
MeSH Terms
- Aging
- Animals
- Biomarkers
- Birds
- Cardiovascular Diseases
- Endocrine System Diseases
- Fibroblast Growth Factors
- Glucuronidase
- Humans
- Hypothalamo-Hypophyseal System
- Kidney Diseases
- Mammals
- Phosphates
- Pituitary-Adrenal System
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
Fibroblast growth factor 21 (FGF21) has been proposed to be an antiaging hormone on the basis of experimental studies in rodent models. However, circulating FGF21 levels are increased with aging in rodents and humans. Moreover, despite the metabolic health-promoting effects of FGF21, the levels of this hormone are increased under conditions such as obesity and diabetes, an apparent incongruity that has been attributed to altered tissue responsiveness to FGF21. Here, we investigated serum FGF21 levels and expression of genes encoding components of the FGF21-response molecular machinery in adipose tissue from healthy elderly individuals (≥70 years old) and young controls. Serum FGF21 levels were increased in elderly individuals and were positively correlated with insulinemia and HOMA-IR, indices of mildly deteriorated glucose homeostasis. Levels of β-Klotho, the coreceptor required for cellular responsiveness to FGF21, were increased in subcutaneous adipose tissue from elderly individuals relative to those from young controls, whereas FGF receptor-1 levels were unaltered. Moreover, total ERK1/2 protein levels were decreased in elderly individuals in association with an increase in the ERK1/2 phosphorylation ratio relative to young controls. Adipose explants from aged and young mice respond similarly to FGF21 "ex vivo". Thus, in contrast to what is observed in obesity and diabetes, high levels of FGF21 in healthy aging are not associated with repressed FGF21-responsiveness machinery in adipose tissue. The lack of evidence for impaired FGF21 responsiveness in adipose tissue establishes a distinction between alterations in the FGF21 endocrine system in aging and chronic metabolic pathologies.
MeSH Terms
- Adipose Tissue
- Adult
- Aged, 80 and over
- Aging
- Biomarkers
- Case-Control Studies
- Female
- Fibroblast Growth Factors
- Humans
- Inflammation
- Male
Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10 ) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.
MeSH Terms
- Aged
- Aging
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO
- Cohort Studies
- Energy Intake
- European Continental Ancestry Group
- Female
- Fibroblast Growth Factors
- Genetic Loci
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Genomics
- Genotype
- Heart Diseases
- Humans
- Male
- Membrane Proteins
- Middle Aged
- Nutrients
- Obesity
- Polymorphism, Single Nucleotide
- Receptors, Retinoic Acid
Mitochondrial stress elicits the production of stress response molecules indicated as mitokines, including fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), and humanin (HN). Many diseases are characterized by progressive mitochondrial dysfunction with alterations of mitokine secretion. It is still controversial whether healthy aging and extreme longevity are accompanied by an altered production of mitokines. We analyzed FGF21, HN, and GDF15 plasma levels in 693 subjects aged from 21 to 113 years, and the association of these mitokines with parameters of health status. FGF21, HN, and GDF15 resulted increased in old age, with the highest levels found in centenarians. These molecules are associated with worsened parameters (such as handgrip strength, insulin sensitivity, triglycerides), particularly in 70-year-old persons, and their levels are inversely correlated with survival in the oldest subjects. Considering the positive biological effect of these molecules, our results can be interpreted in the framework of the hormetic paradigm as an attempt of the cells/tissues to cope with a stress that can have beneficial or detrimental effects depending on its intensity. Finally, persons with Down Syndrome (characterized by accelerated aging) have higher levels of GDF15 and HN with respect to their siblings, suggesting that these molecules, especially GDF15, could be considered markers of biological age.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Biomarkers
- Down Syndrome
- Female
- Fibroblast Growth Factors
- Growth Differentiation Factor 15
- Humans
- Intracellular Signaling Peptides and Proteins
- Longevity
- Male
- Middle Aged
- Mitochondria
- Surveys and Questionnaires
- Unfolded Protein Response
Keywords
- Centenarians
- FGF21
- GDF15
- Humanin
- Mortality
To investigate the impact of fibroblast growth factor 21 (FGF-21) on the severity of androgen deficiency in young and middle-aged men with type 2 diabetes mellitus. The study comprised 100 men with type 2 diabetes mellitus, cardiovascular multi-morbidity, obesity and androgen deficiency (study group) and 20 healthy men aged 35-50 years. The study group was further divided into two subgroups. Patients of the subgroup 1 received the standard treatment for type 2 diabetes and cardiovascular disease. Patients of the subgroup two were treated with conventional therapy concurrently with testosterone undecanoate. The baseline examination included the following parameters: glycated hemoglobin, total testosterone, prolactin, thyroid stimulating hormone and blood FGF-21. At nine months after the treatment, the blood levels of glycated hemoglobin, FGF21 and testosterone were re-examined. The evaluation of the severity of androgen deficiency was carried out using the ICEF-5 questionnaire and the Aging Males Symptoms scale (AMS). In the study group, the mean FGF-21 level was 2.7 times higher, and the total testosterone level was 2-2.5 times lower than in the control group (p<0.05). A negative correlation was found between the blood levels of FGF-21 and total testosterone (r=-0.41, p<0.05). At nine months post treatment, the subgroup with testosterone undecanoate administered as add-on therapy showed a further decrease in FGF-21 levels and improved androgen deficiency symptoms. FGF-21 is one of the markers for type 2 diabetes, cardiovascular multi-morbidity, obesity and androgen deficiency. Given the association of FGF-21 with androgen deficiency, it can be assumed that FGF-21 plays a role in premature aging. Treatment of androgen deficiency as add-on therapy to the standard treatment of this category of patients improves their prognosis and the quality of life. Young and middle-aged men with type 2 diabetes should undergo regular screening for androgen deficiency with the purpose of its early diagnosis and timely treatment. The detection of elevated levels of FGF-21 in young and middle-aged men with type 2 diabetes mellitus and cardiovascular multi-morbidity may indicate premature aging and requires preventive measures.
MeSH Terms
- Adult
- Aging, Premature
- Androgens
- Biomarkers
- Diabetes Mellitus, Type 2
- Early Diagnosis
- Fibroblast Growth Factors
- Humans
- Male
- Middle Aged
- Surveys and Questionnaires
- Testosterone
Keywords
- androgen deficiency
- cardiovascular diseases
- diabetes mellitus type 2
- fibroblast growth factor 21
- obesity
- premature aging
Vascular aging is an independent risk factor for age-related diseases, including atherosclerosis. Fibroblast growth factor 21 (FGF21) has been widely recognized as a metabolic regulator that is elevated in response to caloric and nutritional restrictions. Recent studies have demonstrated its emerging role as a pro-longevity hormone, but its effects on the senescence of human umbilical vascular endothelial cells (HUVECs) remain unclear. In the present study, we explored the anti-senescence effects and underlying mechanism of FGF21 on HUVECs. Co-cultivation of HUVECs with 5 ng/mL FGF21 significantly attenuated the phenotype changes of cells during [i]in vitro[/i] subculture, including increased senescent population, decreased proliferation rate, decreased SIRT1 and elevated P53 and P21 protein levels. FGF21 also protected HUVECs from H O -induced cell damage, including premature cell senescence, intracellular accumulation of reactive oxygen species, increased DNA damage, decreased SIRT1 protein level and elevated protein levels of VCAM-1, ICAM-1, P53 and P21. Transient knockdown of [i]SIRT1[/i] in HUVECs significantly suppressed the protective effects of FGF21 for the rescue of H O -induced premature senescence and DNA damage, which suggests that the anti-senescence effect of FGF21 on HUVECs is SIRT1-dependent. These results support the potential of FGF21 as a therapeutic target for postponing vascular aging and preventing age-related vascular diseases.
Keywords
- Fibroblast growth factor 21
- HUVEC
- SIRT1
- oxidative stress-induced premature senescence
- replicative senescence
FGF21 is a multifunctional metabolic and stress hormone which is normally expressed in liver but cellular stress, e.g. mitochondrial or endoplasmic reticulum (ER) stress, can induce its expression and subsequent secretion from several mammalian tissues. The stress kinases of the integrated stress response (ISR) pathway stimulate the expression of FGF21 through the activation of ATF4 transcription factor, thus enhancing cellular stress resistance. The metabolic and stress-inducible transactivation mechanisms of FGF21 gene are mostly mediated through separate pathways. FGF21 is an interorgan regulator which can alleviate many age-related metabolic and stress disorders, e.g. through the activation of AMPK signaling. FGF21 signaling is also involved in circadian and torpor regulation. Given that circulating FGF21 can attenuate organelle stress, e.g. mitochondrial and ER stresses, it resembles a stress-induced cell non-autonomous regulation of proteostasis and longevity present in model organisms. The overexpression of FGF21 can even extend the lifespan of mice, probably by improving the healthspan. We will clarify the positive and negative signaling mechanisms which control the stress-related expression of FGF21 through the ISR pathway. Moreover, we will examine the role of FGF21 as an interorgan coordinator of survival functions in metabolic and stress disorders. We conclude that FGF21 can be viewed as a cell non-autonomous enhancer of longevity in mammals.
MeSH Terms
- Animals
- Endoplasmic Reticulum Stress
- Fibroblast Growth Factors
- Gene Expression Regulation
- Liver
- Longevity
- Mice
- Mitochondria
- Signal Transduction
Keywords
- AMPK
- Cell non-autonomous
- FGF21
- Healthspan
- Klotho
- Lifespan
- PERK
Fibroblast growth factor 21 (FGF21) is a potent endocrine regulator with physiological effects on glucose and lipid metabolism and thus garners much attention for its translational potential for the management of obesity and related metabolic syndromes. FGF21 is mainly expressed in several metabolically active tissue organs, such as the liver, adipose tissue, skeletal muscle, and pancreas, with profound effects and therapeutic relevance. Emerging experimental and clinical data point to the demonstrated metabolic benefits of FGF21, which include, but are not limited to, weight loss, glucose and lipid metabolism, and insulin sensitivity. In addition, FGF21 also acts directly through its coreceptor β-klotho in the brain to alter light-dark cycle activity. In this review, we critically appraise current advances in understanding the physiological actions of FGF21 and its role as a biomarker of various metabolic diseases, especially type 2 diabetes mellitus. We also discuss the potentially exciting role of FGF21 in improving our health and prolonging our life span. This information will provide a fuller understanding for further research into FGF21, as well as providing a scientific basis for potentially establishing health care guidelines for this promising molecule.
MeSH Terms
- Adipose Tissue
- Biomarkers
- Circadian Rhythm
- Diabetes Mellitus, Type 2
- Fibroblast Growth Factors
- Humans
- Insulin Resistance
- Liver
- Longevity
- Membrane Proteins
- Muscle, Skeletal
- Obesity
- Pancreas
Keywords
- biomarker
- circadian
- energy homeostasis
- life span
- lipid metabolism
Mitochondrial dysfunction occurs during aging, but its impact on tissue senescence is unknown. Here, we find that sedentary but not active humans display an age-related decline in the mitochondrial protein, optic atrophy 1 (OPA1), that is associated with muscle loss. In adult mice, acute, muscle-specific deletion of Opa1 induces a precocious senescence phenotype and premature death. Conditional and inducible Opa1 deletion alters mitochondrial morphology and function but not DNA content. Mechanistically, the ablation of Opa1 leads to ER stress, which signals via the unfolded protein response (UPR) and FoxOs, inducing a catabolic program of muscle loss and systemic aging. Pharmacological inhibition of ER stress or muscle-specific deletion of FGF21 compensates for the loss of Opa1, restoring a normal metabolic state and preventing muscle atrophy and premature death. Thus, mitochondrial dysfunction in the muscle can trigger a cascade of signaling initiated at the ER that systemically affects general metabolism and aging.
MeSH Terms
- Aging
- Animals
- Cellular Senescence
- Endoplasmic Reticulum Stress
- Fibroblast Growth Factors
- GTP Phosphohydrolases
- Inflammation
- Mice
- Muscle, Skeletal
- Muscular Atrophy
- Organ Size
- Unfolded Protein Response
Keywords
- FGF21
- FoxO
- Opa1
- aging
- inflammation
- mitochondria
- muscle
- oxidative stress
- sarcopenia
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.
MeSH Terms
- Animals
- Chronic Disease
- Diabetes Mellitus, Type 2
- Endoplasmic Reticulum Stress
- Energy Metabolism
- Fibroblast Growth Factors
- Glucose
- Humans
- Insulin Resistance
- Lipid Metabolism
- Longevity
- Metabolic Diseases
- Mitochondria
- Obesity
- Stress, Physiological
Keywords
- AMPK
- Ageing
- FGF21
- Healthspan
- Lifespan
- miR-34a
Fibroblast growth factor 21 (FGF21) has a significant role in the regulation of energy metabolism, e.g., in the control of systemic glucose and lipid metabolism. For instance, FGF21 enhances insulin sensitivity, increases glucose uptake, and thus can decrease serum hyperglycemia, while it also increases lipid oxidation and inhibits lipogenesis. AMP-activated protein kinase (AMPK) is a tissue energy sensor involved in maintaining the energy balance and tissue integrity. It is known that AMPK signaling generates an energy metabolic profile which displays a remarkable overlap with that of FGF21. There is convincing evidence that endocrine FGF21 signaling activates the AMPK pathway, either directly through FGFR1/β-klotho signaling or indirectly by stimulating the secretion of adiponectin and corticosteroids, which consequently can activate AMPK signaling in their target tissues. By activating AMPK, FGF21 can promote a healthy aging process and thus extend mammalian lifespan. We will examine the signaling mechanisms through which FGF21 can activate the AMPK pathway and then discuss the significance of the close connection between FGF21 and AMPK signaling in the control of metabolic disorders and the aging process.
MeSH Terms
- AMP-Activated Protein Kinases
- Adiponectin
- Adrenal Cortex Hormones
- Animals
- Energy Metabolism
- Fibroblast Growth Factors
- Glucose
- Humans
- Lipids
- Longevity
- Mice
Keywords
- AMPK
- Adiponectin
- Ageing
- FGF21
- Klotho
- Metabolic disorders
Dietary methionine restriction (MR) leads to loss of adiposity, improved insulin sensitivity and lifespan extension. The possibility that dietary MR can protect the kidney from age-associated deterioration has not been addressed. Aged (10-month old) male and female mice were placed on a MR (0.172% methionine) or control diet (0.86% methionine) for 8-weeks and blood glucose, renal insulin signalling, and gene expression were assessed. Methionine restriction lead to decreased blood glucose levels compared to control-fed mice, and enhanced insulin-stimulated phosphorylation of PKB/Akt and S6 in kidneys, indicative of improved glucose homeostasis. Increased expression of lipogenic genes and downregulation of PEPCK were observed, suggesting that kidneys from MR-fed animals are more insulin sensitive. Interestingly, renal gene expression of the mitochondrial uncoupling protein UCP1 was upregulated in MR-fed animals, as were the anti-ageing and renoprotective genes Sirt1, FGF21, klotho, and β-klotho. This was associated with alterations in renal histology trending towards reduced frequency of proximal tubule intersections containing vacuoles in mice that had been on dietary MR for 190days compared to control-fed mice, which exhibited a pre-diabetic status. Our results indicate that dietary MR may offer therapeutic potential in ameliorating the renal functional decline related to ageing and other disorders associated with metabolic dysfunction by enhancing renal insulin sensitivity and renoprotective gene expression.
MeSH Terms
- Aging
- Animals
- Female
- Gene Expression Regulation
- Insulin
- Kidney
- Male
- Methionine
- Mice
- Signal Transduction
Keywords
- Ageing
- Diet
- Insulin
- Kidney
- Methionine
- Renoprotection
Cerebrovascular aging has a high relationship with stroke and neurodegenerative disease. In the present study, we evaluated the influence of fibroblast growth factor 21 (FGF21) on angiotensin (Ang II)-mediated cerebrovascular aging in human brain vascular smooth muscle cells (hBVSMCs). Ang II induced remarkable aging-phenotypes in hBVSMCs, including enhanced SA-β-gal staining and NBS1 protein expression. First, we used immunoblotting assay to confirm protein expression of FGF21 receptor (FGFR1) and the co-receptor β-Klotho in cultured hBVSMCs. Second, we found that FGF21 treatment partly prevented the aging-related changes induced by Ang II. FGF21 inhibited Ang II-enhanced ROS production/superoxide anion levels, rescued the Ang II-reduced Complex IV and citrate synthase activities, and suppressed the Ang II-induced meprin protein expression. Third, we showed that FGF21 not only inhibited the Ang II-induced p53 activation, but also blocked the action of Ang II on Siah-1-TRF signaling pathway which is upstream factors for p53 activation. At last, either chemical inhibition of AMPK signaling pathway by a specific antagonist Compound C or knockdown of AMPKα1/2 isoform using siRNA, successfully abolished the anti-aging action of FGF21 in hBVSMCs. These results indicate that FGF21 protects against Ang II-induced cerebrovascular aging via improving mitochondrial biogenesis and inhibiting p53 activation in an AMPK-dependent manner, and highlight the therapeutic value of FGF21 in cerebrovascular aging-related diseases such as stroke and neurodegenerative disease.
MeSH Terms
- AMP-Activated Protein Kinases
- Angiotensin II
- Brain
- Cellular Senescence
- Collagen
- Enzyme Activation
- Fibroblast Growth Factors
- Gene Expression Regulation
- Humans
- Mitochondria
- Models, Biological
- Muscle, Smooth, Vascular
- Myocytes, Smooth Muscle
- Nuclear Proteins
- Organelle Biogenesis
- Oxidative Stress
- Signal Transduction
- Telomeric Repeat Binding Protein 2
- Tumor Suppressor Protein p53
- Ubiquitin-Protein Ligases
Keywords
- AMPK
- Aging
- FGF21
- Mitochondrial biogenesis
- p53
Mitochondria are the key players in apoptosis and necrosis. Mitochondrial DNA (mtDNA)-depleted r0 cells were resistant to diverse apoptosis inducers such as TNF-alpha, [[TNFSF10]], staurosporine and p53. Apoptosis resistance was accompanied by the absence of mitochondrial potential loss or cytochrome c translocation. r0 cells were also resistant to necrosis induced by reactive oxygen species (ROS) donors due to upregulation of antioxidant enzymes such as manganese superoxide dismutase. Mitochondria also has a close relationship with autophagy that plays a critical role in the turnover of senescent organelles or dysfunctional proteins and may be included in 'cell death' category. It was demonstrated that autophagy deficiency in insulin target tissues such as skeletal muscle induces mitochondrial stress response, which leads to the induction of FGF21 as a 'mitokine' and affects the whole body metabolism. These results show that mitochondria are not simply the power plants of cells generating ATP, but are closely related to several types of cell death and autophagy. Mitochondria affect various pathophysiological events related to diverse disorders such as cancer, metabolic disorders and aging.
MeSH Terms
- Animals
- Apoptosis
- Autophagy
- Cell Death
- DNA, Mitochondrial
- Humans
- Longevity
- Mitochondria
- Necrosis
- Stress, Physiological
- TNF-Related Apoptosis-Inducing Ligand
Age-related thymic degeneration is associated with loss of naïve T cells, restriction of peripheral T-cell diversity, and reduced healthspan due to lower immune competence. The mechanistic basis of age-related thymic demise is unclear, but prior evidence suggests that caloric restriction (CR) can slow thymic aging by maintaining thymic epithelial cell integrity and reducing the generation of intrathymic lipid. Here we show that the prolongevity ketogenic hormone fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily, is expressed in thymic stromal cells along with FGF receptors and its obligate coreceptor, βKlotho. We found that FGF21 expression in thymus declines with age and is induced by CR. Genetic gain of FGF21 function in mice protects against age-related thymic involution with an increase in earliest thymocyte progenitors and cortical thymic epithelial cells. Importantly, FGF21 overexpression reduced intrathymic lipid, increased perithymic brown adipose tissue, and elevated thymic T-cell export and naïve T-cell frequencies in old mice. Conversely, loss of FGF21 function in middle-aged mice accelerated thymic aging, increased lethality, and delayed T-cell reconstitution postirradiation and hematopoietic stem cell transplantation (HSCT). Collectively, FGF21 integrates metabolic and immune systems to prevent thymic injury and may aid in the reestablishment of a diverse T-cell repertoire in cancer patients following HSCT.
MeSH Terms
- Aging
- Animals
- Fibroblast Growth Factors
- Immunosenescence
- Mice
- Mice, Inbred C57BL
- Receptors, Antigen, T-Cell
- T-Lymphocytes
- Thymus Gland
Keywords
- FGF21
- aging
- inflammation
- metabolism
- thymus
Human differentiated embryo chondrocyte expressed gene 1 (DEC1) is frequently used as a marker of senescence in vivo. Fibroblast growth factor 21 (FGF21), a novel endocrine-like member of the FGF superfamily, is highly expressed in the liver, and FGF21-transgenic mice have extended lifespans. Thus, we hypothesized that FGF21 may play a role in the DEC1-mediated aging process. In this study, DEC1 knockout (KO) mice were used to characterize the mechanism by which FGF21 protects mice from aging. Aging is strongly diminished in DEC1 KO mice, which is reflected by decreased lipid levels and oxidative stress, leading to an amelioration of liver function and structure. The expression of FGF21 decreased with aging in wild-type (WT) mice, whereas ATF4, Phospho-ERK and Phospho-p38 expression was maintained and was accompanied by a compensatory rise of FGF21 mRNA and protein expression in DEC1 KO mice. Over-expression of DEC1 markedly abolished the hepatic expression of FGF21, and siRNA-mediated inhibition of endogenous DEC1 increased the expression of FGF21. DEC1 further diminished the expression of ATF4 in HepG2 cells over-expressing DEC1. The induction of FGF21 and ATF4 at the mRNA and protein levels during the course of aging supports the view that DEC1 KO mice are able to restore the age-related imbalance of metabolism. Collectively, the data obtained in this study suggest that DEC1 is a novel negative regulator of hepatic FGF21 expression.
MeSH Terms
- Aging
- Animals
- Basic Helix-Loop-Helix Transcription Factors
- Cell Line
- Fibroblast Growth Factors
- Gene Expression Regulation, Developmental
- Hepatocytes
- Homeodomain Proteins
- Liver
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
Keywords
- Aging
- DEC1
- FGF21
- Hepatic homeostasis
- Liver
In our studies investigating the role of autophagy in systemic metabolism, we found that mitochondrial dysfunction due to autophagy deficiency in insulin target tissues, such as skeletal muscle or liver, leads to the induction of fibroblast growth factor (FGF)21 as a mitokine and protection against obesity and insulin resistance. In the following studies, we observed that metformin, one of the most widely used antidiabetic medications, induces mitochondrial stress and induces FGF21 through a PERK-eIF2α-ATF4 pathway, which may contribute to the antidiabetic effect of metformin. Amino acid deprivation also induced ATF4 and FGF21, while the role of mitochondrial dysfunction in this condition is not yet clear. These results suggest the possibility that mitochondrial stress inducing an integrated stress response can induce a mitokine response and affect systemic metabolism in a non-cell-autonomous manner, in addition to the well-recognized cell-autonomous role of mitochondrial function in metabolism.
MeSH Terms
- Animals
- Autophagy
- Biomarkers
- Energy Metabolism
- Fibroblast Growth Factors
- Humans
- Hypoglycemic Agents
- Metformin
- Mitochondria
- Mitochondrial Diseases
- Models, Biological
- Stress, Physiological
Keywords
- FGF21
- longevity
- metabolism
- mitochondrial stress
- mitokine
Eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) is a key downstream effector of mTOR complex 1 (mTORC1) that represses cap-dependent mRNA translation initiation by sequestering the translation initiation factor eIF4E. Reduced mTORC1 signaling is associated with life span extension and improved metabolic homeostasis, yet the downstream targets that mediate these benefits are unclear. Here, we demonstrated that enhanced 4E-BP1 activity in mouse skeletal muscle protects against age- and diet-induced insulin resistance and metabolic rate decline. Transgenic animals displayed increased energy expenditure; altered adipose tissue distribution, including reduced white adipose accumulation and preserved brown adipose mass; and were protected from hepatic steatosis. Skeletal muscle-specific 4E-BP1 mediated metabolic protection directly through increased translation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and enhanced respiratory function. Non-cell autonomous protection was through preservation of brown adipose tissue metabolism, which was increased in 4E-BP1 transgenic animals during normal aging and in a response to diet-induced type 2 diabetes. Adipose phenotypes may derive from enhanced skeletal muscle expression and secretion of the known myokine FGF21. Unlike skeletal muscle, enhanced adipose-specific 4E-BP1 activity was not protective but instead was deleterious in response to the same challenges. These findings indicate that regulation of 4E-BP1 in skeletal muscle may serve as an important conduit through which mTORC1 controls metabolism.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Aging
- Animals
- Carrier Proteins
- Cell Cycle Proteins
- Diabetes Mellitus, Type 2
- Eukaryotic Initiation Factors
- Fibroblast Growth Factors
- Mechanistic Target of Rapamycin Complex 1
- Mice
- Mice, Knockout
- Multiprotein Complexes
- Muscle Proteins
- Muscle, Skeletal
- Obesity
- Organ Specificity
- Oxygen Consumption
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- Phosphoproteins
- Signal Transduction
- TOR Serine-Threonine Kinases
- Transcription Factors
Circulating FGF21 levels are commonly elevated in disease states. There is limited information regarding concentrations of circulating FGF21 in the absence of disease, as well as age-related differences in body composition that may contribute to FGF21 regulation across groups. The objectives of this study were to assess FGF21 levels across age groups (childhood to elder adulthood), and investigate whether body composition indices are associated with age-related differences in circulating FGF21. We cross-sectionally analyzed serum concentrations of FGF21 in 184 healthy subjects aged 5-80y (45% male). Multiple linear regression was performed to assess the independent association of categorical age (children: 5-12y, young adults: 20-29y, adults: 30-50y, older adults: 55-64y, elder adults: 65-80y) with FGF21 concentration taking into account DXA-measured body composition indices [bone mineral density (BMD) and percent lean, trunk, and fat mass]. We also stratified analysis by tertile of FGF21. Incremental increases in FGF21 levels were observed across age groups (youngest to highest). Age group was positively associated with FGF21 level independent of body composition indices (age group variable: β=0.25, 0.24, 0.24, 0.23, all [i]P[/i]<0.0001, controlling for percent lean, BMD, percent fat, and percent trunk fat, respectively). By FGF21 tertile, age group was associated with FGF21 in the lowest tertile only (β=13.1, 0.19, 0.18, all P≤0.01, accounting for percent lean, fat and trunk fat, respectively), but not when accounting for BMD. Our findings in a healthy population display an age-related increase in serum FGF21, highlighting a potential age effect in response to metabolic demand over the lifecourse. FGF21 levels increase with age independently of body composition. At lower levels of FGF21, BMD, but not other body composition parameters, attenuates the association between FGF21 level and age, suggesting the metabolic demand of the skeleton may provide a link between FGF21 and energy metabolism.
Keywords
- Fibroblast growth factor 21
- aging
- body composition
Although the number of centenarians is growing worldwide, the potential factors influencing the aging process remain only partially elucidated. Researchers are increasingly focusing toward biomarkers as tools to shed more light on the pathophysiology of complex phenotypes, including the ability to reach successful aging, i.e., free of major chronic diseases. We therefore conducted a case-control study examining the potential associations of multiple candidate biomarkers in healthy centenarians and sex-matched healthy elderly controls. Using a case-control study of 81 centenarians (aged ≥ 100 years) selected based on the fact that they were disease-free and 46 healthy elderly controls (aged 70-80 years), serum levels of 15 different candidate biomarkers involved in the regulation of metabolism, angiogenesis, inflammation, and bone formation were measured. Of the 15 biomarkers tested, four molecules (chemerin, fetuin-A, and fibroblast growth factors [FGF] 19 and 21) were found to be independently associated with successful aging regardless of sex. Logistic regression analysis confirmed that chemerin, fetuin-A, FGF19, and FGF21 were independently associated with successful aging [predicted probability (PP) = 1 / [1 1 / exp (11.832 - 0.027 × (chemerin) - 0.009 × (fetuin-A) 0.014 × (FGF19) - 0.007 × (FGF21)]. The area under the curve (AUC) of predicted probability values for the four-biomarker panel revealed that it can discriminate between centenarians and elderly controls with excellent accuracy (AUC > 0.94, P < 0.001). Although preliminary in essence and limited by the low sample size and lack of replication in other independent cohorts, our data suggest an independent association between successful aging and serum chemerin, fetuin-A, FGF19, and FGF21, which may provide novel information on the mechanisms behind the human aging process. Whether the four-biomarker panel may predict successful aging deserves further scrutiny.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Biomarkers
- Case-Control Studies
- Chemokines
- Female
- Fetuins
- Fibroblast Growth Factors
- Humans
- Intercellular Signaling Peptides and Proteins
- Male
- Predictive Value of Tests
Fibroblast growth factor 21 (FGF21) is a hormone secreted predominantly in the liver, pancreas and adipose tissue. Recently, it has been reported that FGF21-Transgenic mice can extend their lifespan compared with wild type counterparts. Thus, we hypothesize that FGF21 may play some roles in aging of organisms. In this study d-galactose (d-gal)-induced aging mice were used to study the mechanism that FGF21 protects mice from aging. The three-month-old Kunming mice were subcutaneously injected with d-gal (180mg·kg(-1)·d(-1)) for 8weeks and administered simultaneously with FGF21 (1, 2 or 5mg·kg(-1)·d(-1)). Our results showed that administration of FGF21 significantly improved behavioral performance of d-gal-treated mice in water maze task and step-down test, reduced brain cell damage in the hippocampus, and attenuated the d-gal-induced production of MDA, ROS and advanced glycation end products (AGEs). At the same time, FGF21 also markedly renewed the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total anti-oxidation capability (T-AOC), and decreased the enhanced total cholinesterase (TChE) activity in the brain of d-gal-treated mice. The expression of aldose reductase (AR), sorbitol dehydrogenase (SDH) and member-anchored receptor for AGEs (RAGE) declined significantly after FGF21 treatment. Furthermore, FGF21 suppressed inflamm-aging by inhibiting IκBα degradation and NF-κB p65 nuclear translocation. The expression levels of pro-inflammatory cytokines, such as TNF-α and IL-6, decreased significantly. In conclusion, these results suggest that FGF21 protects the aging mice brain from d-gal-induced injury by attenuating oxidative stress damage and decreasing AGE formation.
MeSH Terms
- Aging
- Animals
- Brain
- Cognition Disorders
- Fibroblast Growth Factors
- Galactose
- Glycation End Products, Advanced
- Inflammation Mediators
- Male
- Mice
- Oxidative Stress
- Reactive Oxygen Species
Keywords
- AGEs
- Aging
- FGF21
- Inflammation
- Oxidative stress
- d-galactose
Fibroblast growth factor-21 (FGF21) is an important metabolic regulator suggested to improve glucose metabolism and prevent dyslipidemia. An FGF21-resistant state that increases circulating FGF21 has been reported in obese patients. Although regular exercise prevents metabolic disease, the relationship of the fitness level to serum FGF21 level and body fat distribution in humans remains poorly understood. The objective of the study was to determine the relationship among the serum FGF21 concentration, cardiorespiratory fitness (CRF) level, and visceral fat area (VFA). Serum FGF21 was measured by an ELISA in 166 middle-aged and elderly Japanese men (aged 30-79 y) and 25 untrained and 21 endurance-trained young men (aged 19-29 y). CRF was assessed by measuring the peak oxygen uptake (VO2peak) and VFA by magnetic resonance imaging. In the middle-aged and elderly subjects, the serum FGF21 level correlated with the VO2peak (r = -0.355, P < .001) and VFA (r = 0.487, P < .001). Stepwise multiple regression analysis showed VFA to be most strongly associated with the serum FGF21 level (β = .360, P < .001), and VO2peak was also an independent predictor of the serum FGF21 level (β = -.174, P = .019). Furthermore, the proportion of subjects with an FGF21 level below the limit of detection was significantly higher among the endurance-trained than among the untrained young men (71.4% vs 24.0%, P = .001), and the VO2peak and VFA were independently associated with an undetectable FGF21 level (P < .05). CRF and VFA are key determinants of the circulating FGF21 concentration.
MeSH Terms
- Adult
- Aged
- Aging
- Asian Continental Ancestry Group
- Blood Glucose
- Exercise Test
- Fibroblast Growth Factors
- Humans
- Insulin
- Intra-Abdominal Fat
- Linear Models
- Male
- Middle Aged
- Models, Biological
- Odds Ratio
- Oxygen Consumption
- Physical Endurance
- Physical Fitness
- Risk Factors
- Young Adult
Methionine restriction (MR) decreases body weight and adiposity and improves glucose homeostasis in rodents. Similar to caloric restriction, MR extends lifespan, but is accompanied by increased food intake and energy expenditure. Most studies have examined MR in young animals; therefore, the aim of this study was to investigate the ability of MR to reverse age-induced obesity and insulin resistance in adult animals. Male C57BL/6J mice aged 2 and 12 months old were fed MR (0.172% methionine) or control diet (0.86% methionine) for 8 weeks or 48 h. Food intake and whole-body physiology were assessed and serum/tissues analyzed biochemically. Methionine restriction in 12-month-old mice completely reversed age-induced alterations in body weight, adiposity, physical activity, and glucose tolerance to the levels measured in healthy 2-month-old control-fed mice. This was despite a significant increase in food intake in 12-month-old MR-fed mice. Methionine restriction decreased hepatic lipogenic gene expression and caused a remodeling of lipid metabolism in white adipose tissue, alongside increased insulin-induced phosphorylation of the insulin receptor (IR) and Akt in peripheral tissues. Mice restricted of methionine exhibited increased circulating and hepatic gene expression levels of FGF21, phosphorylation of eIF2a, and expression of ATF4, with a concomitant decrease in IRE1α phosphorylation. Short-term 48-h MR treatment increased hepatic FGF21 expression/secretion and insulin signaling and improved whole-body glucose homeostasis without affecting body weight. Our findings suggest that MR feeding can reverse the negative effects of aging on body mass, adiposity, and insulin resistance through an FGF21 mechanism. These findings implicate MR dietary intervention as a viable therapy for age-induced metabolic syndrome in adult humans.
MeSH Terms
- Animals
- Energy Metabolism
- Fibroblast Growth Factors
- Gene Expression
- Glucose
- Insulin Resistance
- Lipid Metabolism
- Male
- Methionine
- Mice
- Mice, Inbred C57BL
- Obesity
- Phenotype
Keywords
- activating transcription factor 4
- aging
- fibroblast growth factor 21
- lipid
- metabolism
- unfolded protein response
Circulating fibroblast growth factor 21 (FGF21) levels are elevated in diabetic subjects and correlate directly with abnormal glucose metabolism, while pharmacologically administered FGF21 can ameliorate hyperglycemia. The pancreatic islet is an FGF21 target, yet the actions of FGF21 in the islet under normal and diabetic conditions are not fully understood. This study investigated the effects of high glucose on islet FGF21 actions in a diabetic mouse model by investigating db/db mouse islet responses to exogenous FGF21, the direct effects of glucose on FGF21 signaling, and the involvement of peroxisome proliferator-activated receptor γ (PPARγ) in FGF21 pathway activation. Results showed that both adult db/db mouse islets and normal islets treated with high glucose ex vivo displayed reduced β-klotho expression, resistance to FGF21, and decreased PPARγ expression. Rosiglitazone, an antidiabetic PPARγ ligand, ameliorated these effects. Our data indicate that hyperglycemia in type 2 diabetes mellitus may lead to FGF21 resistance in pancreatic islets, probably through reduction of PPARγ expression, which provides a novel mechanism for glucose-mediated islet dysfunction.
MeSH Terms
- Aging
- Animals
- Diabetes Mellitus, Type 2
- Disease Models, Animal
- Fibroblast Growth Factors
- Glucose
- Islets of Langerhans
- Male
- Membrane Proteins
- Mice
- PPAR gamma
- Phosphorylation
- Rosiglitazone
- Signal Transduction
- Thiazolidinediones
Dietary or caloric restriction (DR or CR), typically a 30%-40% reduction in ad libitum or "normal" nutritional energy levels, has been reported to extend life span and health span in diverse organisms, including mammals. Although the life span benefit of DR in primates and humans is unproven, preliminary evidence suggests that DR confers health span benefits. A serious effort is underway to discover or engineer DR mimetics. The most straightforward path to a DR mimetic requires a detailed understanding of the molecular mechanisms that underlie DR and related life span-enhancing protocols. Increased expression of fibroblast growth factor-21 (FGF21), a putative mammalian starvation master regulator, promotes many of the same beneficial physiological changes seen in DR animals, including decreased glucose levels, increased insulin sensitivity, and improved fatty acid/lipid profiles. Ectopic over-expression of FGF21 in transgenic mice (FGF21-Tg) extends life span to a similar extent as DR in a recent study. FGF21 may achieve these effects by attenuating growth hormone (GH)/insulin-like growth factor-1 (IGF1) signaling. Although FGF21 expression does not increase during DR, and therefore is unlikely to mediate DR, it does increase during short-term starvation in rodents, which is a critical component of alternate day fasting, a DR-like protocol that also increases life span and health span in mammals. Various drugs have been reported to induce FGF21, including peroxisome proliferator-activated receptor-α (PPARα) agonists such as fenofibrate, the histone deacetylase inhibitor sodium butyrate, and adenosine monophosphate (AMP) kinase activators metformin and 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR). Of these, only metformin has been reported to extend life span in mammals, and the extent of benefit is less than that seen with ectopic FGF21 expression. Perhaps the most parsimonious explanation is that high, possibly un-physiological, levels of FGF21 are needed to achieve maximum life span and health span benefits and that sufficiently high levels are not achieved by the identified FGF21 inducers. More in-depth studies of the effects of FGF21 and its inducers on longevity and health span are warranted.
MeSH Terms
- Animals
- Caloric Restriction
- Fibroblast Growth Factors
- Health
- Humans
- Longevity
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.DOI:http://dx.doi.org/10.7554/eLife.00065.001.
MeSH Terms
- Adaptation, Physiological
- Adenylate Kinase
- Animals
- Bone Resorption
- Caloric Restriction
- Fasting
- Fatty Acids
- Female
- Fibroblast Growth Factors
- Gene Expression Regulation
- Growth Hormone
- Insulin Resistance
- Insulin-Like Growth Factor I
- Ketone Bodies
- Lipid Metabolism
- Liver
- Longevity
- Male
- Mice
- Mice, Transgenic
- NAD
- Oxidation-Reduction
- Signal Transduction
- TOR Serine-Threonine Kinases
- Transgenes
Keywords
- Mouse
- caloric restriction
- fibroblast growth factor
- growth hormone
- liver
- longevity
Endocrine fibroblast growth factors (FGFs) have been recognized as hormones that regulate a variety of metabolic processes. FGF19 is secreted from intestine upon feeding and acts on liver to suppress bile acid synthesis. FGF21 is secreted from liver upon fasting and acts on adipose tissue to promote lipolysis and responses to fasting. FGF23 is secreted from bone and acts on kidney to inhibit phosphate reabsorption and vitamin D synthesis. One critical feature of endocrine FGFs is that they require the Klotho gene family of transmembrane proteins as coreceptors to bind their cognate FGF receptors and exert their biological activities. This chapter overviews function of Klotho family proteins as obligate coreceptors for endocrine FGFs and discusses potential link between Klothos and age-related diseases.
MeSH Terms
- Aging
- Animals
- Glucuronidase
- Homeostasis
- Humans
- Membrane Proteins
- Phosphates
- Receptors, Cytoplasmic and Nuclear
In the symposium entitled "Transcriptional controls of energy sensing," the authors presented recent advances on 1) AMP kinase, an intracellular energy sensor; 2) PGC-1α (peroxisome proliferator-activated receptor γ co-activator 1α), a transcriptional co-activator that has powerful effects on mitochondria; 3) methylation and demethylation in response to metabolic fluctuations; and 4) FGF21 (fibroblast growth factor 21) as an emerging hormone-like intercellular metabolic coordinator. This introduction places these advances within a broad overview of energy sensing and energy balance, with a focus on human evolution and disease. Four key elements of human biology are analyzed: 1) elevated body temperature; 2) complex prolonged reproductive pathways; 3) emergence of 4 large, well-defined fat depots, each with its own functional role; and 4) an immune system that is often up-regulated by nutrition-related signals, independent of the actual presence of a pathogen. We propose that an overactive immune system, including the "metabolic syndrome," was adopted evolutionarily in the distant past to help hold out against unconquerable infections such as tuberculosis, malaria, and trypanosomiasis. This immune activation is advantageous in the absence of other disease management methods, especially under conditions in which life expectancy is short. The inflammation has become a major agent of pathology in wealthy populations in whom the pathogens are a minor threat and life expectancy is long. The "Conclusions" section sketches cautiously how understanding the molecules involved in energy sensing and energy balance may lead to specific therapies for obesity and diabetes and for their complications.
MeSH Terms
- Adipose Tissue
- Biological Evolution
- Energy Metabolism
- Humans
- Immunity
- Infections
- Life Expectancy
- Obesity
- Reproduction
FGF19, FGF21, and FGF23 form a unique subfamily of fibroblast growth factors. Because they contain intra-molecular disulfide bonds and show reduced affinity toward heparan sulfate located in the extracellular space, it is thought that, in contrast to other FGFs, they function as endocrine hormones. FGF23 and its co-receptor alphaKlotho are involved in the control of aging, but it is not known if the same holds true for FGF19, which can also signal through alphaKlotho. However, considerable evidence supports a role for FGF19 in controlling various aspects of metabolism. We have recently fully characterized FGF19/FGFR/co-factor interactions and signaling, and in the current manuscript discuss the contribution of the FGF19/FGFR4 axis to bile acid and glucose regulation.
MeSH Terms
- Animals
- Bile Acids and Salts
- Blood Glucose
- Fibroblast Growth Factors
- Homeostasis
- Humans
- Mice
- Receptor, Fibroblast Growth Factor, Type 4
Keywords
- FGF19
- FGF21
- FGF23
- aging
- diabetes
- fibroblast growth factors
- insulin
- metabolic diseases