Metabolic rate is negatively linked to adult survival but does not explain latitudinal differences in songbirds, 2019
Fibroblast growth factor 19-targeted therapies for the treatment of metabolic disease. 2015
Fibroblast growth factors (FGFs) belong to the FGF superfamily with diverse biological functions, including proliferation, cellular differentiation, wound repair, angiogenesis and tumorigenesis. The ability to reduce liver fat content and concentrations of triglycerides, total cholesterol and plasma glucose, and to improve sensitivity and limit pro-lipogenic properties of insulin, makes FGF19 a promising therapeutic target for the treatment of metabolic syndrome. FGF19 regulates bile acid biosynthesis in the bile duct, glucose metabolism and vitamin D and phosphate homeostasis, raises the metabolic rate, reduces body weight, and ameliorates diabetes in mice. The therapeutic potential of FGF19 to treat metabolic disorders has been widely studied in animal models, but currently, there are no reports concerning its use in humans.
- AREAS COVERED:
The following article highlights the metabolic effects and mechanism of action of FGF19. It also discusses the potential therapies that target FGF19.
- EXPERT OPINION:
FGF19 is emerging as a new target for the therapy of metabolic disorders, including diabetes. The results obtained from animal models are promising. However, there is still much to be done before the translation of these effects into practice will be possible.
Prevailing vitamin D status influences mitochondrial and glycolytic bioenergetics in peripheral blood mononuclear cells obtained from adults. 2016
Circulating peripheral blood mononuclear cells (PBMCs) are exposed to metabolic and immunological stimuli that influence their functionality. We hypothesized that prevailing vitamin D status [25(OH)D] would modulate the bioenergetic profile of PBMCs derived from humans.
MATERIALS AND METHODS:
38 participants (16 males, 22 females) ranging in body fat from 14-51% were studied. PBMCs were isolated from whole blood, counted and freshly seeded for bioenergetic analysis using the Seahorse XFe96 flux analyzer. Whole-body energy metabolism via indirect calorimetry, body composition by dual-energy X-ray absorptiometry, and relevant clinical biochemistry was measured. Data was analysed based on 25(OH)D cut-offs of <50nmol/L (Group 1, n=12), 50-75nmol/L (Group 2, n=15) and ≥75nmol/L (Group 3, n=11). A multivariate general linear model adjusting for age, fat mass, fat-free mass, parathyroid hormone, and insulin sensitivity was used.
There were significant differences in cellular mitochondrial function between groups. Group 1 had significantly higher basal respiration (p=0.001), non-mitochondrial respiration (p=0.009), ATP production (p=0.001), proton leak (p=0.018), background glycolysis (p=0.023) and glycolytic reserve (p=0.039) relative to either Group 2 or Group 3; the latter two did not differ on any measures. There were no differences in the bioenergetic health index (BHI), resting metabolic rates and systemic inflammatory markers between groups.
Inadequate vitamin D status adversely influenced bioenergetic parameters of PBMCs obtained from adults, in a pattern consistent with increased oxidative metabolism and activation of these cells.
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Metabolomic Analysis Reveals Vitamin D-induced Decrease in Polyol Pathway and Subtle Modulation of Glycolysis in HEK293T Cells. , 2017
How long will we live in 2069, Medium 2019
The influence of pro-longevity gene Gclc overexpression on the age-dependent changes in Drosophila transcriptome and biological functions. 2016
- Gclc level demonstrated associations with the expression of genes involved in a variety of cellular processes including Jak-STAT, MAPK, FOXO, Notch, mTOR, TGF-beta signaling pathways, translation, protein processing in endoplasmic reticulum, proteasomal degradation, glycolysis, oxidative phosphorylation, apoptosis, regulation of circadian rhythms, differentiation of neurons, synaptic plasticity and transmission.
Gclc human analog is GCLC (GSH1_HUMAN)
ATP + L-glutamate + L-cysteine = ADP + phosphate + gamma-L-glutamyl-L-cysteine.
gsh and endoplasmic reticulum
gsh and longevity
A decrease of free radical production near critical targets as a cause of maximum longevity in animals. 1994
- A comprehensive study was performed on the brains of various vertebrate species showing different life energy potentials in order to find out if free radicals are important determinants of species-specific maximum life span. Brain superoxide dismutase, catalase, Se-dependent and independent GSH-peroxidases, GSH-reductase, and ascorbic acid showed significant inverse correlations with maximum longevity, whereas GSH, uric acid, GSSG/GSH, in vitro peroxidation (thiobarbituric acid test), and malondialdehyde (measured by HPLC), did not correlate with maximum life span. Superoxide dismutase, catalase, GSH-peroxidase, GSH and ascorbate results agree with those previously reported in various independent works using different animal species. GSSG/GSH, and true malondialdehyde (HPLC) results are reported for the first time in relation to maximum longevity. The results suggest that longevous species simultaneously show low antioxidant concentrations and low levels of in vivo free radical production (a low free radical turnover) in their tissues. The "free radical production hypothesis of aging" is proposed: a decrease in oxygen radical production per unit of O2 consumption near critical DNA targets (mitochondria or nucleus) increases the maximum life span of extraordinarily long-lived species like birds, primates, and man. Free radical production near these DNA sites would be a main factor responsible for aging in all the species, in those following Pearl's (Rubner's) metabolic rule as well as in those not following it.
gsh and Vitamin D
Vitamin D and L-cysteine levels correlate positively with GSH and negatively with insulin resistance levels in the blood of type 2 diabetic patients. 2014
- Similarly, illustrates that a significant correlation exists between blood levels of LC and those of vitamin D. shows that there was a statistically significant inverse regression dependence of triglyceride levels with blood levels of GSH and LC, but that the inverse relationship between GSH and cholesterol was not statistically significant (r=−0.18, P=0.12, data not given).
An observational approach (not causal)
Find drugs that delay many diseases of old age
- Common mechanisms seem to underpin several age-related diseases, including diabetes, Parkinson’s disease and Alzheimer’s. A review of more than 400 studies of people and animal models indicates that similar mechanisms underlie six conditions2. These can involve DNA damage, such as that caused by free radicals; cellular senescence (in which cells stop dividing and start secreting inflammatory factors); or inflammation and autophagy (the degradation of organelles, misfolded proteins and so on)-
- This may explain why people over 65 are at a higher risk than younger people of developing more than one disease at the same time. In the United States, 7 out of 10 people over 65 with diabetes will die of heart disease, for instance.