Fibroblasts in the Aged Pancreas Drive Pancreatic Cancer Progression.

Pancreatic cancer is more prevalent in older individuals and often carries a poorer prognosis for them. The relationship between the microenvironment and pancreatic cancer is multifactorial, and age-related changes in nonmalignant cells in the tumor microenvironment may play a key role in promoting cancer aggressiveness. Because fibroblasts have profound impacts on pancreatic cancer progression, we investigated whether age-related changes in pancreatic fibroblasts influence cancer growth and metastasis. Proteomics analysis revealed that aged fibroblasts secrete different factors than young fibroblasts, including increased growth/differentiation factor 15 (GDF-15). Treating young mice with GDF-15 enhanced tumor growth, whereas aged GDF-15 knockout mice showed reduced tumor growth. GDF-15 activated AKT, rendering tumors sensitive to AKT inhibition in an aged but not young microenvironment. These data provide evidence for how aging alters pancreatic fibroblasts and promotes tumor progression, providing potential therapeutic targets and avenues for studying pancreatic cancer while accounting for the effects of aging. SIGNIFICANCE: Aged pancreatic fibroblasts secrete GDF-15 and activate AKT signaling to promote pancreatic cancer growth, highlighting the critical role of aging-mediated changes in the pancreatic cancer microenvironment in driving tumor progression. See related commentary by Isaacson et al., p. 1185.

An exploratory metabolomic comparison of participants with fast or absent functional progression from 2CARE, a randomized, double-blind clinical trial in Huntington's disease.

Huntington's disease (HD) is increasingly recognized for diverse pathology outside of the nervous system. To describe the biology of HD in relation to functional progression, we previously analyzed the plasma and CSF metabolome in a cross-sectional study of participants who had various degrees of functional impairment. Here, we carried out an exploratory study in plasma from HD individuals over a 3-year time frame to assess whether differences exist between those with fast or absent clinical progression. There were more differences in circulating metabolite levels for fast progressors compared to absent progressors (111 vs 20, nominal p < 0.05). All metabolite changes in faster progressors were decreases, whereas some metabolite concentrations increased in absent progressors. Many of the metabolite levels that decreased in the fast progressors were higher at Screening compared to absent progressors but ended up lower by Year 3. Changes in faster progression suggest greater oxidative stress and inflammation (kynurenine, diacylglycerides, cysteine), disturbances in nitric oxide and urea metabolism (arginine, citrulline, ornithine, GABR), lower polyamines (putrescine and spermine), elevated glucose, and deficient AMPK signaling. Metabolomic differences between fast and absent progressors suggest the possibility of predicting functional decline in HD, and possibly delaying it with interventions to augment arginine, polyamines, and glucose regulation.

Hypertensive Adults Exhibit Lower Myelin Content: A Multicomponent Relaxometry and Diffusion Magnetic Resonance Imaging Study.

BACKGROUND: It is unknown whether hypertension plays any role in cerebral myelination. To fill this knowledge gap, we studied 90 cognitively unimpaired adults, age range 40 to 94 years, who are participants in the Baltimore Longitudinal Study of Aging and the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing to look for potential associations between hypertension and cerebral myelin content across 14 white matter brain regions. METHODS: Myelin content was probed using our advanced multicomponent magnetic resonance relaxometry method of myelin water fraction, a direct and specific magnetic resonance imaging measure of myelin content, and longitudinal and transverse relaxation rates (R1 and R2), 2 highly sensitive magnetic resonance imaging metrics of myelin content. We also applied diffusion tensor imaging magnetic resonance imaging to measure fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity values, which are metrics of cerebral microstructural tissue integrity, to provide context with previous magnetic resonance imaging findings. RESULTS: After adjustment of age, sex, systolic blood pressure, smoking status, diabetes status, and cholesterol level, our results indicated that participants with hypertension exhibited lower myelin water fraction, fractional anisotropy, R1 and R2 values and higher mean diffusivity, radial diffusivity, and axial diffusivity values, indicating lower myelin content and higher impairment to the brain microstructure. These associations were significant across several white matter regions, particularly in the corpus callosum, fronto-occipital fasciculus, temporal lobes, internal capsules, and corona radiata. CONCLUSIONS: These original findings suggest a direct association between myelin content and hypertension and form the basis for further investigations including longitudinal assessments of this relationship.

Novel Hominid-Specific IAPP Isoforms: Potential Biomarkers of Early Alzheimer's Disease and Inhibitors of Amyloid Formation.

(1) Background and aims: Amyloidosis due to aggregation of amyloid-ß (Aß42) is a key pathogenic event in Alzheimer's disease (AD), whereas aggregation of mature islet amyloid polypeptide (IAPP37) in human islets leads to ß-cell dysfunction. The aim of this study is to uncover potential biomarkers that might additionally point to therapy for early AD patients. (2) Methods: We used bioinformatic approach to uncover novel IAPP isoforms and developed a quantitative selective reaction monitoring (SRM) proteomic assay to measure their peptide levels in human plasma and CSF from individuals with early AD and controls, as well as postmortem cerebrum of clinical confirmed AD and controls. We used Thioflavin T amyloid reporter assay to measure the IAPP isoform fibrillation propensity and anti-amyloid potential against aggregation of Aß42 and IAPP37. (3) Results: We uncovered hominid-specific IAPP isoforms: hIAPPß, which encodes an elongated propeptide, and hIAPPγ, which is processed to mature IAPP25 instead of IAPP37. We found that hIAPPß was significantly reduced in the plasma of AD patients with the accuracy of 89%. We uncovered that IAPP25 and a GDNF derived DNSP11 were nonaggregating peptides that inhibited the aggregation of IAPP37 and Aß42. (4) Conclusions: The novel peptides derived from hIAPP isoforms have potential to serve as blood-derived biomarkers for early AD and be developed as peptide based anti-amyloid medicine.

Comparison of Hormonal Response to a Mixed-Meal Challenge in Hypoglycemia After Sleeve Gastrectomy vs Gastric Bypass.

CONTEXT: Exaggerated postprandial incretin and insulin responses are well documented in postbariatric surgery hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). However, less is known about PBH after sleeve gastrectomy (SG). OBJECTIVE: We sought to compare meal-stimulated hormonal response in those with PBH after SG vs RYGB. METHODS: We enrolled 23 post-SG (12 with and 11 without PBH) and 20 post-RYGB (7 with and 13 without PBH) individuals who underwent bariatric surgery at our institution. PBH was defined as plasma glucose less than 60 mg/dL on 4-hour mixed-meal tolerance test (MTT). Islet and incretin hormones were compared across the 4 groups. RESULTS: Participants (N = 43) were on average 5 years post surgery, with a mean age of 48 years, mean preoperative body mass index of 48.4, 81% female, 61% White, and 53% post SG. Regardless of PBH, the SG group showed lower glucose, glucagon, and glucagon-like peptide 1 (GLP-1) responses to MTT and similar insulin and glucose-dependent insulinotropic polypeptide (GIP) responses compared to the RYGB group. Among those with PBH, the SG group following the MTT showed a lower peak glucose (P = .02), a similar peak insulin (90.3 mU/L vs 171mU/L; P = .18), lower glucagon (P < .01), early GLP-1 response (AUC0-60 min; P = .01), and slower time to peak GIP (P = .02) compared to PBH after RYGB. CONCLUSION: Among individuals with PBH, those who underwent SG were significantly different compared to RYGB in meal-stimulated hormonal responses, including lower glucagon and GLP-1 responses, but similar insulin and GIP responses. Future studies are needed to better understand the differential contribution of insulin and non-insulin-mediated mechanisms behind PBH after SG vs RYGB.

Black Ginseng Ameliorates Cellular Senescence via p53-p21/p16 Pathway in Aged Mice.

Cellular senescence, one of the hallmarks of aging, refers to permanent cell cycle arrest and is accelerated during the aging process. Black ginseng (BG), prepared by a repeated steaming and drying process nine times from fresh ginseng (Panax ginseng C.A. Meyer), is garnering attention for herbal medicine due to its physiological benefits against reactive oxygen species (ROS), inflammation, and oncogenesis, which are common cues to induce aging. However, which key nodules in the cellular senescence process are regulated by BG supplementation has not been elucidated yet. In this study, we investigated the effects of BG on cellular senescence using in vitro and aged mouse models. BG-treated primary mouse embryonic fibroblasts (MEFs) in which senescence was triggered by ionizing radiation (IR) expressed less senescence-associated ß-galactosidase (SA-ß-gal)-positive stained cells. In our aged mice (18 months old) study, BG supplementation (300 mg/kg) for 4 weeks altered hepatic genes involved in the aging process. Furthermore, we found BG supplementation downregulated age-related inflammatory genes, especially in the complement system. Based on this observation, we demonstrated that BG supplementation led to less activation of the canonical senescence pathway, p53-dependent p21 and p16, in multiple metabolic organs such as liver, skeletal muscle and white adipose tissue. Thus, we suggest that BG is a potential senolytic candidate that retards cellular senescence.

GDF15 and Cortisol Response to Meal Tolerance Test in Post-Sleeve Gastrectomy Patients with Weight Regain.

BACKGROUND: Hormonal factors behind weight regain (WR) after surgical weight loss remain inadequately understood. Growth/differentiation factor 15 (GDF15) has emerged as a potential therapeutic target in obesity treatment. Cortisol, another stress hormone, has also been associated with weight gain at both low and high circulating concentrations. We aimed to compare meal-stimulated GDF15 and cortisol response in adults with and without WR after sleeve gastrectomy (SG). We hypothesized that GDF15 and cortisol response to meal tolerance test (MTT) will be lower in those with versus without WR after SG. METHODS: Cross-sectional study comprised 21 adults without diabetes, who underwent SG. WR was defined as 100 × (current weight - nadir)/(preoperative weight - nadir) > 10%. GDF15, cortisol, insulin, glucose, and incretins (total glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) circulating concentrations) were measured during MTT (0-240 min) after 3-6 years post-bariatric surgery. RESULTS: All participants were 48% White, 85% female, with mean (SD) age: 43(10) years, and BMI: 36.2(7.6) kg/m2. Compared to the non-WR group (n = 6), the WR group (n = 15) had significantly higher BMI (WR: 38.6 ± 7.6 kg/m2, non-WR: 30.3 ± 3.5 kg/m2, p = 0.02) and showed lower GDF15 response (WR AUC vs non-WR AUC (116143 ± 13973 vs 185798 ± 38884 ng*min/L, p = 0.047)) and lower cortisol response (WR AUC vs non-WR AUC (3492 ± 210 vs 4880 ± 655 µg*min/dL, p = 0.015)). Incretin response did not differ between the groups. CONCLUSIONS: GDF15 and cortisol responses to MTT were lower in those who regained the weight after SG compared to those who did not, suggesting that dysregulation in GDF15 and cortisol response following bariatric surgery.

Longitudinal trajectories and determinants of human fungiform papillae density.

Tongue fungiform papillae contain taste buds crucial for taste and hormone-producing taste receptor cells; therefore, they may be considered as endocrine organs and have important age-associated physiological implications. We examine the cross-sectional and longitudinal trajectories of fungiform papillae density in 1084 participants from the Baltimore Longitudinal Study of Aging using linear regression models and mixed effects models. At baseline, the mean age was 67.86 ± 14.20 years, with a mean follow-up time among those with repeat visits of 4.24 ± 1.70 years. Women (53%) were younger (66.85 ± 13.78 vs. 69.04 ± 14.61 years, p < 0.001) and had a higher fungiform papillae density than men (16.14 ± 9.54 vs. 13.77 ± 8.61 papillae/cm2, p < 0.001). Whites (67%) had a lower fungiform papillae density than non-Whites after adjusting for age and sex. Factors cross-sectionally associated with a lower fungiform papillae density included a higher waist-hip ratio (ß = -8.525, p = 0.029), current smoking status (ß = -5.133, p = 0.014), and alcohol use within the past 12 months (ß = -1.571, p = 0.025). Longitudinally, fungiform papillae density decreased linearly with follow-up time (ß = -0.646, p < 0.001). The rate of decline was not affected by sex, race, BMI, waist-hip ratio, smoking, or alcohol use. The longitudinal decline of fungiform papillae density over time needs to be explored further in order to identify other possible age-associated physiological determinants.

Novel Human Insulin Isoforms and Cα-Peptide Product in Islets of Langerhans and Choroid Plexus.

Human insulin (INS) gene diverged from the ancestral genes of invertebrate and mammalian species millions of years ago. We previously found that mouse insulin gene (Ins2) isoforms are expressed in brain choroid plexus (ChP) epithelium cells, where insulin secretion is regulated by serotonin and not by glucose. We further compared human INS isoform expression in postmortem ChP and islets of Langerhans. We uncovered novel INS upstream open reading frame isoforms and their protein products. In addition, we found a novel alternatively spliced isoform that translates to a 74-amino acid (AA) proinsulin containing a shorter 19-AA C-peptide sequence, herein designated Cα-peptide. The middle portion of the conventional C-peptide contains ß-sheet (GQVEL) and hairpin (GGGPG) motifs that are not present in Cα-peptide. Islet amyloid polypeptide (IAPP) is not expressed in ChP, and its amyloid formation was inhibited in vitro more efficiently by Cα-peptide than by C-peptide. Of clinical relevance, the ratio of the 74-AA proinsulin to proconvertase-processed Cα-peptide was significantly increased in islets from type 2 diabetes mellitus autopsy donors. Intriguingly, 100 years after the discovery of insulin, we found that INS isoforms are present in ChP from insulin-deficient autopsy donors.

Age-associated expression of p21and p53 during human wound healing.

In mice, cellular senescence and senescence-associated secretory phenotype (SASP) positively contribute to cutaneous wound healing. In this proof-of-concept study, we investigated the expressions of p16, p21, and other senescence-associated biomarkers during human wound healing in 24 healthy subjects using a double-biopsy experimental design. The first punch biopsy created the wound and established the baseline. The second biopsy, concentric to the first and taken several days after wounding, was used to probe for expression of biomarkers by immunohistochemistry and RNA FISH. To assess the effects of age, we recruited 12 sex-matched younger (30.2 ± 1.3 years) and 12 sex-matched older (75.6 ± 1.8 years) subjects. We found that p21 and p53, but not p16, were induced during healing in younger, but not older subjects. A role for Notch signaling in p21 expression was inferred from the inducible activation of HES1. Further, other SASP biomarkers such as dipeptidyl peptidase-4 (DPP4) were significantly induced upon wounding in both younger and older groups, whereas matrix metallopeptidase 9 (MMP9) was induced only in the younger group. Senescence-associated ß-galactosidase (SA-ß-gal) was not detectable before or after wounding. This pilot study suggests the possibility that human cutaneous wound healing is characterized by differential expression of p21 and p53 between younger and older subjects.

Hepatocyte cannabinoid 1 receptor nullification alleviates toxin-induced liver damage via NF-κB signaling.

Cannabinoid 1 receptor (CB1R) expression is upregulated in the liver with viral hepatitis, cirrhosis, and both alcoholic and non-alcoholic fatty liver disease (FLD), whereas its expression is muted under usual physiological conditions. Inhibiting CB1R has been shown to be beneficial in preserving hepatic function in FLD but it is unclear if inhibiting CB1R during an inflammatory response to an acute hepatic injury, such as toxin-induced injury, would also be beneficial. We found that intrinsic CB1R in hepatocytes regulated liver inflammation-related gene transcription. We tested if nullification of hepatocyte-specific CB1R (hCNR1-/-) in mice protects against concanavalin A (Con A)-induced liver injury. We looked for evidence of liver damage and markers of inflammation in response to Con A by measuring liver enzyme levels and proinflammatory cytokines (e.g., TNF-α, IL-1ß, IL-6, IL-17) in serum collected from hCNR1-/- and control mice. We observed a shift to the right in the dose-response curve for liver injury and inflammation in hCNR1-/- mice. We also found less inflammatory cell infiltration and focal necrosis in livers of hCNR1-/- mice compared to controls, resulting from downregulated apoptotic markers. This anti-apoptotic mechanism results from increased activation of nuclear factor kappa B (NF-κB), especially cAMP-dependent cannabinoid signaling and membrane-bound TNF-α, via downregulated TNF-α receptor 2 (TNFR2) transcription levels. Collectively, these findings provide insight into involvement of CB1R in the pathogenesis of acute liver injury.

Disulfiram Treatment Normalizes Body Weight in Obese Mice.

Obesity is a top public health concern, and a molecule that safely treats obesity is urgently needed. Disulfiram (known commercially as Antabuse), an FDA-approved treatment for chronic alcohol addiction, exhibits anti-inflammatory properties and helps protect against certain types of cancer. Here, we show that in mice disulfiram treatment prevented body weight gain and abrogated the adverse impact of an obesogenic diet on insulin responsiveness while mitigating liver steatosis and pancreatic islet hypertrophy. Additionally, disulfiram treatment reversed established diet-induced obesity and metabolic dysfunctions in middle-aged mice. Reductions in feeding efficiency and increases in energy expenditure were associated with body weight regulation in response to long-term disulfiram treatment. Loss of fat tissue and an increase in liver fenestrations were also observed in rats on disulfiram. Given the potent anti-obesogenic effects in rodents, repurposing disulfiram in the clinic could represent a new strategy to treat obesity and its metabolic comorbidities.

An inverse agonist of estrogen-related receptor γ regulates 2-arachidonoylglycerol synthesis by modulating diacylglycerol lipase expression in alcohol-intoxicated mice.

Chronic alcohol feeding increases the levels of 2-arachidonoylglycerol (2-AG) in the liver, which activates hepatic cannabinoid receptor type 1 (CB1R), leading to oxidative liver injury. 2-AG biosynthesis is catalyzed by diacylglycerol lipase (DAGL). However, the mechanisms regulating hepatic DAGL gene expression and 2-AG production are largely unknown. In this study, we show that CB1R-induced estrogen-related receptor γ (ERRγ) controls hepatic DAGL gene expression and 2-AG levels. Arachidonyl-2'-chloroethylamide (ACEA), a synthetic CB1R agonist, significantly upregulated ERRγ, DAGLα, and DAGLß, and increased 2-AG levels in the liver (10 mg/kg) and hepatocytes (10 µM) of wild-type (WT) mice. ERRγ overexpression upregulated DAGLα and DAGLß expressions and increased 2-AG levels, whereas ERRγ knockdown abolished ACEA-induced DAGLα, DAGLß, and 2-AG in vitro and in vivo. Promoter assays showed that ERRγ positively regulated DAGLα and DAGLß transcription by binding to the ERR response element in the DAGLα and DAGLß promoters. Chronic alcohol feeding (27.5% of total calories) induced hepatic steatosis and upregulated ERRγ, leading to increased DAGLα, DAGLß, or 2-AG in WT mice, whereas these alcohol-induced effects did not occur in hepatocyte-specific CB1R knockout mice or in those treated with the ERRγ inverse agonist GSK5182 (40 mg/kg in mice and 10 µM in vitro). Taken together, these results indicate that suppression of alcohol-induced DAGLα and DAGLß gene expressions and 2-AG levels by an ERRγ-specific inverse agonist may be a novel and attractive therapeutic approach for the treatment of alcoholic liver disease.

Incretins in obesity and diabetes.

Incretins are hormones secreted from enteroendocrine cells after nutrient intake that stimulate insulin secretion from ß cells in a glucose-dependent manner. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the only two known incretins. Dysregulation of incretin secretion and actions are noted in diseases such as obesity and diabetes. In this review, we first summarize our traditional understanding of the physiology of GIP and GLP-1, and our current knowledge of the relationships between GIP and GLP-1 and obesity and diabetes. Next, we present the results from major randomized controlled trials on the use of GLP-1 receptor agonists for managing type 2 diabetes, and emerging data on treating obesity and prediabetes. We conclude with a glimpse of the future with possible complex interactions between nutrients, gut microbiota, the endocannabinoid system, and enteroendocrine cells.

Release of insulin produced by the choroid plexis is regulated by serotonergic signaling.

The choroid plexus (ChP) is a highly vascularized tissue found in the brain ventricles, with an apical epithelial cell layer surrounding fenestrated capillaries. It is responsible for the production of most of the cerebrospinal fluid (CSF) in the ventricular system, subarachnoid space, and central canal of the spinal cord, while also constituting the blood-CSF barrier (BCSFB). In addition, epithelial cells of the ChP (EChP) synthesize neurotrophic factors and other signaling molecules that are released into the CSF. Here, we show that insulin is produced in EChP of mice and humans, and its expression and release are regulated by serotonin. Insulin mRNA and immune-reactive protein, including C-peptide, are present in EChP, as detected by several experimental approaches, and appear in much higher levels than any other brain region. Moreover, insulin is produced in primary cultured mouse EChP, and its release, albeit Ca2+ sensitive, is not regulated by glucose. Instead, activation of the 5HT2C receptor by serotonin treatment led to activation of IP3-sensitive channels and Ca2+ mobilization from intracellular storage, leading to insulin secretion. In vivo depletion of brain serotonin in the dorsal raphe nucleus negatively affected insulin expression in the ChP, suggesting an endogenous modulation of ChP insulin by serotonin. Here, we show for the first time to our knowledge that insulin is produced by EChP in the brain, and its release is modulated at least by serotonin but not glucose.

Dietary curcumin enhances insulin clearance in diet-induced obese mice via regulation of hepatic PI3K-AKT axis and IDE, and preservation of islet integrity.

BACKGROUND: Although type 2 diabetes mellitus (T2DM) is primarily characterized by sustained high levels of circulating glucose, other factors, such as obesity, chronic inflammation, fatty liver, and islet dysfunction significantly contribute to the development of this disease. To date, curcumin (CUR), a natural polyphenol and primary component of turmeric, shows putative therapeutic properties such as reducing the incidence of obesity-related diseases in mice. However, the mechanism by which CUR regulates insulin levels remains unclear. METHODS: This study investigates how dietary CUR improves insulin clearance and maintains a proper range of circulating insulin level in the diet-induced obesity (DIO) mouse model. Male C57BL/6 J mice were fed a control, a high fat/high sugar (HFS) or a HFS diet containing 0.4% (w/w) curcumin (HFS + CUR) (N = 16 per group) for 16 weeks. RESULTS: Mice given HFS + CUR had reduced body weight and fat accumulation in the liver and had lower blood insulin levels under fasting conditions compared to mice on HFS alone, resulting from significantly improved insulin clearance via upregulation of hepatic insulin-degrading enzyme (IDE). We also observed restoration of phosphoinositide 3-kinase (PI3K), especially class Ia catalytic subunits, p110α and p110ß, and class Ib regulatory subunit, p101, and phosphorylated protein kinase B (AKT) expression levels in liver on HFS + CUR diet. Additionally, HFS + CUR fed mice had significantly smaller islets of Langerhans and increased glucagon contents compared to HFS fed mice, indicating less secretion of insulin in pancreas. The expression of thioredoxin interacting protein (TXNIP), a pro-oxidant and pro-apoptotic protein, was significantly elevated in mouse and human islets cultured under HFS mimicking conditions, which was mitigated by CUR treatment. CONCLUSIONS: CUR supplementation in obese subjects may alleviate the burden imposed by HFS diets. Our data indicate administration of dietary CUR reinstates PI3K, AKT and IDE levels in obese mice. Additionally, CUR treatment preserves islet integrity by downregulation of TXNIP transcription levels. Therefore, dietary CUR may have the potential to serve as a novel therapeutic agent to address the underlying links of obesity and T2DM.

Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism.

Sarcopenic obesity, the combination of skeletal muscle mass and function loss with an increase in body fat, is associated with physical limitations, cardiovascular diseases, metabolic stress, and increased risk of mortality. Cannabinoid receptor type 1 (CB1R) plays a critical role in the regulation of whole-body energy metabolism because of its involvement in controlling appetite, fuel distribution, and utilization. Inhibition of CB1R improves insulin secretion and insulin sensitivity in pancreatic ß-cells and hepatocytes. We have now developed a skeletal muscle-specific CB1R-knockout (Skm-CB1R-/-) mouse to study the specific role of CB1R in muscle. Muscle-CB1R ablation prevented diet-induced and age-induced insulin resistance by increasing IR signaling. Moreover, muscle-CB1R ablation enhanced AKT signaling, reducing myostatin expression and increasing IL-6 secretion. Subsequently, muscle-CB1R ablation increased myogenesis through its action on MAPK-mediated myogenic gene expression. Consequently, Skm-CB1R-/- mice had increased muscle mass and whole-body lean/fat ratio in obesity and aging. Muscle-CB1R ablation improved mitochondrial performance, leading to increased whole-body muscle energy expenditure and improved physical endurance, with no change in body weight. These results collectively show that CB1R in muscle is sufficient to regulate whole-body metabolism and physical performance and is a novel target for the treatment of sarcopenic obesity. -González-Mariscal, I., Montoro, R. A., O'Connell, J. F., Kim, Y., Gonzalez-Freire, M., Liu, Q.-R., Alfaras, I., Carlson, O. D., Lehrmann, E., Zhang, Y., Becker, K. G., Hardivillé, S., Ghosh, P., Egan, J. M. Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism.

IGFBP-2 and aging: a 20-year longitudinal study on IGFBP-2, IGF-I, BMI, insulin sensitivity and mortality in an aging population.

Objective Insulin-like growth factor-binding protein-2 (IGFBP-2) concentrations are low in subjects with metabolic syndrome and type 2 diabetes. Intriguingly, recent studies have demonstrated an association between high IGFBP-2 concentrations and increased mortality not only in populations with certain types of cancer, but also in relatively healthy populations. We evaluated the role of IGFBP-2 in relation to BMI and mortality. Design and Participants BMI, insulin sensitivity, insulin-like growth factor 1 (IGF-I) and IGFBP-2 were assessed repeatedly in 539 participants of the Baltimore Longitudinal Study of Aging around the ages of 55, 65 and 75 years. Results IGFBP-2 concentrations positively correlated with insulin sensitivity and inversely with BMI, both at baseline and follow-up. Independent of IGF-I, sex, BMI and insulin sensitivity, circulating IGFBP-2 levels positively correlated with age (P < 0.001). Changes over time in BMI were associated with an inverse correlation in IGFBP-2 concentrations. Furthermore, we found indications of a relationship between low baseline IGFBP-2 levels and mortality. Remarkably, after adjustment for insulin sensitivity, the opposite association was found, as a unit increase of log(IGFBP2) was associated with an increase in the log hazard by 1.43 (95% CI: 0.3-2.6). This accounted for both baseline (P = 0.02) as well as serial (P < 0.001) measurements of IGFBP2. Finally, in this longitudinal study, we found that IGF-I concentrations increased with age (0.82 ± 0.2 (µg/L)/year, P < 0.001). Conclusion This is the first study investigating the relationship between IGFBP-2 levels and age in a longitudinal setting. Serum IGFBP-2 levels increase with age after the age of 50 years and evolve in parallel with insulin sensitivity. IGFBP-2 may therefore be a potential marker for insulin sensitivity. We further show that IGFBP-2 levels can predict mortality in this aging population. However, its predictive value for mortality can only be interpreted in relation to insulin sensitivity. After adjustment for insulin sensitivity, high IGFBP-2 levels are predictive of increased mortality.

Relationship of Circulating Growth and Differentiation Factors 8 and 11 and Their Antagonists as Measured Using Liquid Chromatography-Tandem Mass Spectrometry With Age and Skeletal Muscle Strength in Healthy Adults.

Background: Growth and differentiation factors 8 (GDF8) and 11 (GDF11) have attracted attention as targets for rejuvenating interventions. The biological activity of these proteins may be affected by circulating antagonists such as their respective prodomains, follistatin (FST315), WFIKKN1, and WFIKKN2. Reports of the relationship of GDF8 and GDF11 and their antagonists with aging and aging phenotypes such as skeletal muscle strength have been conflicting possibly because of difficulties in measuring these proteins and polypeptides. Methods: Plasma GDF8 and GDF11 and their antagonists were measured using a multiplexed selected reaction monitoring assay and liquid chromatography-tandem mass spectrometry in 160 healthy adults aged 22-93 years. Quadriceps strength was measured by knee extensor torque using isokinetic dynamometry. Results: Spearman correlations with age were the following: GDF11 prodomain (r = .30, p = .001), GDF11 mature protein (r = .23, p = .004), FST315 (r = .32, p < .0001), WFIKKN1 (r = -.21, p = 0.008), and WFIKKN2 (r = .18, p = .02). Independent of age, FST315 and WFIKKN1 were negatively associated with knee strength (p = .02, p = .03, respectively) in a multivariable model that included both GDF8 and GDF11 mature proteins. Conclusions: When measured by an antibody-free selected reaction monitoring assay, GDF8, GDF11, and their antagonists are found in the circulation in the ng/mL range. In healthy adults, plasma GDF11 and antagonists FST315, WFIKKN1, and WFIKKN2 differed by age. Antagonists of GDF8 and GDF11, but not GDF8 and GDF11, were independently associated with skeletal muscle strength. Further work is needed to characterize the relationship of these protein and polypeptides with sarcopenia-related phenotypes such as physical function and walking disability.

Regular low-calorie sweetener consumption is associated with increased secretion of glucose-dependent insulinotropic polypeptide.

Low-calorie sweeteners (LCSs) are widely used for weight control despite limited evidence of their effectiveness and studies linking LCS consumption with incident obesity. We tested the hypothesis that regular LCS consumption is associated with higher postprandial glucose-dependent insulinotropic polypeptide (GIP) secretion, which has been linked to obesity. We used data from participants in the Baltimore Longitudinal Study of Aging who had completed a diet diary, had at least one visit during which they underwent an oral glucose tolerance test (OGTT), and had no diabetes. Of 232 participants, 166 contributed 1, 39 contributed 2, and 27 contributed 3 visits, and 96 (41%) reported using LCS. Plasma OGTT samples were analysed for glucose, insulin and GIP. Fasting glucose, insulin and GIP levels were no different between LCS users and non-users. The association of LCS use with 2-hour OGTT responses after adjustment for covariates was non-significant for glucose (P = .98) and insulin (P = .18), but significant for greater increase in GIP in LCS users (P = .037). Regular consumption of LCSs was associated with greater increases in GIP secretion after food intake, which may potentially lead to weight gain through the lipogenic properties of GIP.