Integrity of hypothalamic-pituitary-testicular axis in exceptional longevity.

Hypothalamic integrity increasingly is being recognized as a marker of healthy longevity in rodent models. Insight into hypothalamic function in humans with exceptional longevity can be gained via investigation of the hypothalamic-pituitary-testicular (HPT) axis in men with exceptional longevity. This study aimed to characterize the HPT axis function, defined by levels of testosterone (T) and luteinizing hormone (LH), in 84 Ashkenazi Jewish men aged 90-106 years. We found that 94% of men exhibited preserved hypothalamic-pituitary function, as evidenced by either normal testosterone and LH levels (25%) or an appropriate rise in LH in response to aging-related primary testicular dysfunction (69%), a hormone pattern mirroring female menopause. Total T level was not associated with metabolic parameters or survival. These results demonstrate a high prevalence of testicular dysfunction with preserved hypothalamic-pituitary function in men with exceptional longevity. Thus, the role of hypothalamic integrity and HPT axis in healthy aging warrants further investigation.

Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization.

Common chronic diseases represent the greatest driver of rising healthcare costs, as well as declining function, independence, and quality of life. Geroscience-guided approaches seek to delay the onset and progression of multiple chronic conditions by targeting fundamental biological pathways of aging. This approach is more likely to improve overall health and function in old age than treating individual diseases, by addressing aging the largest and mostly ignored risk factor for the leading causes of morbidity in older adults. Nevertheless, challenges in repurposing existing and moving newly discovered interventions from the bench to clinical care have impeded the progress of this potentially transformational paradigm shift. In this article, we propose the creation of a standardized process for evaluating FDA-approved medications for their geroscience potential. Criteria for systematically evaluating the existing literature that spans from animal models to human studies will permit the prioritization of efforts and financial investments for translating geroscience and allow immediate progress on the design of the next Targeting Aging with MEtformin (TAME)-like study involving such candidate gerotherapeutics.

Plasma Epinephrine Contributes to the Development of Experimental Hypoglycemia-Associated Autonomic Failure.

BACKGROUND: Recurrent hypoglycemia blunts counter-regulatory responses to subsequent hypoglycemic episodes, a syndrome known as hypoglycemia-associated autonomic failure (HAAF). Since adrenergic receptor blockade has been reported to prevent HAAF, we investigated whether the hypoglycemia-associated rise in plasma epinephrine contributes to pathophysiology and reported interindividual differences in susceptibility to HAAF. METHODS: To assess the role of hypoglycemia-associated epinephrine responses in the susceptibility to HAAF, 24 adult nondiabetic subjects underwent two 2-hour hyperinsulinemic hypoglycemic clamp studies (nadir 54 mg/dL; 0-2 hours and 4-6 hours) on Day 1, followed by a third identical clamp on Day 2. We challenged an additional 7 subjects with two 2-hour infusions of epinephrine (0.03 µg/kg/min; 0-2 hours and 4-6 hours) vs saline on Day 1 followed by a 200-minute stepped hypoglycemic clamp (90, 80, 70, and 60 mg/dL) on Day 2. RESULTS: Thirteen out of 24 subjects developed HAAF, defined by ≥20% reduction in average epinephrine levels during the final 30 minutes of the third compared with the first hypoglycemic episode (P < 0.001). Average epinephrine levels during the final 30 minutes of the first hypoglycemic episode were 2.3 times higher in subjects who developed HAAF compared with those who did not (P = 0.006).Compared to saline, epinephrine infusion on Day 1 reduced the epinephrine responses by 27% at the 70 and 60 mg/dL glucose steps combined (P = 0.04), with a parallel reduction in hypoglycemic symptoms (P = 0.03) on Day 2. CONCLUSIONS: Increases in plasma epinephrine reproduce key features of HAAF in nondiabetic subjects. Marked interindividual variability in epinephrine responses to hypoglycemia may explain an individual's susceptibility to developing HAAF.

Insulin-like Growth Factor-1 and IGF Binding Proteins Predict All-Cause Mortality and Morbidity in Older Adults.

While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of GH/IGF-1 system activity, have not been consistently associated with morbidity and mortality. In a prospective cohort of independently-living older adults (n = 840, mean age 76.1 ± 6.8 years, 54.5% female, median follow-up 6.9 years), we evaluated the age- and sex-adjusted hazards for all-cause mortality and incident age-related diseases, including cardiovascular disease, diabetes, cancer, and multiple-domain cognitive impairment (MDCI), as predicted by baseline total serum IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1 levels. All-cause mortality was positively associated with IGF-1/IGFBP-3 molar ratio (HR 1.28, 95% CI 1.05-1.57) and negatively with IGFBP-3 (HR 0.82, 95% CI 0.680-0.998). High serum IGF-1 predicted greater risk for MDCI (HR 1.56, 95% CI 1.08-2.26) and composite incident morbidity (HR 1.242, 95% CI 1.004-1.538), whereas high IGFBP-1 predicted lower risk for diabetes (HR 0.50, 95% CI 0.29-0.88). In conclusion, higher IGF-1 levels and bioavailability predicted mortality and morbidity risk, supporting the hypothesis that diminished GH/IGF-1 signaling may contribute to human longevity and health-span.

Glycemic management and clinical outcomes in underserved minority kidney transplant recipients with type 2 and posttransplantation diabetes: A single-center retrospective study.

AIMS: Little is known about glycemic management, particularly with novel cardio-nephroprotecive agents, in underserved minority kidney transplant recipients with pre-transplant type 2 (T2DM) and posttransplantation diabetes mellitus (PTDM). We assessed glycemic management and outcomes in this high-risk population. METHODS: We reviewed records of patients who received kidney transplants between June 2012 and December 2014 at a single center. Hemoglobin A1c (HbA1c) and prescribed glucose-lowering medications were examined, and mortality was compared between T2DM, PTDM, and no diabetes (NoDM) patients. RESULTS: We followed 302 patient records (41.1% Hispanic, 41.1% non-Hispanic black) for a median (IQR) of 45.5 (37.0, 53.0) months post-transplant. Pre-transplant T2DM was present in 152 (50.3%), while 58 (19.2%) developed PTDM and 92 (30.4%) remained NoDM. At 1-year post-transplant, the average HbA1c was 8.1 ± 1.8% in T2DM and 6.6 ± 1.3% in PTDM. No glucose-lowering agents were prescribed in 3.4% of T2DM and 44.8% of PTDM. When treated, both received mostly insulin and metformin. Diabetes, HbA1c and insulin therapy were not independently associated with risk of mortality. CONCLUSIONS: Glycemic management was suboptimal and relied on older medications. Further studies are needed to assess longer-term outcomes of more rigorous glycemic management, and the value of novel cardio-nephroprotective agents in kidney transplant recipients.

Central KATP Channels Modulate Glucose Effectiveness in Humans and Rodents.

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this "glucose effectiveness" is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). KATP channels in the central nervous system have been shown to regulate EGP in humans and rodents. We examined the contribution of central KATP channels to glucose effectiveness. Under fixed hormonal conditions (studies using a pancreatic clamp), hyperglycemia suppressed EGP by ∼50% in both humans without diabetes and normal Sprague-Dawley rats. By contrast, antagonism of KATP channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes were abolished in rats by intracerebroventricular administration of the KATP channel agonist diazoxide. These findings indicate that about half of the suppression of EGP by hyperglycemia is mediated by central KATP channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in subjects with T2D.

Decreased Insulin Sensitivity and Impaired Fibrinolytic Activity in Type 2 Diabetes Patients and Nondiabetics with Ischemic Stroke.

We analyzed (a) insulin sensitivity (IS), (b) plasma insulin (PI), and (c) plasminogen activator inhibitor-1 (PAI-1) in type 2 diabetes (T2D) patients with (group A) and without (group B) atherothrombotic ischemic stroke (ATIS), nondiabetics with ATIS (group C), and healthy controls (group D). IS was determined by minimal model (Si). Si was lower in A versus B (1.18 ± 0.67 versus 2.82 ± 0.61 min-1/mU/L × 104; P < 0.001) and in C versus D (3.18 ± 0.93 versus 6.13 ± 1.69 min-1/mU/L × 104; P < 0.001). PI and PAI-1 were higher in A versus B (PI: 19.61 ± 4.08 versus 14.91 ± 1.66 mU/L; P < 0.001, PAI-1: 7.75 ± 1.04 versus 4.57 ± 0.72 mU/L; P < 0.001) and in C versus D (PI: 15.14 ± 2.20 versus 7.58 ± 2.05 mU/L; P < 0.001, PAI-1: 4.78 ± 0.98 versus 3.49 ± 1.04 mU/L; P < 0.001). Si correlated with PAI-1 in T2D patients and nondiabetics, albeit stronger in T2D. Binary logistic regression identified insulin, PAI-1, and Si as independent predictors for ATIS in T2D patients and nondiabetics. The results imply that insulin resistance and fasting hyperinsulinemia might exert their atherogenic impact through the impaired fibrinolysis.

High Risk First Degree Relatives of Type 1 Diabetics: An Association with Increases in CXCR3(+) T Memory Cells Reflecting an Enhanced Activity of Th1 Autoimmune Response.

We analyzed the level of (a) CXCR3(+) (Th1) and CCR4(+) (Th2) T memory cells (b) interferon- γ inducible chemokine (IP-10)(Th1) and thymus and activation-regulated chemokine (TARC)(Th2), in 51 first degree relatives (FDRs) of type 1 diabetics (T1D) (17 high risk FDRs (GADA(+), IA-2(+)) and 34 low risk FDRs (GADA(-), IA-2(-))), 24 recent-onset T1D (R-T1D), and 18 healthy subjects. T memory subsets were analyzed by using four-color immunofluorescence staining and flowcytometry. IP-10 and TARC were determined by ELISA. High risk FDRs showed higher levels of CXCR3(+) and lower level of CCR4(+) T memory cells compared to low risk FDRs (64.98 ± 5.19 versus 42.13 ± 11.11; 29.46 ± 2.83 versus 41.90 ± 8.58%, resp., P < 0.001). Simultaneously, both IP-10 and TARC levels were increased in high risk versus low risk FDRs (160.12 ± 73.40 versus 105.39 ± 71.30; 438.83 ± 120.62 versus 312.04 ± 151.14 pg/mL, P < 0.05). Binary logistic regression analysis identified the level of CXCR3(+) T memory cells as predictors for high risk FDRs, together with high levels of IP-10. The results imply that, in FDRs, the risk for T1D might be strongly influenced by enhanced activity of Th1 and diminished activity of Th2 autoimmune response.

Type 2 diabetic patients with ischemic stroke: decreased insulin sensitivity and decreases in antioxidant enzyme activity are related to different stroke subtypes.

We analyzed (a) insulin sensitivity (IS) and (b) glutathione peroxidase (GSH-Px), glutathione reductase (GR), and superoxide dismutase (SOD) antioxidant enzyme activity in type 2 diabetic (T2D) patients with atherothrombotic infarction (ATI) (group A), lacunar infarction (LI) (B), or without stroke (C) and in nondiabetics with ATI (D), LI (E), or without stroke (F). ATI and LI were confirmed by brain imaging IS levels were determined by minimal model (Si index), and the enzyme activity by spectrophotometry. In T2D patients, Si was lower in A and B versus C (1.14 ± 0.58, 1.00 ± 0.26 versus 3.14 ± 0.62 min(-1)/mU/l × 10(4), P < 0.001) and in nondiabetics in D and E versus F (3.38 ± 0.77, 3.03 ± 0.72 versus 6.03 ± 1.69 min(-1)/mU/l × 10(4), P < 0.001). Also, GSH-Px and GR activities were lower in A and B versus C (GSH-Px: 21.96 ± 3.56, 22.51 ± 1.23 versus 25.12 ± 1.67; GR: 44.37 ± 3.58, 43.50 ± 2.39 versus 48.58 ± 3.67 U/gHb; P < 0.001) and in D and E versus F (GSH-Px: 24.75 ± 3.02, 25.57 ± 1.92 versus 28.56 ± 3.91; GR: 48.27 ± 6.81, 49.17 ± 6.24 versus 53.67 ± 3.96 U/gHb; P < 0.001). Decreases in Si and GR were significantly related to both ATI and LI in T2D. Our results showed that decreased IS and impaired antioxidant enzymes activity influence ischemic stroke subtypes in T2D. The influence of insulin resistance might be exerted on the level of glutathione-dependent antioxidant enzymes.