Effect of the ketone beta-hydroxybutyrate on markers of inflammation and immune function in adults with type 2 diabetes.

Pre-clinical and cell culture evidence supports the role of the ketone beta-hydroxybutyrate (BHB) as an immunomodulatory molecule that may inhibit inflammatory signalling involved in several chronic diseases such as type 2 diabetes (T2D), but studies in humans are lacking. Therefore, we investigated the anti-inflammatory effect of BHB in humans across three clinical trials. To investigate if BHB suppressed pro-inflammatory cytokine secretion, we treated LPS-stimulated leukocytes from overnight-fasted adults at risk for T2D with BHB (Study 1). Next (Study 2), we investigated if exogenously raising BHB acutely in vivo by ketone monoester supplementation (KME) in adults with T2D would suppress pro-inflammatory plasma cytokines. In Study 3, we investigated the effect of BHB on inflammation via ex vivo treatment of LPS-stimulated leukocytes with BHB and in vivo thrice-daily pre-meal KME for 14 days in adults with T2D. Ex vivo treatment with BHB suppressed LPS-stimulated IL-1ß, TNF-α, and IL-6 secretion and increased IL-1RA and IL-10 (Study 1). Plasma IL-10 increased by 90 min following ingestion of a single dose of KME in T2D, which corresponded to peak blood BHB (Study 2). Finally, 14 days of thrice-daily KME ingestion did not significantly alter plasma cytokines or leukocyte subsets including monocyte and T-cell polarization (Study 3). However, direct treatment of leukocytes with BHB modulated TNF-α, IL-1ß, IFN-γ, and MCP-1 secretion in a time- and glucose-dependent manner (Study 3). Therefore, BHB appears to be anti-inflammatory in T2D, but this effect is transient and is modulated by the presence of disease, glycaemia, and exposure time.

Machine Learning Decision Support for Detecting Lipohypertrophy With Bedside Ultrasound: Proof-of-Concept Study.

BACKGROUND: The most common dermatological complication of insulin therapy is lipohypertrophy. OBJECTIVE: As a proof of concept, we built and tested an automated model using a convolutional neural network (CNN) to detect the presence of lipohypertrophy in ultrasound images. METHODS: Ultrasound images were obtained in a blinded fashion using a portable GE LOGIQ e machine with an L8-18I-D probe (5-18 MHz; GE Healthcare). The data were split into train, validation, and test splits of 70%, 15%, and 15%, respectively. Given the small size of the data set, image augmentation techniques were used to expand the size of the training set and improve the model's generalizability. To compare the performance of the different architectures, the team considered the accuracy and recall of the models when tested on our test set. RESULTS: The DenseNet CNN architecture was found to have the highest accuracy (76%) and recall (76%) in detecting lipohypertrophy in ultrasound images compared to other CNN architectures. Additional work showed that the YOLOv5m object detection model could be used to help detect the approximate location of lipohypertrophy in ultrasound images identified as containing lipohypertrophy by the DenseNet CNN. CONCLUSIONS: We were able to demonstrate the ability of machine learning approaches to automate the process of detecting and locating lipohypertrophy.

The Super-Seniors Study: Phenotypic characterization of a healthy 85+ population.

BACKGROUND: To understand why some people live to advanced age in good health and others do not, it is important to study not only disease, but also long-term good health. The Super-Seniors Study aims to identify factors associated with healthy aging. METHODS: 480 healthy oldest-old 'Super-Seniors' aged 85 to 105 years and never diagnosed with cancer, cardiovascular disease, diabetes, dementia, or major pulmonary disease, were compared to 545 mid-life controls aged 41-54, who represent a group that is unselected for survival from late-life diseases. Health and lifestyle information, personal and family medical history, and blood samples were collected from all participants. Super-Seniors also underwent four geriatric tests. RESULTS: Super-Seniors showed high cognitive (Mini-Mental State Exam mean = 28.3) and functional capacity (Instrumental Activities of Daily Living Scale mean = 21.4), as well as high physical function (Timed Up and Go mean = 12.3 seconds) and low levels of depression (Geriatric Depression Scale mean = 1.5). Super-Seniors were less likely to be current smokers than controls, but the frequency of drinking alcohol was the same in both groups. Super-Seniors were more likely to have 4 or more offspring; controls were more likely to have no children. Female Super-Seniors had a mean age of last fertility 1.9 years older than controls, and were 2.3 times more likely to have had a child at ≥ 40 years. The parents of Super-Seniors had mean ages of deaths of 79.3 years for mothers, and 74.5 years for fathers, each exceeding the life expectancy for their era by a decade. CONCLUSIONS: Super-Seniors are cognitively and physically high functioning individuals who have evaded major age-related chronic diseases into old age, representing the approximately top 1% for healthspan. The familiality of long lifespan of the parents of Super-Seniors supports the hypothesis that heritable factors contribute to this desirable phenotype.

DNA methylation signatures in peripheral blood mononuclear cells from a lifestyle intervention for women at midlife: a pilot randomized controlled trial.

Physical activity confers many health benefits, but the underlying mechanisms require further exploration. In this pilot randomized controlled trial we tested the association between longitudinal measures of DNA methylation and changes in objective measures, including physical activity, weight loss, and C-reactive protein levels in community-dwelling women aged 55 to 70 years. We assessed DNA methylation from 20 healthy postmenopausal women, who did not have a mobility disability and allocated them to a group-based intervention, Everyday Activity Supports You, or a control group (monthly group-based health-related education sessions). The original randomized controlled trial was 6 months in duration and consisted of nine 2-h sessions that focused on reducing sedentary behaviour for the intervention group, or six 1-h sessions that focused on other topics for the control group. We collected peripheral blood mononuclear cells, both at baseline and 6 months later. Samples were processed using the Illumina 450k Methylation array to quantify DNA methylation at >485 000 CpG sites in the genome. There were no significant associations between DNA methylation and physical activity, but we did observe alterations at epigenetic modifications that correlated with change in percent body weight over a 6-month period at 12 genomic loci, 2 of which were located near the previously reported weight-associated genes RUNX3 and NAMPT. We also generated a potential epigenetic predictor of weight loss using baseline DNA methylation at 5 CpG sites. These exploratory findings suggest a potential biological link between body weight changes and epigenetic processes.

Aerobic training in older adults with type 2 diabetes and vasodepressive carotid sinus hypersensitivity.

BACKGROUND AND AIMS: Vasodepressive carotid sinus hypersensitivity (V-CSH) is a common but incurable etiology for fainting in older adults with diabetes (OADM), and is diagnosed by carotid sinus massage (CSM). Aerobic exercise has been shown to be an effective therapy for other neuroautonomic etiologies of syncope (such as orthostatic hypotension), but the effectiveness of aerobic training in V-CSH remains unknown. We examined whether aerobic training could attenuate the vasodepressive response to CSM in OADM (older adults with type 2 diabetes) subjects complicated by V-CSH. METHODS: Forty OADM subjects (mean age 72.2 ± 0.7) complicated by V-CSH were recruited. Subjects were randomized to each of two groups: an aerobic group (AT, n = 20, 3 months vigorous aerobic exercise), and a nonaerobic (NA, n = 20, no aerobic exercise) group. Exercise sessions were supervised by a certified exercise trainer three times per week. The vasodepressive response [defined as the decrease in systolic blood pressure (SBP) during CSM] was measured before and after the training intervention using a Finometer. RESULTS: The intervention had no impact on the number of subjects that met the criteria for V-CSM in either the AT or NA groups, regardless of the criteria used (-10, -20, -30, -40 and -50 mmHg). There was no training effect on the vasodepressive response in either the AT or NA group (P = 0.214, 2-way analysis of variance, -30 mmHg definition for V-CSH). CONCLUSIONS: Aerobic training has no effect on the SBP response to CSM in OADM subjects with V-CSH. Unlike in other neuroautonomic etiologies for fainting, aerobic exercise is not effective as a treatment for V-CSH, at least in the OADM population.

Genetic variation in healthy oldest-old.

Individuals who live to 85 and beyond without developing major age-related diseases may achieve this, in part, by lacking disease susceptibility factors, or by possessing resistance factors that enhance their ability to avoid disease and prolong lifespan. Healthy aging is a complex phenotype likely to be affected by both genetic and environmental factors. We sequenced 24 candidate healthy aging genes in DNA samples from 47 healthy individuals aged eighty-five years or older (the 'oldest-old'), to characterize genetic variation that is present in this exceptional group. These healthy seniors were never diagnosed with cancer, cardiovascular disease, pulmonary disease, diabetes, or Alzheimer disease. We re-sequenced all exons, intron-exon boundaries and selected conserved non-coding sequences of candidate genes involved in aging-related processes, including dietary restriction (PPARG, PPARGC1A, SIRT1, SIRT3, UCP2, UCP3), metabolism (IGF1R, APOB, SCD), autophagy (BECN1, FRAP1), stem cell activation (NOTCH1, DLL1), tumor suppression (TP53, CDKN2A, ING1), DNA methylation (TRDMT1, DNMT3A, DNMT3B) Progeria syndromes (LMNA, ZMPSTE24, KL) and stress response (CRYAB, HSPB2). We detected 935 variants, including 848 single nucleotide polymorphisms (SNPs) and 87 insertion or deletions; 41% (385) were not recorded in dbSNP. This study is the first to present a comprehensive analysis of genetic variation in aging-related candidate genes in healthy oldest-old. These variants and especially our novel polymorphisms are valuable resources to test for genetic association in models of disease susceptibility or resistance. In addition, we propose an innovative tagSNP selection strategy that combines variants identified through gene re-sequencing- and HapMap-derived SNPs.

Arterial baroreflex function in older adults with neurocardiogenic syncope.

PURPOSE: Neurocardiogenic syncope (formerly vasovagal) accounts for large numbers of falls in older adults and the mechanisms are poorly understood. This study examined the differences in baseline arterial baroreflex function in older adults with and without a neruocardiovascular response to orthostatic stress. METHODS: Subjects were divided into two groups based on the presence (TT+ group) or absence (TT- group) of a neurocardiovascular response to upright tilting (70 degree head-up tilt for 10 minutes after 400 micrograms of sublingual nitroglycerin). A neurocardiovascular response was defined as presyncopal symptoms (lightheadedness) in association with at least a 30 mm Hg decrease in blood pressure. Before being divided into groups, baroreflex function was assessed using the spontaneous baroreflex method (baroreflex sensitivity, BRS). This method involves the analysis of "spontaneous" swings in blood pressure and heart rate that are mediated by the arterial baroreflexes. RESULTS: 42 older adults (mean age 70.3+/-0.7 yr) were recruited, of which 18 were in the TT+ and 24 were in the TT- group. At baseline, the TT+ group demonstrated increased arterial baroreflex sensitivity in response to negative blood pressure sequences only (BRSdown, 11.2+/-1.9 vs. 7.3+/-1.0 ms/mm Hg, P=0.011). During tilt, the TT+ group demonstrated a much larger decrease in overall arterial baroreflex sensitivity than the TT- group (-6.8+/-1.2 vs. -3.2+/-0.9 ms/mm Hg, P=0.012). There was a negative correlation between BRSdown and length of tilt table test (r=-0.329, P=0.041) in the TT+ subjects. CONCLUSION: Older adults with neurocardiogenic syncope have exaggerated arterial baroreflex sensitivity at baseline.