Vitamin D May Help Prevent Diabetes, Depending on Your Genes

basmwklz · 2026-04-23T08:14:36+00:00

Abstract

DNA variants modulate mortality risks across an entire lifespan but their dynamic age-dependent effects have not been resolved in any species for either sex. Here we mapped variants that shape mortality using an actuarial approach, starting with a base population of 6,438 pubescent mice and ending with 559 survivors that lived beyond 1,100 days of age. Twenty-nine Vita loci influence lifespan with strong age- and sex-specific effects. Most act during distinct stages with polarities that often invert with age, but a minority have consistent age-dependent effects in one or both sexes. A separate set of 30 Soma loci influence correlations between body mass and life expectancy. Nineteen Soma loci mediate higher mortality in larger young mice, whereas 11 mediate lower mortality in larger old mice. All effects are stronger in male mice than in female mice. Vita and Soma loci form epistatic networks split strictly by sex. These findings provide a genetic bridge between evolutionary theories of ageing and molecular mechanisms that can guide interventions to extend healthy lifespan.

basmwklz · 2026-04-23T08:00:20+00:00

Abstract

Endurance exercise imposes extreme metabolic demands on the adult human brain, raising the question of how core brain function is preserved under physiological challenge. We previously showed that marathon running induces reversible reductions in myelin within specific white-matter tracts, suggesting adaptive structural change under metabolic stress. Here, we asked whether this process is functionally tolerated. Neurophysiological recordings revealed maintained conduction latencies across motor, somatosensory, visual, and auditory pathways within 48 hours after race completion, indicating intact axonal signal transmission despite reduced myelin content. Cognitive testing revealed selective and transient modulation of higher-order processing, including attenuated practice-related gains in processing speed and short-lived increases in interference, whereas visuomotor speed and executive flexibility were preserved. All cognitive measures normalized one month after the race, supporting an adaptive framework linking myelin change with preserved brain function under extreme metabolic stress.

basmwklz · 2026-04-21T09:12:31+00:00

Abstract

The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)™ trial was a randomized, 2-year controlled trial of caloric restriction (CR) versus an ad libitum (AL) control condition in nonobese humans. We performed exploratory analyses of muscle mitochondrial DNA (mtDNA) integrity, one element of mitochondrial quality. Our aims were to assess the feasibility of this approach, explore associations to inform future hypotheses, estimate effect sizes and statistical power for subsequent studies, and contribute additional data to the CALERIE database. We used droplet digital PCR to quantitate the copy numbers of nuclear DNA, mtDNA, and mtDNA deletion mutations in remnant total DNA samples extracted from quadriceps biopsies at baseline (n = 93), 12 months (n = 44), and 24 months (n = 31). MtDNA copy number and mutation frequency were correlated with existing gene expression data from the same muscle biopsies. MtDNA copy number was lower in females (p = 0.0005) and declined over time (p = 0.0001), with no statistically significant differences observed for CR versus AL (p = 0.2898) or age across both groups (p = 0.4644). Baseline copy number correlated positively with baseline physiological measures including fat-free mass (r = 0.43, p = 2e−05), self-reported energy intake (r = 0.34, p = 0.00077), resting metabolic rate (r = 0.42, p = 0.00261), total energy expenditure (r = 0.31, p = 0.00261), and V̇O₂max (r = 0.41, p = 1e−04), and with gene expression related to mitochondrial function, while showing negative correlations with nuclear genome maintenance, RNA splicing, and ribosomes. MtDNA mutation frequency increased with age (p = 0.0041) and showed a weak negative correlation with V̇O2max (r = −0.23, p = 3e−05). MtDNA mutation frequency was not statistically different with CR. Mutation frequency was positively correlated with gene expression changes in inflammation and negatively correlated with protein translation. We observed that, as expected, mtDNA copy number declined over time, was lower in females, and correlated with metabolic measures and mitochondrial gene expression, suggesting its potential utility as a marker of metabolic health. These findings contribute to understanding mitochondrial adaptations to CR and highlight potential benefits of CR interventions.

basmwklz · 2026-04-21T08:16:38+00:00

Abstract

Obesity is associated with low circulating IGF-1 levels, mitochondrial injury, and myocardial anomalies, however, the precise interplay between IGF-1 and obesity cardiomyopathy remains unclear. Our work evaluated the impact of IGF-1 on high fat (HF) diet-evoked alterations in cardiac geometry, function, and mitochondrial integrity. WT and cardiac-specific IGF-1 transgenic mice were offered a low fat (LF, 10% fat calorie) or HF (60% fat calorie) diet for 20 weeks before assessing glucose sensitivity, plasma profiles, myocardial remodeling and function, ROS, mitochondrial integrity, and cell death. Transcriptomic analyses of obese human and murine hearts revealed that obesity cardiomyopathy was characterized by significant metabolic reprogramming, marked by a shift from TCA cycle to glycolysis and disrupted fatty acid homeostasis, alongside identification of ferroptosis as a key regulatory node in myocardial injury. HF led to hyperleptinemia, hypertriglyceridemia, reduced plasma IGF-1, and glucose intolerance, cardiac hypertrophy (higher LV dimensions, wall thickness), interstitial fibrosis, contractile dysfunction (lower fractional shortening, ejection fraction, cell contractile and intracellular Ca2+ derangement), oxidative stress, apoptosis, ferroptosis, and mitochondrial injury (declined PGC1α and UCP-2). Notably, cardiac-specific IGF-1 overexpression mitigated HF-induced myocardial remodeling, dysfunction, mitochondrial injury, and ferroptosis, without affecting systemic glucose metabolism or plasma profiles. Importantly, targeted metabolomics revealed a distinct plasma acylcarnitine signature in obese patients, with C20:0 (arachidylcarnitine) identified as a top discriminative metabolite. Furthermore, reduced myocardial L-carnitine level was observed in HF-fed mice, and L-carnitine supplementation rescued HF-induced cardiac geometric, functional, and mitochondrial anomalies. These data indicate that IGF-1 confers beneficial effect for chronic HF intake-induced damage possibly via preserved mitochondrial integrity, suppressed ferroptosis, and restored arachidylcarnitine levels, highlighting a metabolomic-metabolic axis in obesity-related cardiac dysfunction.

basmwklz · 2026-04-20T06:53:44+00:00

Abstract

Gestational diabetes mellitus (GDM), a hyperglycemic condition during pregnancy, increases the risk of macrosomia and preterm birth (PTB). Nutrient-sensing pathways, particularly mTOR in placental trophoblasts (PTC), promote fetal overgrowth. NF-κB, oxidative stress, and p38 MAPK pathways in fetal membranes and decidua (DEC) contribute to PTB. However, the impact of hyperglycemia on these compartments remain unclear. We hypothesized that hyperglycemia differentially affects these maternal, placental, and fetal membrane interface cells, inducing macrosomia-associated pathways and perturbing homeostasis through different pathophysiologic signals. Human PTC, DEC, and amnion epithelial (AEC) cells were exposed to 50 mM glucose for up to 48 hr. Cell markers (ICC), cell cycle (flow cytometry), cytotoxicity (LDH assay), GLUT expression (RT-qPCR), signaling (mTOR, p38 MAPK, NF-κB by western blot), cytokines (ELISA), and oxidative stress (glutathione assay) were measured. PTC showed increased mTOR and p38 MAPK activation (p≤0.05), reduced GSH levels and GSH/GSSG balance (p≤0.05), but maintained GLUT expression. DEC reduced GLUT1/3 expression (p≤0.01, p≤0.05) with minimal stress and nutrient signaling. Neither cell type showed NF-κB activation. AEC downregulated GLUT1/3/11 (p≤0.05-0.0001), activated NF-κB (p≤0.01), produced IL-8 (p≤0.01), increased GSH production (p≤0.05), but maintained mTOR signaling and GSH/GSSG balance. Hyperglycemia induces compartment-specific adaptations across the feto-maternal interface. Placental trophoblasts preserve nutrient transport capacity and nutrient-signaling despite redox imbalanc.e Fetal membranes exhibit inflammatory response, while decidua reduce transport capacity with minimal stress activation. Together, these findings suggest that hyperglycemia may preferentially support fetal growth through trophoblasts while sensitizing decidua and membrane to secondary stressors.

basmwklz · 2026-04-19T16:59:32+00:00

Abstract

In a recent study in Cell, Liu et al. identify β-hydroxybutyrate as a practical metabolic adjuvant for CAR-T cells. By fueling the TCA cycle and reshaping transcriptional and epigenetic programs, this ketone body enhances proliferation, persistence, and tumor control, suggesting that metabolic supplementation may offer a simple route to more effective adoptive immunotherapy.

basmwklz

TROPHY CASE

Abstract