Ketosis Suppression and Ageing (KetoSAge): The Effects of Suppressing Ketosis in Long Term Keto-Adapted Non-Athletic Females.

Most studies on ketosis have focused on short-term effects, male athletes, or weight loss. Hereby, we studied the effects of short-term ketosis suppression in healthy women on long-standing ketosis. Ten lean (BMI 20.5 ± 1.4), metabolically healthy, pre-menopausal women (age 32.3 ± 8.9) maintaining nutritional ketosis (NK) for > 1 year (3.9 years ± 2.3) underwent three 21-day phases: nutritional ketosis (NK; P1), suppressed ketosis (SuK; P2), and returned to NK (P3). Adherence to each phase was confirmed with daily capillary D-beta-hydroxybutyrate (BHB) tests (P1 = 1.9 ± 0.7; P2 = 0.1 ± 0.1; and P3 = 1.9 ± 0.6 pmol/L). Ageing biomarkers and anthropometrics were evaluated at the end of each phase. Ketosis suppression significantly increased: insulin, 1.78-fold from 33.60 (± 8.63) to 59.80 (± 14.69) pmol/L (p = 0.0002); IGF1, 1.83-fold from 149.30 (± 32.96) to 273.40 (± 85.66) µg/L (p = 0.0045); glucose, 1.17-fold from 78.6 (± 9.5) to 92.2 (± 10.6) mg/dL (p = 0.0088); respiratory quotient (RQ), 1.09-fold 0.66 (± 0.05) to 0.72 (± 0.06; p = 0.0427); and PAI-1, 13.34 (± 6.85) to 16.69 (± 6.26) ng/mL (p = 0.0428). VEGF, EGF, and monocyte chemotactic protein also significantly increased, indicating a pro-inflammatory shift. Sustained ketosis showed no adverse health effects, and may mitigate hyperinsulinemia without impairing metabolic flexibility in metabolically healthy women.

Sprint interval training (SIT) reduces serum epidermal growth factor (EGF), but not other inflammatory cytokines in trained older men.

PURPOSE: The present study aimed to investigate the effect of age on circulating pro- and anti-inflammatory cytokines and growth factors. A secondary aim was to investigate whether a novel sprint interval training (SIT) intervention (3 × 20 s 'all out' static sprints, twice a week for 8 weeks) would affect inflammatory markers in older men. METHODS: Nine older men [68 (1) years] and eleven younger men [28 (2) years] comprised the younger group. Aerobic fitness and inflammatory markers were taken at baseline for both groups and following the SIT intervention for the older group. RESULTS: Interleukin (IL)-8, vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein-1 (MCP-1) were unchanged for the older and younger groups at baseline (IL-8, p = 0.819; MCP-1, p = 0.248; VEGF, p = 0.264). Epidermal growth factor (EGF) was greater in the older group compared to the younger group at baseline [142 (20) pg mL-1 and 60 (12) pg mL-1, respectively, p = 0.001, Cohen's d = 1.64]. Following SIT, older men decreased EGF to 100 (12) pg mL-1 which was similar to that of young men who did not undergo training (p = 0.113, Cohen's d = 1.07). CONCLUSION: Older aerobically trained men have greater serum EGF than younger aerobically trained men. A novel SIT intervention in older men can shift circulating EGF towards trained younger concentrations. As lower EGF has previously been associated with longevity in C. elegans, the manipulative effect of SIT on EGF in healthy ageing in the human may be of further interest.

Bio-Hacking Better Health-Leveraging Metabolic Biochemistry to Maximise Healthspan.

In the pursuit of longevity and healthspan, we are challenged with first overcoming chronic diseases of ageing: cardiovascular disease, hypertension, cancer, dementias, type 2 diabetes mellitus. These are hyperinsulinaemia diseases presented in different tissue types. Hyperinsulinaemia reduces endogenous antioxidants, via increased consumption and reduced synthesis. Hyperinsulinaemia enforces glucose fuelling, consuming 4 NAD+ to produce 2 acetyl moieties; beta-oxidation, ketolysis and acetoacetate consume 2, 1 and 0, respectively. This decreases sirtuin, PARPs and oxidative management capacity, leaving reactive oxygen species to diffuse to the cytosol, upregulating aerobic glycolysis, NF-kB and cell division signalling. Also, oxidising cardiolipin, reducing oxidative phosphorylation (OXPHOS) and apoptosis ability; driving a tumourigenic phenotype. Over time, increasing senescent/pathological cell populations occurs, increasing morbidity and mortality. Beta-hydroxybutyrate, an antioxidant, metabolite and signalling molecule, increases synthesis of antioxidants via preserving NAD+ availability and enhancing OXPHOS capacity. Fasting and ketogenic diets increase ketogenesis concurrently decreasing insulin secretion and demand; hyperinsulinaemia inhibits ketogenesis. Lifestyles that maintain lower insulin levels decrease antioxidant catabolism, additionally increasing their synthesis, improving oxidative stress management and mitochondrial function and, subsequently, producing healthier cells. This supports tissue and organ health, leading to a better healthspan, the first challenge that must be overcome in the pursuit of youthful longevity.

Thyroid markers and body composition predict LDL-cholesterol change in lean healthy women on a ketogenic diet: experimental support for the lipid energy model.

Introduction: There is a large heterogeneity in LDL-cholesterol change among individuals adopting ketogenic diets. Interestingly, lean metabolically healthy individuals seem to be particularly susceptible, with an inverse association between body mass index and LDL-cholesterol change. The lipid energy model proposes that, in lean healthy individuals, carbohydrate restriction upregulates systemic lipid trafficking to meet energy demands. To test if anthropometric and energy metabolism markers predict LDL-cholesterol change during carbohydrate restriction. Methods: Ten lean, healthy, premenopausal women who habitually consumed a ketogenic diet for ≥6 months were engaged in a three-phase crossover study consisting of continued nutritional ketosis, suppression of ketosis with carbohydrate reintroduction, and return to nutritional ketosis. Each phase lasted 21 days. The predictive performance of all available relevant variables was evaluated with the linear mixed-effects models. Results: All body composition metrics, free T3 and total T4, were significantly associated with LDL-cholesterol change. In an interaction model with BMI and free T3, both markers were significant independent and interacting predictors of LDL-cholesterol change. Neither saturated fat, HOMA-IR, leptin, adiponectin, TSH, nor rT3 was associated with LDL-cholesterol changes. Discussion: Among lean, healthy women undergoing carbohydrate restriction, body composition and energy metabolism markers are major drivers of LDL-cholesterol change, not saturated fat, consistent with the lipid energy model.

The effect of Omega-3 polyunsaturated fatty acid supplementation on exercise-induced muscle damage.

BACKGROUND: Exercise-induced muscle damage (EIMD) results in transient muscle inflammation, strength loss, muscle soreness and may cause subsequent exercise avoidance. Omega-3 (n-3) supplementation may minimise EIMD via its anti-inflammatory properties, however, its efficacy remains unclear. METHODS: Healthy males (n = 14, 25.07 ± 4.05 years) were randomised to 3 g/day n-3 supplementation (N-3, n = 7) or placebo (PLA, n = 7). Following 4 weeks supplementation, a downhill running protocol (60 min, 65% V̇O2max, - 10% gradient) was performed. Creatine kinase (CK), interleukin (IL)-6 and tumour necrosis factor (TNF)-α, perceived muscle soreness, maximal voluntary isometric contraction (MVIC) and peak power were quantified pre, post, and 24, 48 and 72 h post-EIMD. RESULTS: Muscle soreness was significantly lower in N-3 vs PLA group at 24 h post-EIMD (p = 0.034). IL-6 was increased in PLA (p = 0.009) but not in N-3 (p = 0.434) following EIMD, however, no significant differences were noted between groups. Peak power was significantly suppressed in PLA relative to pre-EIMD but not in N-3 group at 24 h post-EIMD. However, no significant difference in peak power output was observed between groups. MVIC, CK and TNF-α were altered by EIMD but did not differ between groups. CONCLUSION: N-3 supplementation for 4 weeks may successfully attenuate minor aspects of EIMD. Whilst not improving performance, these findings may have relevance to soreness-associated exercise avoidance.

Preliminary Investigations Into the Effect of Exercise-Induced Muscle Damage on Systemic Extracellular Vesicle Release in Trained Younger and Older Men.

Background: Exercise-induced muscle damage (EIMD) results in transient muscle inflammation, strength loss, and muscle soreness and may cause subsequent exercise avoidance. Research has recently proven that skeletal muscle can also release extracellular vesicles (EVs) into the circulation following a bout of exercise. However, EV's potential role, including as a biomarker, in the response to eccentric resistance exercise stimulus remains unclear. Methods: Twelve (younger, n=7, 27.0±1.5years and older, n=5, 63.0±1.0years) healthy, physically active males, undertaking moderate, regular physical activity (3-5 times per week) performed a unilateral high intensity eccentric exercise protocol. Venous plasma was collected for assessment of EVs and creatine kinase (CK) prior to EIMD, immediately after EIMD, and 1-72h post-EIMD, and maximal voluntary isometric contraction (MVIC) and delayed onset muscle soreness (DOMS) were assessed at all time points, except 1 and 2h post-EIMD. Results: A significant effect of both time (p=0.005) and group (p<0.001) was noted for MVIC, with younger participants' MVIC being higher throughout. Whilst a significant increase was observed in DOMS in the younger group (p=0.014) and in the older group (p=0.034) following EIMD, no significant differences were observed between groups. CK was not different between age groups but was altered following the EIMD (main effect of time p=0.026), with increased CK seen immediately post-, at 1 and 2h post-EIMD. EV count tended to be lower in older participants at rest, relative to younger participants (p=0.056), whilst EV modal size did not differ between younger and older participants pre-EIMD. EIMD did not substantially alter EV modal size or EV count in younger or older participants; however, the alteration in EV concentration (ΔCount) and EV modal size (ΔMode) between post-EIMD and pre-EIMD negatively associated with CK activity. No significant associations were noted between MVIC or DOMS and either ΔCount or ΔMode of EVs at any time point. Conclusion: These findings suggest that profile of EV release, immediately following exercise, may predict later CK release and play a role in the EIMD response. Exercise-induced EV release profiles may therefore serve as an indicator for subsequent muscle damage.

Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm.

Unlike bolus insulin secretion mechanisms, basal insulin secretion is poorly understood. It is essential to elucidate these mechanisms in non-hyperinsulinaemia healthy persons. This establishes a baseline for investigation into pathologies where these processes are dysregulated, such as in type 2 diabetes (T2DM), cardiovascular disease (CVD), certain cancers and dementias. Chronic hyperinsulinaemia enforces glucose fueling, depleting the NAD+ dependent antioxidant activity that increases mitochondrial reactive oxygen species (mtROS). Consequently, beta-cell mitochondria increase uncoupling protein expression, which decreases the mitochondrial ATP surge generation capacity, impairing bolus mediated insulin exocytosis. Excessive ROS increases the Drp1:Mfn2 ratio, increasing mitochondrial fission, which increases mtROS; endoplasmic reticulum-stress and impaired calcium homeostasis ensues. Healthy individuals in habitual ketosis have significantly lower glucagon and insulin levels than T2DM individuals. As beta-hydroxybutyrate rises, hepatic gluconeogenesis and glycogenolysis supply extra-hepatic glucose needs, and osteocalcin synthesis/release increases. We propose insulin's primary role is regulating beta-hydroxybutyrate synthesis, while the role of bone regulates glucose uptake sensitivity via osteocalcin. Osteocalcin regulates the alpha-cell glucagon secretory profile via glucagon-like peptide-1 and serotonin, and beta-hydroxybutyrate synthesis via regulating basal insulin levels. Establishing metabolic phenotypes aids in resolving basal insulin secretion regulation, enabling elucidation of the pathological changes that occur and progress into chronic diseases associated with ageing.

Relationships between hyperinsulinaemia, magnesium, vitamin D, thrombosis and COVID-19: rationale for clinical management.

Risk factors for COVID-19 patients with poorer outcomes include pre-existing conditions: obesity, type 2 diabetes mellitus, cardiovascular disease (CVD), heart failure, hypertension, low oxygen saturation capacity, cancer, elevated: ferritin, C reactive protein (CRP) and D-dimer. A common denominator, hyperinsulinaemia, provides a plausible mechanism of action, underlying CVD, hypertension and strokes, all conditions typified with thrombi. The underlying science provides a theoretical management algorithm for the frontline practitioners.Vitamin D activation requires magnesium. Hyperinsulinaemia promotes: magnesium depletion via increased renal excretion, reduced intracellular levels, lowers vitamin D status via sequestration into adipocytes and hydroxylation activation inhibition. Hyperinsulinaemia mediates thrombi development via: fibrinolysis inhibition, anticoagulation production dysregulation, increasing reactive oxygen species, decreased antioxidant capacity via nicotinamide adenine dinucleotide depletion, haem oxidation and catabolism, producing carbon monoxide, increasing deep vein thrombosis risk and pulmonary emboli. Increased haem-synthesis demand upregulates carbon dioxide production, decreasing oxygen saturation capacity. Hyperinsulinaemia decreases cholesterol sulfurylation to cholesterol sulfate, as low vitamin D regulation due to magnesium depletion and/or vitamin D sequestration and/or diminished activation capacity decreases sulfotransferase enzyme SULT2B1b activity, consequently decreasing plasma membrane negative charge between red blood cells, platelets and endothelial cells, thus increasing agglutination and thrombosis.Patients with COVID-19 admitted with hyperglycaemia and/or hyperinsulinaemia should be placed on a restricted refined carbohydrate diet, with limited use of intravenous dextrose solutions. Degree/level of restriction is determined by serial testing of blood glucose, insulin and ketones. Supplemental magnesium, vitamin D and zinc should be administered. By implementing refined carbohydrate restriction, three primary risk factors, hyperinsulinaemia, hyperglycaemia and hypertension, that increase inflammation, coagulation and thrombosis risk are rapidly managed.