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Metabolic dysfunctions are among the best documented hallmarks of ageing. Cardiovascular disease, Alzheimer's disease, cancer, type 2 diabetes mellitus, metabolic-dysfunction-associated steatosis liver disease, and fragility fractures are diseases of hyperinsulinaemia that reduce life and healthspan. We studied the effect of suppressing ketosis in 10 lean (BMI 20.5 kg/m2 ± 1.4), metabolically healthy, pre-menopausal women (age 32.3 ± 8.9 years) maintaining nutritional ketosis (NK) for an average of 3.9 years (± 2.3) who underwent three 21-day phases: nutritional ketosis (NK; P1), suppressed ketosis (SuK; P2), and returned to NK (P3). Ketosis suppression significantly increased insulin, 1.83-fold (p = 0.0006); glucose, 1.17-fold (p = 0.0088); homeostasis model assessment for insulin resistance (HOMA-IR), 2.13-fold (p = 0.0008); leptin, 3.35-fold (p = 0.0010); total osteocalcin, 1.63-fold (p = 0.0138); and uncarboxylated osteocalcin, 1.98-fold (p = 0.0417) and significantly decreased beta-hydroxybutyrate, 13.50-fold (p = 0.0012) and glucagon-like peptide-1 (GLP-1), 2.40-fold (p = 0.0209). Sustained NK showed no adverse health effects and may mitigate hyperinsulinemia. All biomarkers returned to basal P1 levels after removing the intervention for SuK, indicating that metabolic flexibility was maintained with long-term euketonaemia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Context: Research has shown the modulations of Follistatin (FST) and Myostatin (MST) following weight loss. Objective: We evaluated the effects of gradual weight loss (GWL) and rapid weight loss (RWL) on serum MST, FST, and body composition in overweight and obese females. Materials and methods: Thirty-six overweight and obese females successfully completed the study interventions: GWL (n = 18) or RWL (n = 18). Serum MST and FST concentrations, as well as anthropometric measurements, were collected at baseline and at the conclusion of each weight loss intervention. Results: MST concentration significantly (p <.05) decreased in the GWL; while FST concentration, body fat percentage and skeletal muscle mass significantly declined in both conditions. The loss in skeletal muscle mass was significantly greater in RWL relative to GWL. Discussion and conclusion: GWL was more effective than RWL in preserving skeletal muscle mass in overweight and obese females. Moreover, GWL leads to declines in MST concentrations. [ABSTRACT FROM AUTHOR]

In vitro models provide an important platform for the investigation of cellular growth and atrophy to inform, or extend mechanistic insights from, logistically challenging in vivo trials. Although these models allow for the identification of candidate mechanistic pathways, many models involve supraphysiological dosages, nonphysiological conditions, or experimental changes relating to individual proteins or receptors, all of which limit translation to human trials. To overcome these drawbacks, the use of ex vivo human plasma and serum has been used in cellular models to investigate changes in myotube hypertrophy, cellular protein synthesis, anabolic and catabolic markers in response to differing age, disease states, and nutrient status. However, there are currently no concurrent guidelines outlining the optimal methodology for this model. This review discusses the key methodological considerations surrounding the use of ex vivo plasma and serum with a focus in application to skeletal muscle cell lines (i.e., C2C12, L6, and LHCN-M2) and human primary skeletal muscle cells (HSMCs) as a means to investigate molecular signaling in models of atrophy and hypertrophy, alongside future directions. [ABSTRACT FROM AUTHOR]

Due to the important roles of resistance training and protein consumption in the prevention and treatment of sarcopenia, we assessed the efficacy of post-exercise Icelandic yogurt consumption on lean mass, strength and skeletal muscle regulatory factors in healthy untrained older males. Thirty healthy untrained older males (age = 68 ± 4 years) were randomly assigned to Icelandic yogurt (IR; n 15, 18 g of protein) or an iso-energetic placebo (PR; n 15, 0 g protein) immediately following resistance training (3×/week) for 8 weeks. Before and after training, lean mass, strength and skeletal muscle regulatory factors (insulin-like growth factor-1 (IGF-1), transforming growth factor-beta 1 (TGF-β1), growth differentiation factor 15 (GDF15), Activin A, myostatin (MST) and follistatin (FST)) were assessed. There were group × time interactions (P < 0·05) for body mass (IR: Δ 1, PR: Δ 0·7 kg), BMI (IR: Δ 0·3, PR: Δ 0·2 kg/m2), lean mass (IR: Δ 1·3, PR: Δ 0·6 kg), bench press (IR: Δ 4, PR: 2·3 kg), leg press (IR: Δ 4·2, PR: Δ 2·5 kg), IGF-1 (IR: Δ 0·5, Δ PR: 0·1 ng/ml), TGF-β (IR: Δ − 0·2, PR: Δ − 0·1 ng/ml), GDF15 (IR: Δ − 10·3, PR: Δ − 4·8 pg/ml), Activin A (IR: Δ − 9·8, PR: Δ − 2·9 pg/ml), MST (IR: Δ − 0·1, PR: Δ − 0·04 ng/ml) and FST (IR: Δ 0·09, PR: Δ 0·03 ng/ml), with Icelandic yogurt consumption resulting in greater changes compared with placebo. The addition of Icelandic yogurt consumption to a resistance training programme improved lean mass, strength and altered skeletal muscle regulatory factors in healthy untrained older males compared with placebo. Therefore, Icelandic yogurt as a nutrient-dense source and cost-effective supplement enhances muscular gains mediated by resistance training and consequently may be used as a strategy for the prevention of sarcopenia. [ABSTRACT FROM AUTHOR]

Ultra-endurance athletes accumulate an energy deficit throughout their events and those competing in self-sufficient multi-stage races are particularly vulnerable due to load carriage considerations. Whilst urinary ketones have previously been noted in ultra-endurance exercise and attributed to insufficient carbohydrate (CHO) availability, not all studies have reported concomitant CHO intake. Our aim was to determine changes in blood glucose and β-hydroxybutyrate concentrations over five days (240 km) of a self-sufficient multi-stage ultramarathon in combination with quantification of energy and macronutrient intakes, estimated energy expenditure and evaluation of energy balance. Thirteen runners (8 male, 5 female, mean age 40 ± 8 years) participated in the study. Glucose and β-hydroxybutyrate were measured every day immediately post-running, and food diaries completed daily. CHO intakes of 301 ± 106 g·day−1 (4.3 ± 1.8 g·kg−1·day−1) were not sufficient to avoid ketosis (5-day mean β-hydroxybutyrate: 1.1 ± 0.6 mmol.L−1). Furthermore, ketosis was not attenuated even when CHO intake was high (9 g·kg−1·day−1). This suggests that competing in a state of ketosis may be inevitable during multi-stage events where load reduction is prioritised over energy provisions. Attenuating negative impacts associated with such a metabolic shift in athletes unaccustomed to CHO and energy restriction requires further exploration. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is a metabolic disease categorized primarily by reduced insulin sensitivity, β-cell dysfunction, and elevated hepatic glucose production. Treatments reducing hyperglycemia and the secondary complications that result from these dysfunctions are being sought after. Two distinct pathways encourage glucose transport activity in skeletal muscle, ie, the contraction-stimulated pathway reliant on Ca2+/5'-monophosphate-activated protein kinase (AMPK)-dependent mechanisms and an insulin-dependent pathway activated via upregulation of serine/threonine protein kinase Akt/PKB. Metformin is an established treatment for type 2 diabetes due to its ability to increase peripheral glucose uptake while reducing hepatic glucose production in an AMPK-dependent manner. Peripheral insulin action is reduced in type 2 diabetics whereas AMPK signaling remains largely intact. This paper firstly reviews AMPK and its role in glucose uptake and then focuses on a novel mechanism known to operate via an insulin-dependent pathway. Inositol hexakisphosphate (IP6) kinase 1 (IP6K1) produces a pyrophosphate group at the position of IP6 to generate a further inositol pyrophosphate, ie, diphosphoinositol pentakisphosphate (IP7). IP7 binds with Akt/PKB at its pleckstrin homology domain, preventing interaction with phosphatidylinositol 3,4,5-trisphosphate, and therefore reducing Akt/PKB membrane translocation and insulin-stimulated glucose uptake. Novel evidence suggesting a reduction in IP7 production via IP6K1 inhibition represents an exciting therapeutic avenue in the treatment of insulin resistance. Metformin-induced activation of AMPK is a key current intervention in the management of type 2 diabetes. However, this treatment does not seem to improve peripheral insulin resistance. In light of this evidence, we suggest that inhibition of IP6K1 may increase insulin sensitivity and provide a novel research direction in the treatment of insulin resistance. [ABSTRACT FROM AUTHOR]