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Healthy aging can be promoted by enhanced metabolic fitness and physical capacity. Mitochondria are chief metabolic organelles with strong implications in aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome. However, mitochondrial-encoded factors that actively regulate aging are unknown. Here, we report that mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 mo.), middle-age (12 mo.), and old (22 mo.) mice. MOTS-c can regulate (i) nuclear genes, including those related to metabolism and proteostasis, (ii) skeletal muscle metabolism, and (iii) myoblast adaptation to metabolic stress. We provide evidence that late-life (23.5 mo.) initiated intermittent MOTS-c treatment (3x/week) can increase physical capacity and healthspan in mice. In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation. Our data indicate that aging is regulated by genes encoded in both of our co-evolved mitochondrial and nuclear genomes.

Aims: To test if a New Zealand food–based Mediterranean diet (NZMedDiet) with behavioural intervention improves cardiometabolic health and wellbeing. Methods: A randomised controlled trial comparing 12 weeks of the NZMedDiet to usual diet in participants with increased cardiometabolic risk (metabolic syndrome severity score [MetSSS] > 0.35). The intervention group was provided with food and recipes to meet 75% of their energy requirements, supported by a behavioural intervention to improve adherence. The primary outcome measure was (MetSSS) after 12 weeks. Results: Two hundred individuals with mean (SD) age 49.9 (10.9) years of which 62% women were enrolled with their household/whānau. After 12 weeks, the mean (SD) MetSSS was 1.0 (0.7) in the control (n = 98) and 0.8 (0.5) in the intervention (n = 102) group; estimated difference (95% confidence interval [CI]) of −0.05 (−0.16 to 0.06), p = 0.35. The Mediterranean diet score (PyrMDS) was greater in the intervention group 1.6 (1.1–2.1), p < 0.001, consistent with a change to a more Mediterranean dietary pattern. Weight reduced in the NZMedDiet group compared with control (−1.9 kg [−2.0 to −0.34]), p = 0.006 and wellbeing, assessed by the SF‐36 quality of life questionnaire, and improved across all domains. For example, the physical component summary score difference (95% CI) was 4.0 (2.4–5.7), p < 0.001, and the mental component summary score difference was 3.0 (0.7–5.2), p = 0.01. Conclusion: In participants with increased cardiometabolic risk, food provision with a Mediterranean dietary pattern and a behavioural intervention did not improve metabolic risk scores but was associated with reduced weight and improved quality of life. [ABSTRACT FROM AUTHOR]

Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL)-like particle in which the apolipoprotein B component is covalently linked to apolipoprotein(a) (apo(a)). Lp(a) is a well-established independent risk factor for cardiovascular diseases. Plasma Lp(a) concentrations vary enormously between individuals and ethnic groups. Several nucleotide polymorphisms in the SLC22A3 gene associate with Lp(a) concentration in people of different ethnicities. We investigated the association of a Polynesian-specific (M¯ aori and Pacific peoples) SLC22A3 gene coding variant p.Thr44Met) with the plasma concentration of Lp(a) in a cohort of 302 healthy Polynesian males. An apo(a)-size independent assay assessed plasma Lp(a) concentrations; all other lipid and apolipoprotein concentrations were measured using standard laboratory techniques. Quantitative real-time polymerase chain reaction was used to determine apo(a) isoforms. The range of metabolic (HbA1c, blood pressure, and blood lipids) and blood lipid variables were similar between the non-carriers and carriers in age, ethnicity and BMI adjusted models. However, rs8187715 SLC22A3 variant was significantly associated with lower Lp(a) concentrations. Median Lp(a) concentration was 10.60 nmol/L (IQR: 5.40--41.00) in non-carrier group, and was 7.60 nmol/L (IQR: 5.50--12.10) in variant carrier group (P<0.05). Lp(a) concentration inversely correlated with apo(a) isoform size. After correction for apo(a) isoform size, metabolic parameters and ethnicity, the association between the SLC22A3 variant and plasma Lp(a) concentration remained. The present study is the first to identify the association of this gene variant and low plasma Lp(a) concentrations. This provides evidence for better guidance on ethnic specific cut-offs when defining 'elevated' and 'normal' plasma Lp(a) concentrations in clinical applications. [ABSTRACT FROM AUTHOR]

Pancreatitis is increasingly recognized as not merely a local inflammation of the pancreas but also a disease with high frequency of systemic sequelae. Current understanding of the cellular mechanisms that trigger it and affect the development of sequelae are limited. Genetically engineered mouse models can be a useful tool to study the pathophysiology of pancreatitis. This article gives an overview of the genetically engineered mouse models that spontaneously develop pancreatitis and discusses those that most closely replicate different pancreatitis hallmarks observed in humans.

3,6,7-trimethyllumazine (Lepteridine™) is a newly discovered natural pteridine derivative unique to Mānuka (Leptospermum scoparium) nectar and honey, with no previously reported biological activity. Pteridine derivative-based medicines, such as methotrexate, are used to treat auto-immune and inflammatory diseases, and Mānuka honey reportedly possesses anti-inflammatory properties and is used topically as a wound dressing. MMP-9 is a potential candidate protein target as it is upregulated in recalcitrant wounds and intestinal inflammation. Using gelatin zymography, 40 μg/mL LepteridineTM inhibited the gelatinase activities of both pro- (22%, p < 0.0001) and activated (59%, p < 0.01) MMP-9 forms. By comparison, LepteridineTM exerted modest (~10%) inhibition against a chromogenic peptide substrate and no effect against a fluorogenic peptide substrate. These findings suggest that LepteridineTM may not interact within the catalytic domain of MMP-9 and exerts a negligible effect on the active site hydrolysis of small soluble peptide substrates. Instead, the findings implicate fibronectin II domain interactions by LepteridineTM which impair gelatinase activity, possibly through perturbed tethering of MMP-9 to the gelatin matrix. Molecular modelling analyses were equivocal over interactions at the S1′ pocket versus the fibronectin II domain, while molecular dynamic calculations indicated rapid exchange kinetics. No significant degradation of synthetic or natural LepteridineTM in Mānuka honey occurred during simulated gastrointestinal digestion. MMP-9 regulates skin and gastrointestinal inflammatory responses and extracellular matrix remodelling. These results potentially implicate LepteridineTM bioactivity in Mānuka honey's reported beneficial effects on wound healing via topical application and anti-inflammatory actions in gastrointestinal disorder models via oral consumption. [ABSTRACT FROM AUTHOR]

There is evidence that nitric oxide (NO) is required for the normal increases in skeletal muscle glucose uptake during contraction, but the mechanisms involved have not been elucidated. We examined whether NO regulates glucose uptake during skeletal muscle contractions via cGMP-dependent or cGMP-independent pathways. Isolated extensor digitorum longus (EDL) muscles from mice were stimulated to contract ex vivo, and potential NO signaling pathways were blocked by the addition of inhibitors to the incubation medium. Contraction increased (P < 0.05) NO synthase (NOS) activity (40%) and dichlorofluorescein (DCF) fluorescence (a marker of oxidant levels; 95%), which was prevented with a NOS inhibitor [N.sup.G]-monomethyl-L-arginine (L-NMMA), and antioxidants [nonspecific antioxidant, N-acetylcysteine (NAC); thiol-reducing agent, DTT], respectively. L-NMMA and NAC both attenuated glucose uptake during contraction by 50% (P < 0.05), and their effects were not additive. Neither the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-l-one, which prevents the formation of cGMP, the cGMP-dependent protein (PKG) inhibitor Rp-8-bromo-[beta]-phenyl-l,N2ethenoguanosine 3',5'-cyclic monophosphorothioate sodium salt nor white light, which breaks S-nitrosylated bonds, affects glucose uptake during contraction; however, DTT attenuated (P < 0.05) contraction-stimulated glucose uptake (by 70%). NOS inhibition and antioxidant treatment reduced contraction-stimulated increases in protein S-glutathionylation and tyrosine nitration (P < 0.05), without affecting AMPK or p38 MAPK phosphorylation. In conclusion, we provide evidence to suggest that NOS-derived oxidants regulate skeletal muscle glucose uptake during ex vivo contractions via a cGMP/PKG-, AMPK-, and p38 MAPK-independent pathway. In addition, it appears that NO and ROS may regulate skeletal muscle glucose uptake during contraction through a similar pathway. reactive oxygen species; peroxynitrite; S-glutathionylation; AMP-activated protein kinase doi: 10.1152/ajpregu.00433.2010

Reactive oxygen species (ROS) and nitric oxide (NO) have been implicated in the regulation of skeletal muscle glucose uptake during contraction, and there is evidence that they do so via interaction with AMP-activated protein kinase (AMPK). In this study, we tested the hypothesis that ROS and NO regulate skeletal muscle glucose uptake during contraction via an AMPK-independent mechanism. Isolated extensor digitorum longus (EDL) and soleus muscles from mice that expressed a muscle-specific kinase dead AMPK[alpha]2 isoform (AMPK-KD) and wild-type litter mates (WT) were stimulated to contract, and glucose uptake was measured in the presence or absence of the antioxidant N-acetyl-L-cysteine (NAC) or the nitric oxide synthase (NOS) inhibitor [N.sup.G]-monomethyl-L-arginine (L-NMMA). Contraction increased AMPK[alpha]2 activity in WT but not AMPK-KD EDL muscles. However, contraction increased glucose uptake in the EDL and soleus muscles of AMPK-KD and WT mice to a similar extent. In EDL muscles, NAC and L-NMMA prevented contraction-stimulated increases in oxidant levels (dichloroflourescein fluorescence) and NOS activity, respectively, and attenuated contraction-stimulated glucose uptake in both genotypes to a similar extent. In soleus muscles of AMPK-KD and WT mice, NAC prevented contraction-stimulated glucose uptake and L-NMMA had no effect. This is likely attributed to the relative lack of neuronal NOS in the soleus muscles compared with EDL muscles. Contraction increased AMPK[alpha] [Thr.sup.172] phosphorylation in EDL and soleus muscles of WT but not AMPK-KD mice, and this was not affected by NAC or L-NMMA treatment. In conclusion, ROS and NO are involved in regulating skeletal muscle glucose uptake during contraction via an AMPK-independent mechanism. nitric oxide; reactive oxygen species; exercise; metabolism; contraction; glucose uptake doi:10.1152/ajpendo.00239.2009.