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Found 2 results

  1. Dean Pomerleau

    New Insights into Muscle Loss

    [Note: This is another post that would fit best on a "Non-CR health science" forum. I'm posting it here on "CR Practice" because it has to do with a concern of people practicing CR.] Excessive muscle loss and wasting (sarcopenia) is a concern as people age, and since CRers weigh less, they also (generally) have less muscle mass to lose as they age, so it is a potential issue for us too. This new study [1], described in this popular press article, provides new understanding of this problem. It describes research identifying a protein (ATF4) that appears to be causally related to muscle wasting. Here is the main points of the research, summarized in the article: The protein, ATF4, is a transcription factor that alters gene expression in skeletal muscle, causing reduction of muscle protein synthesis, strength, and mass. The UI study also identifies two natural compounds, one found in apples and one found in green tomatoes, which reduce ATF4 activity in aged skeletal muscle. The findings, which were published online Sept. 3 in the Journal of Biological Chemistry, could lead to new therapies for age-related muscle weakness and atrophy. Previously, Adams and his team had identified ursolic acid, which is found in apple peel, and tomatidine, which comes from green tomatoes, as small molecules that can prevent acute muscle wasting caused by starvation and inactivity. An example of the previous work by these authors that identified ursolic acid and tomatidine as protective against muscle wasting is this publication [2]. The possible downside of these compounds is that they appear to have their effect by "enhancing skeletal muscle insulin/IGF-I signaling", which CR is known to downregulate, an effect which may very well be important for CR's health/longevity benefits. In the meantime, I'm going to continue exercising, eating apple peels and tomatoes (although usually red rather than green), to hopefully maintain skeletal muscle mass and health. --Dean ------------ [1] J Biol Chem. 2015 Sep 3. pii: jbc.M115.681445. [Epub ahead of print] Identification and Small Molecule Inhibition of an ATF4-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy. Ebert SM(1), Dyle MC(1), Bullard SA(1), Dierdorff JM(1), Murry DJ(1), Fox DK(1), Bongers KS(1), Lira VA(1), Meyerholz DK(1), Talley JJ(2), Adams CM(3). Aging reduces skeletal muscle mass and strength, but the underlying molecular mechanisms remain elusive. Here, we used mouse models to investigate molecular mechanisms of age-related skeletal muscle weakness and atrophy, as well as new potential interventions for these conditions. We identified two small molecules that significantly reduce age-related deficits in skeletal muscle strength, quality and mass: ursolic acid (a pentacyclic triterpenoid found in apples) and tomatidine (a steroidal alkaloid derived from green tomatoes). Because small molecule inhibitors can sometimes provide mechanistic insight into disease processes, we used ursolic acid and tomatidine to investigate the pathogenesis of age-related muscle weakness and atrophy. We found that ursolic acid and tomatidine generate hundreds of small positive and negative changes in mRNA levels in aged skeletal muscle, and the mRNA expression signatures of the two compounds are remarkably similar. Interestingly, a subset of the mRNAs are repressed by ursolic acid and tomatidine in aged muscle are positively regulated by the transcription factor ATF4. Based on this finding, we investigated ATF4 as a potential mediator of age-related muscle weakness and atrophy. We found that a targeted reduction in skeletal muscle ATF4 expression reduces age-related deficits in skeletal muscle strength, quality and mass, similar to ursolic acid and tomatidine. These results elucidate ATF4 as a critical mediator of age-related muscle weakness and atrophy. In addition, these results identify ursolic acid and tomatidine as potential agents and/or lead compounds for reducing ATF4 activity, weakness, and atrophy in aged skeletal muscle. Copyright © 2015, The American Society for Biochemistry and Molecular Biology. PMID: 26338703 ---------------------------- [2] Cell Metab. 2011 Jun 8;13(6):627-38. doi: 10.1016/j.cmet.2011.03.020. mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass. Kunkel SD(1), Suneja M, Ebert SM, Bongers KS, Fox DK, Malmberg SE, Alipour F, Shields RK, Adams CM. Skeletal muscle atrophy is a common and debilitating condition that lacks a pharmacologic therapy. To develop a potential therapy, we identified 63 mRNAs that were regulated by fasting in both human and mouse muscle, and 29 mRNAs that were regulated by both fasting and spinal cord injury in human muscle. We used these two unbiased mRNA expression signatures of muscle atrophy to query the Connectivity Map, which singled out ursolic acid as a compound whose signature was opposite to those of atrophy-inducing stresses. A natural compound enriched in apples, ursolic acid reduced muscle atrophy and stimulated muscle hypertrophy in mice. It did so by enhancing skeletal muscle insulin/IGF-I signaling and inhibiting atrophy-associated skeletal muscle mRNA expression. Importantly, ursolic acid's effects on muscle were accompanied by reductions in adiposity, fasting blood glucose, and plasma cholesterol and triglycerides. These findings identify a potential therapy for muscle atrophy and perhaps other metabolic diseases. PMCID: PMC3120768 PMID: 21641545
  2. All, It looks like an apple a day helps keep the grim reaper away, at least in elderly women according to this new study [1] shared by Al Pater (thanks Al!). Researchers followed 1500 Australian women for 15 years, assessing their intake of various fruits every few years. Over the years their reported intake of apples and other fruits remained quite stable. The authors focused on the four fruits that made up the bulk (75%) of total fruit consumption - apples (20%), pears (11%), citrus fruit (23%), & bananas (21%). They found that women who ate more than 100g of apple per day (for reference, an average medium apple weighs 182g) had a 35% lower risk of all-cause mortality during the follow-up period, even after adjusting for a bunch of potential confounders, including age, BMI, smoking status, socio-economic status, diabetes, CVD, cancer, use of antihypertensive medication, use of cholesterol-lowering medication, use of low-dose aspirin, physical activity, energy intake and alcohol intake. Here are a couple interesting figures from the full text (available from Al). First, a needle plot of morality for the different fruits and causes of death: As you can see, pears and especially citrus weren't all that great for mortality. But apples, bananas and total fruit were all beneficial. Interestingly, bananas were the best of all these fruit for cardiovascular mortality, perhaps because of the important role potassium plays in CVD risk [2]. The one reservation/caveat I can see is that higher apple intake is associated with lots of other markers for an overall healthy diet, as you can see from this figure: Women who ate a lot of apples also ate (not surprisingly) a lot more fiber, flavonoids, total fruit etc. Although the authors didn't report on it, I suspect they also probably ate more vegetables, less trans and saturated fat, etc. So while apples are certainly healthy, they may also be an indicator of an overall healthy diet and lifestyle, and therefore not the (entire) cause of reduced mortality in these women. --Dean -------------- [1] Apple intake is inversely associated with all-cause and disease-specific mortality in elderly women. Hodgson JM, Prince RL, Woodman RJ, Bondonno CP, Ivey KL, Bondonno N, Rimm EB, Ward NC, Croft KD, Lewis JR. Br J Nutr. 2016 Mar;115(5):860-7. doi: 10.1017/S0007114515005231. Epub 2016 Jan 20. Abstract Higher fruit intake is associated with lower risk of all-cause and disease-specific mortality. However, data on individual fruits are limited, and the generalisability of these findings to the elderly remains uncertain. The objective of this study was to examine the association of apple intake with all-cause and disease-specific mortality over 15 years in a cohort of women aged over 70 years. Secondary analyses explored relationships of other fruits with mortality outcomes. Usual fruit intake was assessed in 1456 women using a FFQ. Incidence of all-cause and disease-specific mortality over 15 years was determined through the Western Australian Hospital Morbidity Data system. Cox regression was used to determine the hazard ratios (HR) for mortality. During 15 years of follow-up, 607 (41·7 %) women died from any cause. In the multivariable-adjusted analysis, the HR for all-cause mortality was 0·89 (95 % CI 0·81, 0·97) per sd (53 g/d) increase in apple intake, HR 0·80 (95 % CI 0·65, 0·98) for consumption of 5-100 g/d and HR 0·65 (95 % CI 0·48, 0·89) for consumption of >100 g/d (an apple a day), compared with apple intake of <5 g/d (P for trend=0·03). Our analysis also found that higher apple intake was associated with lower risk for cancer mortality, and that higher total fruit and banana intakes were associated lower risk of CVD mortality (P<0·05). Our results support the view that regular apple consumption may contribute to lower risk of mortality. Key words Apples; Fruits; All-cause mortality; Disease-specific mortality; CVD; Cancer PMID: 26787402 -------------- [2] J Clin Hypertens (Greenwich). 2002 May-Jun;4(3):198-206. Importance of potassium in cardiovascular disease. Sica DA(1), Struthers AD, Cushman WC, Wood M, Banas JS Jr, Epstein M. Author information: (1)Section of Clinical Pharmacology and Hypertension, Division of Nephrology, Medical College of Virginia/Virginia Commonwealth University, Richmond, VA 23298, USA. dsica@hsc.vcu.edu The pivotal role of potassium (K+) in cardiovascular disease and the importance of preserving potassium balance have become clinical hot points, particularly as relates to new and emerging cardioprotective and renoprotective therapies that promote potassium retention. Although clinicians may be aware of the critical nature of this relationship, quite frequently there is some uncertainty as to the best way to monitor potassium levels in the face of a host of pathologic states and/or accompanying drug therapies that affect serum levels and/or total body potassium balance. Moreover, guidelines for monitoring of serum potassium levels are at best tentative and oftentimes are translated according to the level of concern of the respective physician. To address these uncertainties, an expert group was convened that included representatives from multiple disciplines. They attempted to reach consensus on the importance of K+ in hypertension, stroke, and arrhythmias as well as practical issues on maintaining K+ balance and avoiding K+ depletion. Because of the complexity of this topic, issues of hyperkalemia will be addressed in a forthcoming manuscript. Copyright 2002 Le Jacq Communications, Inc. PMID: 12045369
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