Sarcopenia Especially Loss of Strength Indicates Age Related Mortality

Strength as a product of muscle mass, neuromuscular control and energetics is a better predictor of impending mortality.

Age related sarcopenia is a result of decreased regeneration of muscle mass but also relates to the brain body network disconnection syndrome and the decreased strength and endurance.

BDNF increases muscle endurance and network connectivity.

Exercise and fasting increase BDNF.

Ursolic acid increases strength and is an exercise and fasting mimetic.  Ursolic acid likely increases BDNF.

Exercise, fasting and Ursolic acid is likely synergistic in increasing strength, reducing dementia (brain network disconnection syndrome)  and reducing mortality.

https://biomedgerontology.oxfordjournals.org/content/61/1/72.full

Strength, But Not Muscle Mass, Is Associated With Mortality in the Health, Aging and Body Composition Study Cohort

1. Anne B. Newman ¹ , 
2. Varant Kupelian ² , 
3. Marjolein Visser ³ , 
4. Eleanor M. Simonsick ⁴ , 
5. Bret H. Goodpaster ⁵ , 
6. Stephen B. Kritchevsky ⁶ , 
7. Frances A. Tylavsky ⁷ , 
8. Susan M. Rubin ⁸ , 
9. Tamara B. Harris ⁴ and 
10. on Behalf of the Health, Aging and Body Composition Study Investigators

+ Author Affiliations

1. Address correspondence to Anne B. Newman, MD, MPH, University of Pittsburgh, Department of Epidemiology, 130 N. Bellefield Avenue, Room 532, Pittsburgh, PA 15213. E-mail: newmana@edc.pitt.edu

• Received January 28, 2005.
• Accepted July 30, 2005.

Abstract

Background. Although muscle strength and mass are highly correlated, the relationship between direct measures of low muscle mass (sarcopenia) and strength in association with mortality has not been examined.

Methods. Total mortality rates were examined in the Health, Aging and Body Composition (Health ABC) Study in 2292 participants (aged 70–79 years, 51.6% women, and 38.8% black). Knee extension strength was measured with isokinetic dynamometry, grip strength with isometric dynamometry. Thigh muscle area was measured by computed tomography (CT) scan, and leg and arm lean soft tissue mass were determined by dual energy x-ray absorptiometry (DXA). Both strength and muscle size were assessed as in gender-specific Cox proportional hazards models, with age, race, comorbidities, smoking status, level of physical activity, fat area by CT or fat mass by DXA, height, and markers of inflammation, including interleukin-6, C-reactive protein, and tumor necrosis factor-α considered as potential confounders.

Results. There were 286 deaths over an average of 4.9 (standard deviation = 0.9) years of follow-up. Both quadriceps and grip strength were strongly related to mortality. For quadriceps strength (per standard deviation of 38 Nm), the crude hazard ratio for men was 1.51 (95% confidence interval, 1.28–1.79) and 1.65 (95% confidence interval, 1.19–2.30) for women. Muscle size, determined by either CT area or DXA regional lean mass, was not strongly related to mortality. In the models of quadriceps strength and mortality, adjustment for muscle area or regional lean mass only slightly attenuated the associations. Further adjustment for other factors also had minimal effect on the association of quadriceps strength with mortality. Associations of grip strength with mortality were similar.

Conclusion. Low muscle mass did not explain the strong association of strength with mortality, demonstrating that muscle strength as a marker of muscle quality is more important than quantity in estimating mortality risk. Grip strength provided risk estimates similar to those of quadriceps strength.

OLDER adults with reduced muscle strength have higher mortality (1–6). Muscle strength is closely related to the absolute quantity of muscle mass, which is also reduced with aging (7–10). This decrease in muscle mass (sarcopenia) is thought to contribute to the development of functional limitations and disability in old age (11,12), and potentially might explain part of the association between strength and mortality. Previous studies (1–4) have used only weight, creatinine excretion, or derived anthropometric measures to estimate muscle mass. Thus the role of muscle mass in mediating the strength–mortality association has not been adequately determined.

Strength might also predict mortality because it is reduced with disease and deconditioning. For example, lower extremity arterial ischemia can cause lower muscle strength and function (13). Pain from osteoarthritis may prevent activity resulting in atrophy from disuse. Intervention studies show the potential for large improvements in strength with small increases in lean mass (14), illustrating the importance of activity and exercise. Markers of inflammation are also related to lower strength (15) and lean mass, as well as to a decline in strength (16). However, in the Women's Health and Aging Study, comorbidity and inflammatory markers did not explain the association of lower grip strength with mortality (3).

The Health, Aging and Body Composition (Health ABC) Study was designed to determine the role of body composition changes in the risk of poor health outcomes including death and functional limitation in older adults. In this report, we sought to determine whether low muscle mass, measured with computed tomography (CT) scanning and dual energy x-ray absorptiometry (DXA), would explain an association of strength with mortality with and without adjusting for hypothesized causes of sarcopenia, including physical activity, disease, and inflammatory markers. Finally, we were able to compare associations on the basis of isokinetic quadriceps strength versus isometric grip strength

Grow Lean Mass, Burn Fat Mass- A Signaling Cycle!

This study below is pregnant with a small difference that makes a great difference.  Calorie restricted animals before  bariatric surgery post surgery gained lean body mass and loss identical fat mass to their controls therefore intermittent calorie restriction likely "programmed" lean muscle growth and regeneration while increasing fat burning!

Two possibilities are 1. positive lean body mass growth factors produced from the stress or 2. Reduced myostatin an antagonist for increasing lean body mass.  I favor the latter of down regulated myostatin which shifts anabolism of protein intake to muscle building while shifting energy needs to triglycerides.  One could confirm this by measuring the respiratory quotient with a calorimeter.  The calorie restricted group would have a lower respiratory quotient closer to 0.7 for complete triglyceride oxidation meaning the protein and branched amino acids were directed at anabolism rather than diverted to carbohydrate metabolism.

Exercise, supplements or medications that mimic this exercise and calorie restriction effect would give a bariatric surgery effect for calorie restriction alone if the bariatric signal could be raised!  

What about the Roux in y causes this lean anabolic effect?  Is it basically enforced calorie restriction without lean body mass growth above the baseline?

Would anti myostatin medications have a lean anabolic effect and triglyceride catabolic effect when combined with intermittent calorie restriction?  Candidates are the following:

Creatine mono phosphate? 

Ursolic acid?  

Resistance exercise?  

Anti myostatin antibody? 

Combined with daily 16-20 hour fast and ad lib Mediterranean diet to grow lean body mass for 4 -8 hours and catabolize triglycerides for 16-20 hours?

High intensity exercise to increase norepinephrine and growth hormone should partially deplete stored glycogen (and triglyceride) in liver and muscle and aid both anabolism of lean and catabolism of triglyceride when performed at the conclusion of the feed period and before the fasting period.

Reprogramming of defended body weight after Roux-En-Y gastric bypass surgery in diet-induced obese mice - Hao - 2016 - Obesity - Wiley Online Library

http://onlinelibrary.wiley.com/doi/10.1002/oby.21400/abstract?userIsAuthenticated=false&deniedAccessCustomisedMessage=

Joseph Thomas (Tony) Liverman, Jr.

Metabolic Clarity is Promoted by Clock Gene Signaling

Melatonin appears to be permissive for increased fat metabolism, especially visceral body fat.  This appears to be associated with increased Irisin.

Ursolic acid increases Irisin and has increased triglyceride metabolism.

Perhaps Ursolic acid during wake/feeding time and Melatonin during sleep/fasting time promotes both growth and recovery simultaneously with variable calorie burn.  Stored fat may be unfinished business of growth and incomplete recovery in an adjustable just in time metabolism!

I conjecture that the thrifty phenotype that cannot lose weight without excessive privation has "unfinished business" because they are simultaneously trying to perform growth and recovery at the same time due to mixed signaling.

One way to clarify metabolic signaling for clock genes is a prolonged fast period.  Therefore a restricted feeding cycle of 4-8 hours and a fasting cycle of 16-20 hours would restore "go slow complete your task functioning" would be beneficial to badly disrupted metabolic health.  Weekly intermittent fasting may be sufficient for milder disruptions.

http://www.fasebj.org/content/30/1_Supplement/907.9.short

Effects of melatonin on lipid metabolism and circulating irisin in diet-induced obese Sprague-Dawley rats

1. Pei-Chin Chiang, 
2. Chung-Cheng Lo, 
3. Chih-Yi Lin and 
4. Yi-wen Chien

+ Author Affiliations

Globesity refers to the worldwide increase of excess weight and obesity according to World Health Organization. Previous studies indicated melatonin, master clock controlling circadian rhythm, may halt body weight gain by increasing recruitment of brown adipose tissues. In light of the pressing need to check the progression of obesity, our study was aimed at investigating effects of oral melatonin administration on body fat accumulation and lipid parameters. Especially, we analyzed irisin, a novel myokine associated with browning effect of white adipose tissues, as the biomarker of brite/beige adipocytes. Forty 8-wk-old male Sprague-Dawley rats were divided into 5 groups: vehicle control (VC), positive control (PC), MEL10 (10 mg melatonin/kg BW), MEL20 (20 mg melatonin/kg BW) and MEL50 (50 mg melatonin/kg BW). Vehicle control group was fed control diet, and the other groups were fed high fat and high calorie diet for 6 weeks before melatonin treatment to induce obesity. Melatonin was dissolved in ethanol and diluted in drinking water with aluminum foil covering water bottle. Rats were treated for 8 weeks and sacrificed. We found that there is no deference in food and water intake, and melatonin administration can halt body weight gain, decrease accumulation and distribution of white adipose tissues, increase brown adipose tissue and brite/beige adipocytes, and lipid parameters were improved. Serum irisin concentration was significantly increased in melatonin-treated groups.

Exercise and Calorie Restriction Mimetics and Direct Antioxidants

Interesting abstract.  The issue with antioxidants and carbohydrate avoidance may not be true.  One can categorize antioxidants as direct and indirect.  Indirect produces a hormetic stress that induces antioxidant capacity.  The other is a direct antioxidant.  Give together they cancel out net positive effects.  For example green tea epicatechin is cancelled out by melatonin in studies.

Therefore direct antioxidants eg melatonin at sleep or recovery and indirect epicatechin during active or stress periods.

Ursolic acid is indirect and increased strength 30% over 8 weeks.  However sleep and recovery were also important.  Sleep after inducing anti oxidation is best.

Exercise and calorie restriction is an indirect antioxidant!

http://www.sciencedirect.com/science/article/pii/S0891584916000307

New strategies in sport nutrition to increase exercise performance

Despite over 50 years of research, the field of sports nutrition continues to grow at a rapid rate. Whilst the traditional research focus was one that centred on strategies to maximise competition performance, emerging data in the last decade has demonstrated how both macronutrient and micronutrient availability can play a prominent role in regulating those cell signalling pathways that modulate skeletal muscle adaptations to endurance and resistance training. Nonetheless, in the context of exercise performance, it is clear that carbohydrate (but not fat) still remains king and that carefully chosen ergogenic aids (e.g. caffeine, creatine, sodium bicarbonate, beta-alanine, nitrates) can all promote performance in the correct exercise setting. In relation to exercise training, however, it is now thought that strategic periods of reduced carbohydrate and elevated dietary protein intake may enhance training adaptations whereas high carbohydrate availability and antioxidant supplementation may actually attenuate training adaptation. Emerging evidence also suggests that vitamin D may play a regulatory role in muscle regeneration and subsequent hypertrophy following damaging forms of exercise. Finally, novel compounds (albeit largely examined in rodent models) such as epicatechins, nicotinamide riboside, resveratrol, β-hydroxy β-methylbutyrate, phosphatidic acid and ursolic acid may also promote or attenuate skeletal muscle adaptations to endurance and strength training. When taken together, it is clear that sports nutrition is very much at the heart of the Olympic motto, Citius, Altius, Fortius (faster, higher, stronger

Sarcopenia, Energy Production and Redox Signaling

This article shows that crosstalk between immune cells and organ cell determines integrity, function and the maintenance of the cell network.  The Redox signaling determines the rate of aging or degeneration of muscle or sarcopenia/osteopenia.

In the brain and in the skeletal system decreased energy production, increased redox signaling leads to inflammation, loss of function and structure.

Note how sarcopenia, and by extension dementia, is blocked by substances that increase energy production, and reverse signaling of declining energy production.  Below is a sample of age reversal agents that signal restoration of structure and function and longevity

DHA an omega 3 fatty acid that increases fluidity of membranes and the receptors that enter and exit the cell membrane

Green Tea Extract increases mobilization  and use of visceral body fat by being an O-methyl transferase inhibitor which blocks the breakdown of noradrenalin releasing more glucose and fatty acids for energy production.

Ursolic acid, an exercise and intermittent fasting mimetic, increases and shifts energy production from glucose to fatty acids to help both brain and muscle.  The latter becomes 30% stronger in human studies and metabolized 3.6% of body fat over 8 weeks.

BDNF is a bio marker of lifestyle effects that shift energy production from glucose to fatty acids/ketones. The indirect proof of this is trained soldiers from identical physical training and identical measured VO2 max (peak energy output measure) one half of whom added brain speed training which increases BDNF on testing endurance in an exercise to exhaustion were able to cycle 72% farther.  The putative increase in endurance was the result of producing more energy from fat.  

If my hypothesis that HRV index is a functional test of energy production is true, the above soldiers would have varied in HRV even though VO2 max was identical.

As today is the running of the Kentucky Derby 5/7/2016, I have a thought experiment that HRV index would predict the order the horses would finish in a straight run without interference!  Of course running economy would be an independent variable.

Highlights

• •
  The capacity of skeletal muscle to regenerate declines with aging.
• •
  Skeletal muscle repair involves a cross-talk between immune and muscle cells.
• •
  The physiological activities of immune and muscle stem cells decline with aging.
• •
  Nutrients can act as controllers of immune and muscle cell function.
• •
  Nutrition may help in preserving the capacity for muscle to repair during aging.

http://www.sciencedirect.com/science/article/pii/S1568163715300398

Abstract

After skeletal muscle injury a regeneration process takes place to repair muscle. Skeletal muscle recovery is a highly coordinated process involving cross-talk between immune and muscle cells. It is well known that the physiological activities of both immune cells and muscle stem cells decline with advancing age, thereby blunting the capacity of skeletal muscle to regenerate. The age-related reduction in muscle repair efficiency contributes to the development of sarcopenia, one of the most important factors of disability in elderly people. Preserving muscle regeneration capacity may slow the development of this syndrome. In this context, nutrition has drawn much attention: studies have demonstrated that nutrients such as amino acids, n-3 polyunsaturated fatty acids, polyphenols and vitamin D can improve skeletal muscle regeneration by targeting key functions of immune cells, muscle cells or both.

 (MY CONJECTURE  ;  FROM INCREASED ENERGY). 

Here we review the process of skeletal muscle regeneration with a special focus on the cross-talk between immune and muscle cells. We address the effect of aging on immune and skeletal muscle cells involved in muscle regeneration. Finally, the mechanisms of nutrient action on muscle regeneration are described, showing that quality of nutrition may help to preserve the capacity for skeletal muscle regeneration with age.

Increasing Cellular Energy Slows Aging Through Redox Signaling

See bolded below.

More cellular energy production, less aging and neuroinflammation!

Sarcopenia results essentially from decreased energy production, not from lack of combustible food or oxygen but due to mitochondrial dysfunction and lack of maintenance. 

BDNF is a bio marker of longevity and restorative gene expression.  

Increased HRV index is a functional marker of longevity and restorative gene effects.

Highlights

• •
  Mitochondrial hypometabolism, perturbed redox homeostasis, and chronic neuroinflammation characterize brain aging and Alzheimer’s disease
• •
  Increasing evidence from basic and clinical studies suggests that redox control serves as a bidirectional link between energy metabolism and inflammatory responses in the brain
• •
  This review focuses on the brain metabolic-inflammatory axis entailing the alterations in energy metabolism and inflammatory responses and their interconnected cross-talks via redox regulation in brain aging and Alzheimer’s disease

http://www.sciencedirect.com/science/article/pii/S0891584916302167

Energy Metabolism and Inflammation in Brain Aging and Alzheimer’s Disease

This review focuses on the brain metabolic-inflammatory axis entailing the alterations in energy metabolism and inflammatory responses and their interconnected cross-talks via redox regulation in brain aging and Alzheimer’s disease

The high energy demand of the brain renders it sensitive to changes in energy fuel supply and mitochondrial function. Deficits in glucose availability and mitochondrial function are well-known hallmarks of brain aging and are particularly accentuated in neurodegenerative disorders such as Alzheimer’s disease. As important cellular sources of H₂O₂, mitochondrial dysfunction is usually associated with altered redox status. Bioenergetic deficits and chronic oxidative stress are both major contributors to cognitive decline associated with brain aging and Alzheimer’s disease. Neuroinflammatory changes, including microglial activation and production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging. The bioenergetic hypothesis advocates for sequential events from metabolic deficits to propagation of neuronal dysfunction, to aging, and to neurodegeneration, while the inflammatory hypothesis supports microglia activation as the driving force for neuroinflammation. Nevertheless, growing evidence suggests that these diverse mechanisms have redox dysregulation as a common denominator and connector. An independent view of the mechanisms underlying brain aging and neurodegeneration is being replaced by one that entails multiple mechanisms coordinating and interacting with each other. This review focuses on the alterations in energy metabolism and inflammatory responses and their connection via redox regulation in normal brain aging and Alzheimer’s disease. Interactions of these systems is reviewed based on basic research and clinical studies.

Control Signaling, Control and Prevent Diabetes and Glycosylation

Interesting article on glucose transit from diet through body.

Stevia, my sugar free additive, has not been associated with insulin resistance.  In fact it is associated with improved glucose tolerance testing.

Fructose was appropriately highlighted as a bad sweetener and food additive.

Finally, the importance of signaling as the path to improvement is the take home message and my current understanding of metabolic or energy health.  I would highlight particularly the ability of the low glycogen liver to block gluconeogenesis from glucagon signaling when blood glucose is already elevated.

Dad,  we have known for years that fasting 48 hours restores insulin sensitivity.  I believe that diabetics should do the following:

Eat a low glycemic diet or Mediterranean diet.

Intermittently fast, deplete liver glycogen stores.

High intensity exercise, fastest way to deplete muscle glycogen (and liver glycogen.)

Resistance train to increase lean muscle to store and use glycogen without high blood levels.

Increase BDNF from brain and endothelial cells to maximally use glucose as the brain uses 20% of the bodies glucose.  Low BDNF is associated with brain insulin resistance.

http://nopr.niscair.res.in/handle/123456789/33739

NISCAIR ONLINE PERIODICALS REPOSITORY (NOPR) : A glucose-centric perspective of hyperglycemia

Abstract:     Digestion of food in the intestines converts the compacted storage carbohydrates, starch and glycogen, to glucose. After each meal, a flux of glucose (>200 g) passes through the blood pool (4-6 g) in a short period of 2 h, keeping its concentration ideally in the range of 80-120 mg/100 mL. Tissue-specific glucose transporters (GLUTs) aid in the distribution of glucose to all tissues. The balance glucose after meeting the immediate energy needs is converted into glycogen and stored in liver (up to 100 g) and skeletal muscle (up to 300 g) for later use. High blood glucose gives the signal for increased release of insulin from pancreas. Insulin binds to insulin receptor on the plasma membrane and activates its autophosphorylation. This initiates the post-insulin-receptor signal cascade that accelerates synthesis of glycogen and triglyceride. Parallel control by phos-dephos and redox regulation of proteins exists for some of these steps. A major action of insulin is to inhibit gluconeogensis in the liver decreasing glucose output into blood. Cases with failed control of blood glucose have alarmingly increased since 1960 coinciding with changed life-styles and large scale food processing. Many of these turned out to be resistant to insulin, usually accompanied by dysfunctional glycogen storage. Glucose has an extended stay in blood at 8 mM and above and then indiscriminately adds on to surface protein-amino groups. Fructose in common sugar is 10-fold more active. This random glycation process interferes with the functions of many proteins (e.g., hemoglobin, eye lens proteins) and causes progressive damage to heart, kidneys, eyes and nerves.
    Some compounds are known to act as insulin mimics. Vanadium-peroxide complexes act at post-receptor level but are toxic. The fungus-derived 2,5-dihydroxybenzoquinone derivative is the first one known to act on the insulin receptor. The safe herbal products in use for centuries for glucose control have multiple active principles and targets. Some are effective in slowing formation of glucose in intestines by inhibiting α–glucosidases (e.g., salacia/saptarangi). Knowledge gained from French lilac on active guanidine group helped developing Metformin (1,1-dimethylbiguanide) one of the popular drugs in use. One strategy of keeping sugar content in diets in check is to use artificial sweeteners with no calories, no glucose or fructose and no effect on blood glucose (e.g., steviol, erythrytol). However, the three commonly used non-caloric artificial sweeteners, saccharin, sucralose and aspartame later developed glucose intolerance, the very condition they are expected to evade. Ideal way of keeping blood glucose under 6 mM and HbA1c, the glycation marker of hemoglobin, under 7% in blood is to correct the defects in signals that allow glucose flow into glycogen, still a difficult task with drugs and diets.