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

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  The capacity of skeletal muscle to regenerate declines with aging.
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  Skeletal muscle repair involves a cross-talk between immune and muscle cells.
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  The physiological activities of immune and muscle stem cells decline with aging.
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  Nutrients can act as controllers of immune and muscle cell function.
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  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

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  Mitochondrial hypometabolism, perturbed redox homeostasis, and chronic neuroinflammation characterize brain aging and Alzheimer’s disease
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  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
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  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.

Signaling Growth and Regeneration in Brain and Body

Micro needling the skin to a depth of 0.5 mm improves regeneration of skin and reduced aging of skin to a depth of 12 mm due to signalling and increasing growth and regenerative peptides.

Knees undergoing sham arthroscopy improved equal to "clean out" procedures.

Knee synvisc injections divided into 5 shots were better than 3 shots were better than 1 shot.

Red Near infrared laser light improved joint pain by signalling growth and regeneration.

Red Near infrared laser light treatment of leg bone marrow activated adult mesenchymal stem cells to travel and relocated to injured brain where they attracted growth and regenerative peptides including BDNF.

The concept is clear that growth and regenerative peptides can be increased and work through a variety of signaling mechanisms.

One should not have to needle the hippocampus to signal.  Transcranial direct current, transcranial magnetic stimulation, red near infrared light stimulation or deep brain electrical stimulators would probably all work!

http://www.kurzweilai.net/micro-needle-insertion-into-hippocampus-helps-brain-regeneration-in-animal-model-of-ad

Urosolic Acid May Prevent Monocyte Activation and Prevent Inflammatory Diseases

Ursolic acid is derived from Apple skins.  50 mgs per medium sized Apple.  Also available as a supplement.

This article below shows that urosolic acid prevents "monocyte activation." Monocyte activation mobilizes glial cells to home in on cytokine releasing cells that are damaged in some way such as ischemia reperfusion which results in pyroptosis (inflamed cells) and apoptosis (death of cells) of the cells.  In effect collateral damage is increased and recovery is thwarted for damaged cells.  Using other terms metabolically stunned cells are programmed to die by releasing cytokines and activating glial cells.  Blocking cytokine derived death would prevent cell death and promote cell survival and recovery.

 If this is true for all monocyte cells including Microglial cells in brain, Kupffer cells in liver and Muller cells in the retina, it might prevent the following:

bipolar inflammation and symptoms, 

systemic sclerosis inflammation and symptoms, 

Alzheimer's inflammation and symptoms, 

nonalcoholic liver disease and symptoms, 

Parkinson's inflammation and symptoms, 

atherosclerosis inflammation and symptoms

Acute kidney injury inflammation and symptoms

Macular degeneration and vision loss.

Antioxidant action of most antioxidants has been measurably active mostly against ROS or reactive oxygen species. Reactive nitrogen species RNS antioxidant activity should also be reduced after metabolic stress such as ischemia reperfusion  stress.

Is urosolic acid a unique buffer of RNS directly or indirectly as an exercise and calorie restriction mimetic?  I suspect that the action is indirect or epigenic as it activates Sirtuin pathways in the same way as calorie restriction or exercise, both indirect epigenic modifiers of antioxidant pathway.

 Reservatrol, another antioxidant derived from the skin of grapes,  is an exercise and calorie restriction mimetic.  These plant skin products likely evolved to protect seeds and plants from harsh UVA and UVB damage of nuclear and mitochondrial dna.  It is logical that they would also affect mammalian cells with similar protection.  In effect, plants cannot exercise or voluntarily avoid calories from sunlight, therefore they would require their exercise and calorie restriction mimetics be derived from the energy produced from their genes.  If that is true, plants at the equator or desert (without shade) would likely have greater levels of these mimetics.

Ironically, a stress like exercise or calorie restriction induces a stronger antioxidant capability in mammals.

Exercise is a potent antioxidant.

Highlights

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  Ursolic acid protects monocytes from metabolic stress-induced dysfunction or “metabolic priming” by preventing the induction of Nox4.
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  Ursolic acid restores p38 MAP kinases activation and chemotactic responses to MCP-1 in monocytes exposed to metabolic stress.
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  Ursolic acid prevents increased protein S-glutathionylation, including actin-S-glutathionylation, in metabolically stressed monocytes.
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  Ursolic acid prevents MKP-1 degradation and restores MKP-1 activity in metabolically stressed monocytes.

http://www.sciencedirect.com/science/article/pii/S2213231714000184

Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4 ☆

Build a Better Network, Build a Better Teen?

The heritage and lessons of hard physical work is not easily available to teens today.  Think we need a proxy?
As I think about wilderness adventures, boot camps, team sport and education camps perhaps there is a wage based expenses required experience to allow coming of age to mean something.
Philmont, scouts, sports camps, sports, and summer jobs were significant for me.  Church camp not so much.  Ironically the physical and social quest of the former engendered more spiritual assets for me than the chapel of church camp.  The former was real and the second felt virtual.  Isn't it ironic that emphasizing the physical and social leads to the spiritual.
Similarly, cleaning bricks and building a retaining wall during our church building program engendered more tangible spiritual assets for me.  How much of spiritual growth is physical? Struggle? Doubt?
Faith exist beyond the mind and heart and physical and social portals have less barriers to strong imputs of character building works.
My current science insight is that lifestyles that increase BDNF brain derived neurotrophic factor and HRV heart rate variability index builds the network of mind and body to appreciate better the creator who designed us all to fast, pray work, learn and share hospitality in order to grow mentally, physically and spiritually.

I thought you would be interested in the following story from The Wall Street Journal.

Lessons From the Ranch: Schooling a Teen in Hard Work

http://www.wsj.com/articles/lessons-from-the-ranch-schooling-a-teen-in-hard-work-1459899578
Download the Wall Street Journal app here: WSJ.