Optimal Eating for Weight Loss and Disease Prevention

The world is in the grip of an epidemic of obesity and age related degenerative diseases caused by recent distortions in our diet, reducing calories but not changing the type of food results in semi-starvation and hunger and therefore unsustainable. These guidelines are much more focused and will guarantee weight loss but are especially important for those who suffer from illnesses such as, heart attacks, strokes, dementia, high blood pressure, diabetes, high cholesterol, prostatic hypertrophy, peptic ulcer, arthritis, fibromyalgia, the list goes on but the cause is a universal cellular dysfunction associated with aging and this can be improved with diet and exercise.

Gradual changes in food habits over the years have reached a situation where 60-70% of calories consumed are quickly digested carbohydrates resulting in large increases in blood glucose that prompts insulin secretion causing fat deposition and quick return of hunger.  Long term effects of frequent spikes of high blood sugar are cell damage and inflammation, hypertension, metabolic syndrome, leading to heart attacks, strokes, cancer and dementia.

Avoid

  • Sugar, High Fructose Corn syrup, all caloric sweeteners including honey and agave syrup, sweets & candies.  Use low calorie sugar substitutes if necessary
  • All Juices, even orange juice, eat the fruit instead, sodas, energy drinks, gatorade, powerade, grape juice, cranberry juice, etc. Also avoid cocktail drink mixes like margarita and sweet and sour mix.
  • White flour, bread, pasta, cakes, cookies, biscuits, etc.
  • Potatoes, white rice, corn flour products, chips, etc.

Eat a High Fiber “Ketogenic” Diet

Carbohydrates can be roughly categorized by the speed of their digestion into simple sugars; the faster the worse for health and slower the better, with fiber on the most beneficial end of the spectrum.  “Ketogenic” is simply using fat for energy and results from minimizing the amount of simple sugars obtained from your diet. Choose superfoods which are defined by their health benefits; eat them whenever hungry and stop when you are satisfied.  The choices, vast, varied and enjoyable include many foods that were previously stigmatized like eggs, dairy and meat.  Calorie counting is unnecessary if high fiber plant foods are the bulk of your diet as they are satiating and suppress hunger due to slow digestion and low insulin response, in addition they contain thousands of phytonutrients which protect against oxidative stress, inflammation and cell damage. 

  •  Unlimited consumption of salads, leafy green vegetables, whole fruits, and nuts.
  • Moderation but not overindulgence in all sorts of interesting foods, including meat, fish, cheese, butter, eggs, olive oil, rape seed/canola oil, herbs and spices. These are what make foods enjoyable and they are mostly nonfattening and nutritionally beneficial
  • Peas, lentils, legumes and beans are high in protein and fiber good in moderation as they still contain digestible carbohydrates.
  • Whole grains, while much better than refined flour are still high glycemic carbohydrates and counteract ketogenesis if you are trying to lose weight or reverse hypertension and metabolic syndrome.  Oat bran and oat germ are an inexpensive alternative, as are wheat bran and wheat germ.
  • Drink: water or tea (green tea), coffee, diet drinks if necessary. Again avoid drinks with any sugar, HFCS, or any other calorie containing syrup.
  • Alcohol: Fine in moderation: red wine may have particular benefits.
  • Supplements should be unnecessary other than a source of omega3 and vitamin D such as cod liver oil

Two Very Different Phases of Life: Growth and Aging

“Natural selection, the blind, unconscious, automatic process…has no purpose in mind. It has no mind and no mind’s eye. It does not plan for the future. It has no vision, no foresight, no sight at all. If it can be said to play the role of watchmaker in nature, it is the blind watchmaker.” Richard Dawkins, The Blind Watchmaker: Why the Evidence of Evolution Reveals a Universe without Design.

 Very broadly animal life has two phases: growth and development to achieve sexual maturity followed by a long period of aging.  Most living organisms are programmed to grow to sexual maturity reproduce and die and it appears that the conditions that promote growth also accelerate the aging process and hasten death.  While growth to sexual maturity has a specific evolutionary purpose the long involutionary period of human aging is likely to be random and purposeless [ (1).  Nature blindly selects for short-term benefits of robust developmental growth, aging is a wasteful and aimless continuation of developmental growth, driven by nutrient-sensing, growth promoting signaling pathways such as mTOR (mammalian target of rapamycin). A continuous post-developmental activity of such gerogenic pathways leads to loss of homeostasis, “inflammaging (2)”, age-related diseases, organ damage and death. ]

 

Biology is replete with improvised and adapted systems that may not be logical but work sufficiently well under prevailing environmental circumstances to ensure survival of a species and be handed down (conserved) in the evolutionary chain.  An example of this appears to be the signaling mechanisms that enhance growth which ironically also increase the likelihood of age related disease and an earlier death. Growth is enhance by abundant nutrients which along with insulin/insulin like growth factor (IGF) pathways activate the critical controller, mTOR that promotes growth and cell division but also suppresses mobilization of internal food stores including glucose, lipids and amino-acids by a process called autophagy.  Autophagy is also adapted to perform another vital life process which is refuse disposal and cellular house cleaning: critically important in maintaining efficient energy production from mitochondria by recycling of malfunctioning components of the electron transport chain which can produce oxidative stress and cell damage if not constantly renewed.  To a large extent aging diseases are caused by mitochondrial dysfunction and intracellular garbage accumulation that lead to cellular dysfunction and programmed cell death (apoptosis).

The most common causes of death in past generations have been infections, trauma and starvation but this has changed over the last century and now non communicable diseases associated with aging such as heart attacks, strokes, cancer, loss of nerve, bone and muscle cells, etc., cause most deaths, disability and suffering and they consume huge financial and emotional resources.  Furthermore organ degeneration once occurred is largely irreversible and treatments are expensive and of marginal benefit, therefore understanding aging and prevention of age related diseases are an imperative public health concern.  However, age related diseases while more frequent with aging also occur at all ages and, for lifestyle related reasons, are becoming increasingly common in children, adolescents and young adults.  The process of life generates large amounts of redundant and damaged protoplasm that has to be recycled and repaired on a daily basis and defects in protein recycling are key to premature degenerative conditions as well as age related diseases: for instance recovery from injury is much more rapid in younger individuals and healing takes longer with increasing age.  Neuronal degeneration so common in the very old is now seen in adolescents unfortunate enough to have obesity and early signs of adult onset diabetes (3).

Two recent epidemiological studies warn of potential dangers associated with relatively higher dietary protein consumption: In Swedish women higher protein relative to carbohydrate intake was associated with an increase in incidence of cardiovascular diseases (4) and another observational study on the effect of macronutrient composition of diets found protein content to be the only significant predictor of increased obesity (5).  These associations may have some plausibility in view of recent findings on amino-acid regulation of autophagy. Note that autophagy is key process in detoxifying cells as described in the section on Cell Refuse Disposal.  An abundance of amino-acids quickly suppresses autophagy (6) as does an abundance of glucose via insulin (7) both by separate pathways impacting mTOR, the master controller of autophagy.

In very broad terms, aging and many of the diseases related to aging are caused by deterioration in various aspects of cell function that lead to cell death and inflammation.  Increasing degrees of mitochondrial dysfunction leading to widespread disruption of mitochondrial integrity within the cell is one of the final events in cell death.  One must appreciate the highly dynamic state of protein recycling in order to understand how critical autophagy relates to cell function; for instance mitochondria are the pivotal components of cells that generate energy and they are subject to wear and tear necessitating complete recycling over a 20 to 30 day time frame.  Dysfunctional components of mitochondria split off by fission from larger networks and are engulfed in “autophagosomes” broken down and their amino-acids and other building blocks recycled for mitochondrial resynthesis.  Autophagy is therefore critical to quality control of mitochondrial function which if left to deteriorate results in cell death.  In the wider context of the whole organism excessive rates of cell death can overload the scavenging (immune) system and lead to inflammation in various organs and tissues that are the hallmarks of age related diseases such as atherosclerosis, neurodegeneration, arthritis and so on.

Two aspects of recent food trends combine to impact autophagy via its regulator mTOR: chronically high glucose and insulin levels and, to a lesser degree, excessive protein consumption.  Just as it was a mistake of the last 40 to 50 years to replace fat with carbohydrates it would be ill-advised to replace carbohydrates with protein. The bottom line as far as dietary advice on protein consumption is that a level of 0.8 gm/kg body weight may be ideal (8).  This amounts to just 56 gms (2 oz) of protein a day, much more than we might be accustomed to in our typical Western Diet whereas protein supplementation at least for mature adults is likely to do much more harm than good.  There is however a strategy to achieve multiple worthwhile biological objectives at the same time in view of most recent evidence on the benefits of prebiotics and the dangers of hyperglycemia/hyperinsulinemia:  the replacement of high glycemic carbohydrates (rapidly digested carbohydrates) with those resistant to digestion i.e. fiber.

Works Cited

1. Blagosklonny., Mikhail V. MTOR-driven quasi-programmed aging as a disposable soma theory. Blind watchmaker vs. intelligent designer. . s.l. : Cell Cycle 12:12, 1842–1847; June 15, 2013; © 2013 Landes Bioscience. .

2. Antero Salminen, Kai Kaarniranta, Anu Kauppinen. Inflammaging: disturbed interplay between autophagy and inflammasomes. . s.l. : AGING, March 2012, Vol.4 No.3.

3. Ageing brain abnormalities in young obese patients with type 2 diabetes: a cause for concern. Nolan, J. J. s.l. : Diabetologia, 2010, Vol. 10. DOI 10.1007/s00125-010-1890-x.

4. Lagiou, Sandin, Weiderpass, et al. Low carbohydrate-high protein diet and incidence of cardiovascular diseases in Swedish women: prospective cohort study. . s.l. : BMJ 2012;344:e4026.

5. Vergnaud A-C, Norat T, Mouw T, Romaguera D, May AM, et al. Macronutrient Composition of the Diet and Prospective Weight Change in Participants of the EPIC-PANACEA Study. s.l. : PLoS ONE (2013) 8(3): e57300. doi:10.1371/journal.pone.0057300.

6. Efeyan, Zoncu, Sabatini. Amino acids and mTORC1: from lysosomes to disease. s.l. : Trends Mol Med. 2012 September ; 18(9): 524–533. doi:10.1016/j.molmed.2012.05.007.

7. Emilie Vander Haar, Seong-il Lee, Sricharan Bandhakavi, Timothy J. Griffin, Do-Hyung Kim. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. . s.l. : Nature Cell Biology 9, 316 – 323 (2007) | doi:10.1038/ncb1547.

8. Edda Cava, Luigi Fontana. Will calorie restriction work in humans? . s.l. : AGING, July 2013, Vol. 5 No.7. http://www.impactaging.com.

Dangers of Too Much Protein

Warning signs for Protein Over-consumption

Two recent epidemiological studies warn of potential dangers associated with relatively higher dietary protein consumption: In Swedish women higher protein relative to carbohydrate intake was associated with an increase in incidence of cardiovascular diseases (1) and another observational study on the effect of macronutrient composition of diets found protein content to be the only significant predictor of increased obesity (2).  These associations may have some plausibility in view of recent findings on amino-acid regulation of autophagy. Note that autophagy is key process in detoxifying cells as described in the section on Cell Refuse Disposal.  An abundance of amino-acids quickly suppresses autophagy (3) as does an abundance of glucose via insulin (4) both by separate pathways impacting mTOR, the master controller of autophagy.

In very broad terms, aging and many of the diseases related to aging are caused by deterioration in various aspects of cell function that lead to cell death and inflammation.  Increasing degrees of mitochondrial dysfunction leading to widespread disruption of mitochondrial integrity within the cell is one of the final events in cell death.  One must appreciate the highly dynamic state of protein recycling in order to understand how critical autophagy relates to cell function; for instance mitochondria are the pivotal components of cells that generate energy and they are subject to wear and tear necessitating complete recycling over a 20 to 30 day time frame.  Dysfunctional components of mitochondria split off by fission from larger networks and are engulfed in “autophagosomes” broken down and their amino-acids and other building blocks recycled for mitochondrial resynthesis.  Autophagy is therefore critical to quality control of mitochondrial function which if left to deteriorate results in cell death.  In the wider context of the whole organism excessive rates of cell death can overload the scavenging (immune) system and lead to inflammation in various organs and tissues that are the hallmarks of age related diseases such as atherosclerosis, neurodegeneration, arthritis and so on.

 The bottom line as far as dietary advice on protein consumption is that a level of 0.8 gm/kg body weight may be ideal (5).  This amounts to just 56 gms (2 oz) of protein a day, much more than we might be accustomed to in our typical Western Diet.  The challenge is how to comfortably restrict protein whereas protein supplementation at least for mature adults is likely to do much more harm than good.

Works Cited

1. Lagiou, Sandin, Weiderpass, et al. Low carbohydrate-high protein diet and incidence of cardiovascular diseases in Swedish women: prospective cohort study. . s.l. : BMJ 2012;344:e4026.

2. Vergnaud A-C, Norat T, Mouw T, Romaguera D, May AM, et al. Macronutrient Composition of the Diet and Prospective Weight Change in Participants of the EPIC-PANACEA Study. s.l. : PLoS ONE (2013) 8(3): e57300. doi:10.1371/journal.pone.0057300.

3. Efeyan, Zoncu, Sabatini. Amino acids and mTORC1: from lysosomes to disease. s.l. : Trends Mol Med. 2012 September ; 18(9): 524–533. doi:10.1016/j.molmed.2012.05.007.

4. Emilie Vander Haar, Seong-il Lee, Sricharan Bandhakavi, Timothy J. Griffin, Do-Hyung Kim. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. . s.l. : Nature Cell Biology 9, 316 – 323 (2007) | doi:10.1038/ncb1547.

5. Edda Cava, Luigi Fontana. Will calorie restriction work in humans? . s.l. : AGING, July 2013, Vol. 5 No.7. http://www.impactaging.com.

New Insights into Health Effects of Alcohol

Alcohol: an important prevention tool?

Epidemiological studies and controlled trials on alcohol consumption invariably show a U shaped mortality curve where abstinence is associated with higher mortality and increasing alcohol consumption improves health until mortality begins to rise again with high alcohol consumption.  As well as all-cause mortality there is a greater reduction of cardiovascular mortality (1) that apparently exceeds the protection afforded by taking statins. While the toxic effects of excess alcohol on brain and liver cells have been known for some time the biological mechanisms behind the protective effect of moderate alcohol consumption are less clear (2) but documented effects include increased high-density lipoprotein cholesterol and fibrinolysis, decreased platelet aggregation and coagulation factors, and beneficial effects on endothelial function and inflammation (3).

It has been just 10 years since the publication of the discovery of receptors for short chain fatty acids in 2003 (4) and there has been a huge interest generated in their important signaling functions and understanding of the relationship of gut microbiota and health, particularly inflammation (5).  The main source of short chain fatty acids is bacterial fermentation of fiber but alcohol is another important source of acetate which in some circumstances can be greater than the amount generated from fiber fermentation (6).  After consumption alcohol is quickly absorbed and metabolized to acetate increasing blood levels 10-20 fold.  Acetate is an energy source for most organs including brain cells and it is also a signaling molecule by at least two mechanisms; as an inhibitor of Histone Deacetylases and an agonist of free fatty acid receptors (FFAR2).  Because alcohol is converted to acetate after absorption mainly by liver cells the FFAR2 receptors primarily targeted would be on cells of the immune system and fat cells rather than intestinal epithelial cells.

Acetate is the most abundant SCFA, followed by propionate and butyrate, produced by bacterial fermentation of fiber which takes place mainly in the terminal ileum and large intestine (7).  The SCFA’s, particularly butyrate, are important energy substrates for intestinal epithelial cells and excess SCFA passes through to the liver and systemic circulation performing dual roles as an energy substrate and cell signaling.  Two G-protein coupled receptors for SCFA have been identified FFAR2 and FFAR3 which preferentially bind acetate/propionate and butyrate respectively (8).  There is a direct link between fiber consumption producing SCFA and increased GLP1 secretion from intestinal L cells which is triggered via the SCFA receptors FFAR2 and 3.  In addition SCFA’s can have direct effects on gene expression by inhibition of Histone Deacetylases HDAC(9) which has anti-proliferative and anti-inflammatory effects in vitro, and in in vivo models of intestinal inflammation (10) and either of these mechanisms are thought to be responsible for widespread beneficial effects of SCFA as listed below:

  • FFAR2 agonists reduce inflammation and regulate adipokine secretion in adipose tissue (11) increasing leptin and decreasing the pro-inflammatory resistin.
  • FFAR2 agonists have anti-inflammatory effects in colitis, arthritis and asthma (12)
  • FFAR2 agonists, SCFA induce T regulatory cells important in controlling intestinal barrier functions and immunity (9)
  • Acetate via acetylation effects protein function and gene expression and inhibits histone deacetylases.  Increased acetate levels stimulates mitochondrial function and has been linked to delaying the aging process (13).
  • FFAR2 agonist SCFA’s control Glucagon Like Peptide release from intestinal L cells (14). GLP1 slows gastric emptying, lowers glucose levels, and reduces food consumption.  GLP1 is an important regulator of glucose metabolism and also suppresses appetite (14).
  • GLP1 has been recently shown to stimulate apolipoprotein A-I gene expression in hepatocytes in culture (15) with important implications for increasing plasma HDL and protection against cardiovascular disease.
  • GLP1 prevents the accumulation of monocytes and macrophages in arterial wall and suppresses proinflammatory cytokine expression in macrophages (16).
  • FFAR2 agonists SCFA stimulate secretion of anorexic hormone PYY from intestinal L cells (14).
  • FFAR2 agonists SCFA also inhibit the secretion of the orexigenic hormone ghrelin (17).
  • FFAR2 agonists reduce endothelial cell expression of leukocyte adhesion molecules VCAM and ICAM which are important in the development of cardio-vascular diseases (18)

Summary

Acetate and other short chain fatty acids activate specific receptors that are widely expressed throughout body tissue importantly on immune cells and adipose tissue and suppress inflammation while the FFAR2 receptors in intestinal cells produce additional signaling molecules GLP1 and PYY which suppress appetite, stimulate hepatic HDL production and contribute to further anti-inflammatory and metabolic regulatory functions.  Pharmaceutical companies see a multibillion dollar business in producing drugs which mimic SCFA’s and Glucagon Like Peptides. GLP1 agonists exenatide and liraglutide are approved and widely prescribed for weight loss treatment programs but are already subject of claims of complications and class action law suits.  Although not profitable to “big pharma”, we suggest much better results are achievable with lifestyle measures involving increased fiber consumption and appropriate use of alcohol.

Works Cited

1. Streppel MT, Ocké MC, Boshuizen HC, Kok FJ, Kromhout D. Long-term wine consumption is related to cardiovascular mortality and life expectancy independently of moderate alcohol intake: the Zutphen Study. . s.l. : J Epidemiol Community Health. 2009 Jul;63(7):534-40.

2. Augusto Di Castelnuovo, Simona Costanzo, Vincenzo Bagnardi, Maria Benedetta Donati, Licia Iacoviello, Giovanni de Gaetano. Alcohol Dosing and Total Mortality in Men and WomenAn Updated Meta-analysis of 34 Prospective Studies. . s.l. : Arch Intern Med. 2006;166(22):2437-2445.

3. Michel M. Joosten, Marjan J. van Erk, Linette Pellis, Renger F. Witkamp, Henk F. J. Hendriks. Moderate alcohol consumption alters both leucocyte gene expression profiles and circulating proteins related to immune response and lipid metabolism in men. s.l. : British Journal of Nutrition (2012), 108, 620–627 doi:10.1017/S0007114511005988.

4. Andrew J. Brown, Susan M. Goldsworthy, Ashley A. Barnes, et al. The Orphan G Protein-coupled Receptors GPR41 and GPR43 Are Activated by Propionate and Other Short Chain Carboxylic Acids. s.l. : THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 278, No. 13, Issue of March 28, pp. 11312–11319, 2003.

5. Gijs den Besten, Karen van Eunen, Albert K. Groen, Koen Venema, Dirk-Jan Reijngoud, Barbara M. Bakker. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. . s.l. : J. Lipid Res. 2013 54:(9) 2325-2340. .

6. al., Lihong Jiang et. Increased brain uptake and oxidation of acetate in heavy drinkers. . s.l. : J Clin Invest. 2013;123(4):1605–1614. doi:10.1172/JCI65153.

7. al., Brian T. Layden et. Short chain fatty acids and their receptors: new metabolic targets. . s.l. : Translational Research2013;161:131–140.

8. Brian T. Layden, Anthony R. Angueira, Michael Brodsky, Vivek Durai, William L. Lowe Jr.. Short chain fatty acids and their receptors: new metabolic targets. . s.l. : Translational Research2013;161:131–140.

9. Patrick M. Smith, Michael R. Howitt, Nicolai Panikov, Monia Michaud, Carey Ann Gallini, Mohammad Bohlooly-Y, Jonathan N. Glickman, Wendy S. Garrett. The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis. . s.l. : Science 341, 569 (2013). DOI: 10.1126/science.1241165.

10. Schilderink R, Verseijden C, de Jonge WJ. Dietary inhibitors of histone deacetylases in intestinal immunity and homeostasis. . s.l. : Front Immunol. 2013 Aug 1;4:226. doi: 10.3389/fimmu.2013.00226. eCollection 2013.

11. Sa’ad H. Al-Lahham, Han Roelofsen†, Marion Priebe†, Desiree Weening†, Martijn Dijkstra, Annemieke Hoek, Farhad Rezaee, Koen Venema, Roel J. Vonk. Regulation of adipokine production in human adipose tissue by propionic acid. . s.l. : Eur J Clin Invest 2010; 40 (5): 401–407.

12. Maslowski, Vieira, Aylwin, Kranich, Sierro, Di Yu, Schilter, Rolph, Mackay, Artis, Xavier, Teixeira, Mackay. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. . s.l. : Nature. 2009 October 29; 461(7268): 1282–1286. .

13. Tadahiro Shimazu, Matthew D. Hirschey, Jing-Yi Huang, Linh T.Y. Ho, Eric Verdin. Acetate metabolism and aging: An emerging connection. . s.l. : Mechanisms of Ageing and Development 131 (2010) 511–516.

14. Gwen Tolhurst, Helen Heffron, Yu Shan Lam, Helen E. Parker, Abdella M. Habib, Eleftheria Diakogiannaki, Jennifer Cameron, Johannes Grosse,2 Frank Reimann, Fiona M. Gribble. Short-Chain Fatty Acids Stimulate Glucagon-Like Peptide-1 Secretion via the G-Protein–Coupled Receptor FFAR2. s.l. : Diabetes 61:364–371, 2012.

15. Chehade JM, Alcalde R, Naem E, Mooradian AD, Wong NC, Haas MJ. Induction of apolipoprotein A-I gene expression by glucagon-like peptide-1 and exendin-4 in hepatocytes but not intestinal cells. s.l. : Metabolism. 2013 Feb;62(2):265-74. doi: 10.1016/j.metabol.2012.07.005. Epub 2012 Aug 16.

16. Masayuki Arakawa, Tomoya Mita, Kosuke Azuma, Chie Ebato, Hiromasa Goto, Takashi Nomiyama, Yoshio Fujitani, Takahisa Hirose, Ryuzo Kawamori, Hirotaka W. Inhibition of Monocyte Adhesion to Endothelial Cells and Attenuation of Atherosclerotic Lesion by a Glucagon-like Peptide-1 Receptor Agonist, Exendin-4. s.l. : Diabetes 59:1030–1037, 2010.

17. Julie-Anne Nazare, PhD, Vale´rie Sauvinet, BS, Sylvie Normand, PhD, Laetitia Gue´rin-Deremaux, PhD, Laure Gabert, BS, Michel De´sage, PhD, Daniel Wils, PhD, and Martine Laville, MD, PhD. Impact of a Resistant Dextrin with a Prolonged Oxidation Pattern on Day-Long Ghrelin Profile. s.l. : Journal of the American College of Nutrition, Vol. 30, No. 1, 63–72, 2011.

18. D. Zapolska-Downar, M. Naruszewicz. Propionate Reduces The Cytokine-Induced Vcam-1 And Icam-1 Expression By Inhibiting Nuclear Factor-K B (Nf-Kb) Activation . s.l. : Journal Of Physiology And Pharmacology 2009, 60, 2, 123-131. http://www.jpp.krakow.pl.

Nutritional Influences on “Cell Refuse Disposal”

Beyond Obesity

Non-communicable diseases  (NCD) are the main causes of death in developed countries and are largely associated with aging.  The worrying trend is that they becoming more common in younger age groups and the increase in life expectancy we have seen in people born in the 1920’s and 1930’s will likely be reversed in the age group born in the 60’s, 70’s & 80’s caught up in the obesity epidemic (1).  Obesity is a risk factor for NCD but does not explain the cause as NCD are also the major killers of normal weight people as well.  The difference between long living mammals such as naked mole rats and their shorter live cousins is thought to be due to their superior cellular protection and repair processes (2) and age related diseases in humans may be related to deficiencies in these processes too.

Constant Turnover of Protoplasm

The material makeup of living things is gradually broken down and rebuilt on a daily cycle resulting in profound changes over time during the different phases of life from growth and development to the long involutionary period of aging in adulthood (3). Cleaning up residual protein fragments generated as a byproduct of metabolism is thought to be the underlying function of sleep in virtually all animals (4) and explains the molecular basis of impairment associated with sleep deprivation.  Efficient removal of protein residues is an essential life function and the regulation of these processes is inextricably tied up with nutritional status of cells (5) as is the protein synthesis side of the recycling equation (6).  Autophagy or “self-eating” is the term given to cell refuse disposal and is regulated by recognition of the fasting (7) and feeding cycles, which is dependent on glucose abundance in foods. In this way glucose abundance in the diet can be linked to underlying causes of NCD (8).

Health Benefits of Calorie Restriction: 

It is generally agreed that over-nutrition is responsible for obesity, diabetes and many age related diseases and it is well known that calorie restriction, even intermittent fasting, benefits all of these things and it is thought that possibly the main mechanism of these benefits is due to up-regulation of autophagy (9) which recycles redundant, potentially toxic material (10). Sensing mechanisms of nutritional status trigger cell signaling that regulates basal autophagy where survival requires mobilization of body stores during fasting.  Fat mobilization (lipophagy) takes place by a process akin to autophagy (11) and mobilization of glucose from glycogen is also accomplished via autophagy (12).  It may be an opportunist adaption of evolution that autophagy is employed for mobilization of substrate stores during fasting as well as protein recycling and intracellular “refuse disposal” processes.  Feeding inhibits and fasting stimulates autophagy through the actions of insulin and glucagon respectively and the primary determinant of insulin and glucagon secretion is blood glucose.  Insulin and glucagon control autophagy via their opposing effects on mTOR (mammalian target of rapamycin) whereby mTOR activity suppresses autophagy (5).  Glucagon via glucagon receptor activates adenylate cyclase which increases cAMP and activates PKA (cAMP activated protein kinase) which inhibits mTOR thereby stimulating autophagy in situations of fasting.  On the other hand glucose stimulated insulin secretion suppresses autophagy via Akt (PKB) activation of mTOR.  A ketogenic diet was found to inhibit the mTOR pathway via decreased Akt signaling as well as increased AMPK signaling in the liver of rats (13).  Through similar pathways Insulin and glucagon also have a role in regulating mitochondrial biogenesis.  Mitochondrial biogenesis is regulated by the master-controller, PGC1 nuclear receptor coactivators.  Fernandez and Auwerx (14) discovered how the pancreatic hormones insulin and glucagon play an opposing role in PGC1a transcription.  Insulin secretion which by activating Akt(PKB) depresses mitochondrial biogenesis by inhibiting PGC1a transcription while PGC1a transcription is increased via the glucagon receptor-PKA pathway.

NRF2:  Recent research by Rochelle Buffenstein’s group into the differences between long lived species the naked mole rat with a 40 year maximum life expectancy compared with 4 years in their short lived relatives, focuses on their superior detoxification and repair abilities largely mediated by the master controller NRF2 (NFE2L2) enhancing transcription of multiple proteins involved in cell protection and detoxification as well as chaperones involved in autophagy and protein stability (2).  The activity of two master controller transcription factors NRF2 and PGC1a appear to function in tandem, as they are increased by the same environmental stimuli and cell signaling pathways regulating multiple genes involved in autophagy (15) and mitochondrial regeneration (14) respectively.  Both NRF2 and PGC1a are increased by a ketogenic diet (16) (17) (18).

AMPK    Another sensor of cellular energy levels is AMP activated protein kinase (AMPK) functions in a different way to the glucagon receptor activated cyclic AMP activated protein kinase (PKA).  AMPK responds to increased AMP/ATP levels that occur with exercise.  A recent review highlights a central role for AMPK in disease resistance and longevity (19) promoting transcription of FOXO dependent proteins such as PGC1a and NRF2 while promoting autophagy by inhibiting mTOR.  Of particular relevance to the mechanism of ketogenic diets is that insulin signaling powerfully suppresses AMPK activation via Akt/PKB (20) while glucagon activates AMPK by activating CaMKIV (21)

Autophagy is induced with ketogenic diet

Because a ketogenic diet profoundly suppresses insulin secretion even in the presence of adequate calorie intake (22) it follows that ketogenic diets enhance basal autophagy (13).  A ketogenic diet as in fasting also requires glucose production from glycogenolysis and gluconeogenesis which is controlled be glucagon secretion which via the PKA pathway suppresses mTOR to enhance autophagy and on the other hand carbohydrate foods that increase glucose and insulin levels activate mTOR via akt/PKB pathway to suppress basal autophagy.

Conclusions

Widespread appreciation of the emerging importance of autophagy in life and disease is likely to focus attention on ways to optimize these processes and macronutrients and phytonutrients have a profound impact as seen from the lessons from epidemiological and basic science studies on restriction of glucose abundance through low glycemic and ketogenic diets (23).

Works Cited

1. A Potential Decline in Life Expectancy in the United States in the 21st Century. S. Jay Olshansky, Ph.D., Douglas J. Passaro, M.D., Ronald C. Hershow, M.D.,Jennifer Layden, M.P.H., Bruce A. Carnes, Ph.D., Jacob Brody, M.D., Leonard Hayflick, Ph.D.,Robert N. Butler, M.D., David B. Allison, Ph.D., and David S. Ludwig, M.D., Ph.D. s.l. : n engl j med, 352;11, March 17, 2005.

2. Viviana I. Pereza, Rochelle Buffenstein, Venkata Masamsetti, Shanique Leonard, Adam B. Salmon, James Meleb, Blazej Andziakd, Ting Yangd, Yael Edreyd, Bertrand Friguete, Walter Ward, Arlan Richardsona, and Asish Chaudhur. Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole rat. s.l. : PNAS March 3, 2009 vol. 106 no. 9 3059–3064.

3. Li-qiang HE, Jia-hong LU, Zhen-yu YUE. Autophagy in ageing and ageing-associated diseases. . s.l. : Acta Pharmacologica Sinica (2013) 34: 605–611; ; published online 18 Feb 2013. doi: 10.1038/aps.2012.188.

4. Varshavsky., Alexander. Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis. . s.l. : PROTEIN SCIENCE 2012 VOL 21:1634—1661 Published by Wiley-Blackwell. VC 2012 The Protein Society.

5. Rajat Singh, Ana Maria Cuervo. Autophagy in the Cellular Energetic Balance. . s.l. : Cell Metab. 2011 May 4; 13(5): 495–504. doi:10.1016/j.cmet.2011.04.004.

6. Carles Canto, Johan Auwerx. PGC-1a, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. s.l. : Current Opinion in Lipidology 2009, 20:98–105.

7. Mehrdad Alirezaei, Christopher C. Kemball, Claudia T. Flynn, Malcolm R. Wood, J. Lindsay Whitton, William B. Kiosses. Short-term fasting induces profound neuronal autophagy. s.l. : Autophagy 6:6, 702-710; August 16, 2010; © 2010 Landes Bioscience.

8. Livesey G, Taylor R, Livesey H, Liu S. Is there a dose-response relation of dietary glycemic load to risk of type 2 diabetes? Meta-analysis of prospective cohort studies. . s.l. : Am J Clin Nutr. 2013 Mar;97(3):584-96. doi: 10.3945/ajcn.112.041467. Epub 2013 Jan.

9. Autophagy and Aging. David C. Rubinsztein, Guillermo Marin, Guido Kroemer. s.l. : Cell 146, September 2, 2011 Elsevier Inc. DOI 10.1016/j.cell.2011.07.030.

10. Selective degradation of mitochondria by mitophagy . Insil Kim, Sara Rodriguez-Enriquez, John J. Lemasters. s.l. : Archives of Biochemistry and Biophysics , 2007, Vols. 462 (2007) 245–253.

11. H. Knævelsrud, A. Simonsen,. Lipids in autophagy: Constituents, signaling molecules and cargo with relevance to disease,. s.l. : Biochim. Biophys. Acta (2012), . doi:10.1016/j.bbalip.2012.01.001.

12. O.B. Kotoulas, S.A. Kalamidas, D.J. Kondomerkos. Glycogen autophagy in glucose homeostasis. s.l. : Pathology – Research and Practice 202 (2006) 631–638.

13. Sharon S. McDaniel, Nicholas R. Rensing, Liu Lin Thio, Kelvin A. Yamada, and Michael Wong. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. . s.l. : Epilepsia. 2011 March ; 52(3): e7–e11. doi:10.1111/j.1528-1167.2011.02981.x.

14. Pablo J Fernandez-Marcos, and Johan Auwerx. Regulation of PGC-1a, a nodal regulator of mitochondrial biogenesis. s.l. : Am J Clin Nutr 2011;93(suppl):884S–90S.

15. Kaitlyn N. Lewis, James Mele, John D. Hayes and Rochelle Buffenstein. Nrf2, a Guardian of Healthspan and Gatekeeper of Species Longevity. s.l. : Integrative and Comparative Biology, volume 50, number 5, pp. 829–843.

16. Julie B. Milder, Li-Ping Liang and Manisha Patel. Acute oxidative stress and systemic Nrf2 activation by the ketogenic diet. s.l. : Neurobiology of Disease 2010: Volume 40, Issue 1, 238-244.

17. Bough, Kristopher. Energy metabolism as part of the anticonvulsant mechanism of the ketogenic diet. s.l. : Epilepsia 2008, 49: 91-93.

18. Douglas Wallace, Weiwei Fan, Vincent Procaccio. Mitochondrial Energetics and Therapeutics. s.l. : Annual Review of Pathology: Mechanisms of Disease 2010 5:297-348, 2010.

19. Antero Salminen, Kai Kaarniranta. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. s.l. : Ageing Research Reviews 11 (2012) 230– 241.

20. Suzanne Kovacic, Carrie-Lynn M. Soltys, Amy J. Barr, Ichiro Shiojima, Kenneth Walsh and Jason R. B. Dyck. Akt Activity Negatively Regulates Phosphorylation of AMP-activated Protein Kinase in the Heart. s.l. : The Journal of Biological Chemistry, 2003: 278, 39422-39427.

21. I-Chen Peng, Zhen Chen, Pang-Hung Hsu, Mei-I Su, Ming-Daw Tsai and John Y-J. Shyy. Glucagon Activates the AMP-Activated Protein Kinase/Acetyl-CoA Carboxylase Pathway in Adipocytes. s.l. : FASEB J.April 201024 (Meeting Abstract 995.4).

22. Adam R. Kennedy, Pavlos Pissios, Hasan Otu, Bingzhong Xue, Kenji Asakura, Noburu Furukawa, Frank E. Marino, Fen-Fen Liu, Barbara B. Kahn, Towia A. Libermann, Eleftheria Maratos-Flier. A high-fat, ketogenic diet induces a unique metabolic state in mice. s.l. : Am J Physiol Endocrinol Metab 292:E1724-E1739, 2007. First published 13 February 2007;.

23. Marwan A Maalouf, Jong M Rho, Mark Mattson. The neuroprotective properties of calorie restriction, the ketogenic diet and ketone bodies. s.l. : Brain Res Rev 2009: March 59: 293-315.

 

Calorie Counting

Calorie Hypothesis of Obesity

Everyone knows starvation makes you thin and overeating makes you fat and the “calorie in calorie out” theory of weight control is at the heart of nutritional advice and food labelling, nevertheless for many reasons counting calories usually fails over the long term. Calorie restriction no doubt has health benefits but a lifetime of hunger is not likely to catch on with most people. We eat food not calories and there are staggering numbers of possible food combinations to choose that can have distinct effects on appetite, physiological responses and cell signaling. There are physical limitations to consuming plant foods with high fiber and water content (1) and there is evidence to suggest hunger is accentuated when attempting calorie restriction with diets containing high glycemic filler foods like bread, potatoes, rice, pasta, flour and sugar as opposed to high fiber (2) and ketogenic diets (3) (4) (5)

On the other side of the equation calories out is equally complicated with physical activity, heat generation, work of metabolism, growth and development, healing processes, calorie losses in faeces and urine all having significant effects.

Exercise is a highly beneficial activity but the impact of exercise on “calories out” is commonly overestimated, and exercise alone is unlikely to reverse obesity unless you put in the sort of time required of professional athletes.  For instance resting energy expenditure is typically 100 Calories per hour and the most vigorous exercise would expend 10 times that figure while moderate exercise increases to 3 to 4 times resting metabolic rate, so that 30 minutes of moderate exercise results in additional calories out of around 150 Cals the equivalent of 17 gms of fat.

Faecal loss of calories is frequently underestimated particularly so with increased faecal output from high fiber consumption (6).  Calorie content of faeces is around 2 Cals per gm (7) and the typical low fiber Western Diet (10-15 gms/d) might be associated with a faecal output of 100 g/day and this could rise to 200-400 g/d with recommended (35 g/d) or even higher fiber intakes (6) which may result in faecal calorie output of between 400 and 800 Cals/day.  Studies have indicated a 1 g/d increase in fiber results in a 5 gm/d increase in stool weight but of that the calorie content, particularly from fat, increases proportionately more (8).

Resting energy expenditure varies considerably with stages in life; proportionately much higher with growth and development, levelling off in adulthood and progressively declining with age.  There is a well-known thermal effect of foods whereby energy expenditure increases after meals proportionately with calorie content although, in experimental rodents a ketogenic diet increases oxygen consumption and causes weight loss in spite of increased calorie intake (9) although this has not been clearly demonstrated in human studies there are mechanisms related to energy uncoupling through fatty acid metabolism and up-regulation of uncoupling proteins to explain how these things might happen.  In addition, there have been many studies comparing unrestricted ketogenic diets with calorie restricted low fat diets for weight loss and most have shown greater weight loss with ketogenic diets despite higher calorie intake (10) (11) (1).

Works Cited

1. D J A Jenkins, J M Wong, CWC Kendall, A Esfahani, T Leong, DA Faulkner, E Vidgen, KA Greaves, G Paul, W Singer. The effect of a Plant based low carbohydrate (ECO-Atkins) diet of body weight and blood lipid concentrations in hyperlipidemic subjects. s.l. : Arch Intern Med 169: 11 June 8, 2009 1046-1054, 2009.

2. Elin V Johansson, Anne C Nilsson, Elin M Östman and Inger M E Björck . Effects of indigestible carbohydrates in barley on glucose metabolism, appetite and voluntary food intake over 16 h in healthy adults. . s.l. : Nutrition Journal 2013, 12:46.

3. P Sumithran, LA Prendergast, E Delbridge, K Purcell, A Shulkes, A Kriketos, J Proietto. Ketosis and appetite-mediating nutrients and hormones after weight loss. . s.l. : European Journal of Clinical Nutrition (2013) 67, 759–764; doi:10.1038/ejcn.2013.90;.

4. Margriet A. B. Veldhorst1, Klaas R. Westerterp, Anneke J. A. H. van Vught, Margriet S. Westerterp-Plantenga. Presence or absence of carbohydrates and the proportion of fat in a high-protein diet affect appetite suppression but not energy expenditure in normal-weight human subjects fed in energy balance. s.l. : British Journal of Nutrition 2010: 1-11 doi:10.1017/S000711451000206.

5. SCHARRER, ERWIN. Control of Food Intake by Fatty Acid Oxidation and Ketogenesis. . s.l. : Nutrition Vol. 15, No. 9, 1999.

6. K. L. Wrick, J. B. Robertson, P. J. Van Soest, B. A. Lewis, J. M. Rivers, D. A. Roe, L. R. Hackler. The Influence of Dietary Fiber Source on Human Intestinal Transit and Stool Output. . s.l. : J. Nutr. 113: 1464-1479, 1983.

7. J L Murphy, S A Wootton, S A Bond, A A Jackson. Energy content of stools in normal healthy controls and patients with cystic fibrosis. . s.l. : Archives of Disease in Childhood 1991; 66: 495-500.

8. Hsiao-Ling Chen, Valerie S Haack, Corey W Janecky, Nicholas W Vollendorf, Judith A Marlett. Mechanisms by which wheat bran and oat bran increase stool weight in humans. . s.l. : Am J Clin Nutr 1998;68:711–9.

9. Adam R. Kennedy, Pavlos Pissios, Hasan Otu, Bingzhong Xue, Kenji Asakura, Noburu Furukawa, Frank E. Marino, Fen-Fen Liu, Barbara B. Kahn, Towia A. Libermann, Eleftheria Maratos-Flier. A high-fat, ketogenic diet induces a unique metabolic state in mice. s.l. : Am J Physiol Endocrinol Metab 292:E1724-E1739, 2007. First published 13 February 2007;.

10. Jeff S Volek, Richard D Feinman. Carbohydrate restriction improves the features of Metabolic Syndrome: Metabolic Syndrome may be defined by the response to carbohydrate restriction. s.l. : Nutrition & Metabolism 2005: 2:31, 2005.

11. Eric C Westman, William S Yancy Jr, John C Mavropoulos, Megan Marquart and Jennifer R McDuffie. The effect of a low-carbohydrate, ketogenic diet versus a low fat diet to treat type 2 diabetes. s.l. : Nutrition & Metabolism 2008 5:36, 2008.

News

Calorie Hypothesis of Obesity

Everyone knows starvation makes you thin and overeating makes you fat, therefore the “calorie in calorie out” theory of weight control is pretty much unshakeable but what has gone wrong on such a global scale where two thirds of the population have lost control of their weight.  Restricting calories in the face of hunger only works if you have the self-discipline of a monk but there are painless ways to correct the calorie imbalance as well as an optimal health span as will be discussed in the following chapters.

 

  • Calorie Restriction and Hunger
  • High Glycemic Hypothesis
  • Are high fat foods the root cause of obesity
  • Lessons from 100 years ketogenic diets.
  • The Remarkable Functions of Fiber