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 the major killers of normal weight people as well. Research into the differences between long living mammals and their shorter life cousins have identified superior cell detoxification and repair processes (2) as the key to healthy aging and deficiencies in these processes may be a major cause of the age related diseases in man.
Constant Turnover of Protoplasm
The material make-up 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 later adulthood (3). Cleaning up residual protein fragments generated as a by-product of metabolism is thought to be the underlying function of sleep (4) and explains the molecular basis of neurological 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) (6). Protein recycling is accomplished by a process called autophagy or “self-eating” and the material targeted for recycling is highly selected cell refuse. Autophagy is regulated by recognition of the fasting (7) and feeding cycles and this in turn is dependent primarily on glucose abundance in foods. Here we present the signalling pathways where glucose abundance in the diet can be linked to underlying causes of non-communicable diseases (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). 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).
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).
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.