phenotype
In the temperate zones of the Earth, late summer into autumn has been a time of celebration in many cultures. This is the time when all creatures breathe a sigh of relief as the hard work of growth slows. The cooler air transforms summer’s searing rays of sunshine into loving, golden warmth. Pregnant with sugar, fruits of flowering plants hang heavy from the branches and dapple the landscape in a mosaic of reds, blues and purples from anthocyanins and carotenoids. On the ground, combinations of lutein and zeaxanthin color the winter squashes of the Cucurbita family with the same oranges and yellows that are revealed as chlorophyll relinquishes its dominion over the foliage.
Colorful pigments that once acted as a beacon for pollinators in an array of colors and hormones[1] assume a new form that will serve as this year’s bridge of survival for numerous species of birds and mammals, including humans.
Over these precious few weeks, concentrated glucose and fructose flow in like the ocean tide. With them, the stomach’s master hormones of appetite flip flop. Ghrelin’s waxing and leptin’s waning[2] impose an ever-rising voracity of appetite that has driven successful survival of species over hundreds of millions of years. Inside the sweet goodness lurks even more treasures. Fresh omega-six oils from seeds and grains give a fresh boost to dwindling eicosanoids that are crucial for cell-to-cell communication. Vitamin E, selenium[3], vitamin C and phytonutrients stand like a levy to ensure the rising tide of inflammation doesn’t breach its banks.
In Traditional Chinese Medicine Theory, this time of year was considered the fifth season associated with the Earth element. Warmth, sunshine, water and Earth have been magically transformed by a billion tiny seeds into a form that passes life’s nourishment unto us. In the Jewish tradition, this season beckons the new year known as Rosh Hashanah.
“Blessed are you, sovereign of the Universe who brings forth bread to the Earth…who has kept us in life, has sustained us and brought us to this season.” Torah
Lurking deep within the cell, all the way down to the nuclear membrane, a sugar-laden surge of insulin nudges a sleeping Goddess from her torpor. 2.1 billion years ago[4],[5] some of the earliest fungi birthed this goddess and time kindly bequeathed her unto humans. In science she is known as SREBP or sterol regulatory elemental binding proteins. She is the one who, as if by magic, signals that transformation of sugar into a form that can be stored for later use as triglycerides[6] and fat[7]. Without her, most animals in the temperate and arctic zones are unlikely to survive even one winter.
Because of SREBP’s, every cell can make its own LDL cholesterol for membrane repair and vitamin D synthesis. However, without a way to supply basic antioxidants to the cell, LDL quickly oxidizes. This transformation from Dr. Jeckel to Mr. Hyde damages everything it touches[8] and is considered to be one of the driving forces of atherosclerosis7. In order to protect her inner world and ensure a constant supply of antioxidants, SREBP must ask for a little help from one of her cousins in the liver, SREBP-1. While most of the cells of the body settle for glucose as an energy source, the liver engages in a more refined taste for fructose. In fact, liver cells are the only ones that can use fructose and its effects are incendiary. Fructose drives rapid production of LDL cholesterol, fats and inflammation in the liver[9],[10]. This preference for fructose acts as a supply chain for the trillions of cells’ insatiable need for antioxidants during times like these. But without SREBP, these antioxidants are useless. She alone is the key master who permits passage of these antioxidants across the cell membrane. Under the dominion of SREBP, the LDL cholesterol receptor rises to the surface of the cell like a fish rising to feed. If it is lucky, LDL cholesterol will land in its mouth. Along for the ride, precious antioxidants like vitamins A, C, and E are granted access to the cell’s inner world[11].
As this season wanes, berries hang dried and scant on the branches. Insulin recedes as the sugar festival comes to a close. The Earth cools. SREBP breathes a deep sigh as her hard work comes to an end. As she falls into her winter nap, she brings many of the creatures of the Earth with her. Only one creature has successfully escaped the dominion of this goddess. Humans innovated to store carbohydrates externally. This consistent supply of sugar drives insulin to ensure that SREBP never sleeps. Her unrelenting state of slavery drives disorders like obesity[12],[13], fatty liver[14], insulin resistance[15] and atherosclerosis[16], [17]. Perhaps this goddess would argue that these are not diseases at all but are phenotypes brought on by depriving her of a proper rest.
[1] Cutler A.J., Krochko J.E. Formation and breakdown of ABA. Trends Plant. Sci. 1999;4:472–478. doi: 10.1016/S1360-1385(99)01497-1
[2] Teff KL, Elliott, SS, Tschop M, Kieffer TJ, Rader D., Heiman M., Townsend RR., Keim NL, D’Alesso D, Havel Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. PJ J Clin Endocrinol Metab. 2004 Jun;89(6):2963-72
[3] Giacomo dugo, Lara La Pera, Donatella Pollicino, marello Saitta. Determination of Selenium Content in Different Types of Seed Oils by Cathodic Stripping Potentiometry (CSP) J. Agric. Food Chem., 2003, 51 (19), pp 5598–5601
[4] Timothy F. Osborne, Peter J. Espenshade Evolutionary Conservation and Adaptation in the Mechanism that Regulates SREBP Action: What a Long Strange tRIP It’s Been. Genes & Dev. 2009. 23: 2578-2591, doi:10.1101/gad.1854309
[5] V Laudet Evolution of the Nuclear Receptor Superfamily: Early Diversification from an Ancestral Orphan Receptor. Journal of Molecular Endocrinology Dec. 1, 1997. 19 2-7-226
[6] Colleen K. Nye Glyceroneogenesis Is the Dominant Pathway for Triglyceride Glycerol Synthesis in Vivo in the Rat The Journal of Biological Chemistry, 283, 27565-27574. October 10, 2008
[7] Hitoshi Shimano, SREBPs: physiology and pathophysiology of the SREBP family. The FEBS Journal 2009 276:3 616-621
[8] Low Density Lipoprotein Can Cause Death of Islet β-Cells by Its Cellular Uptake and Oxidative Modification Miriam Cnop, Jean Claude Hannaert, Annick Y. Grupping, and Daniel G. Pipeleers Endocrinology 2002 143:9 , 3449-3453 http://dx.doi.org/10.1210/en.2002-220273
[9] Zhang C, Chen X, Zhu RM, Zhang Y, Tu T, Wang H., Zhao H, Zhao M, Ji YL, Chen YH, Meng XH, Wei W, Xu DX. “Endoplasmic reticulum stress is involved in hepatic SREBP-1c activation and lipid accumulation in fructose-fed mice.” 2012 Aug 3;212(3):229-40. doi: 10.1016/j.toxlet.2012.06.002. Epub 2012 Jun 12.
“ER stress contributes, at least in part, to hepatic SREBP-1c activation and lipid accumulation in fructose-evoked NAFLD.”
[10] Koo HY, Miyashita M, Cho BH, Nakamura MT. Replacing dietary glucose with fructose increases ChREBP activity and SREBP-1 protein in rat liver nucleus. 2009 Dec 11;390(2):285-9. doi: 10.1016/j.bbrc.2009.09.109. Epub 2009 Sep 30.
“Nuclear SREBP-1 was 2.2 times higher in fructose-fed rats than glucose-fed rats.”
[11] Maret G Traber, Herbert J Kayden “Vitamin E is Delivered to Cells via the High Affinity Receptor for Low-Density Lipoprotein” The American Journal of Clinical Nutrition 40: October 1984, pp 747-51.
[12] Hitoshi Shimano, SREBPs: physiology and pathophysiology of the SREBP family. The FEBS Journal 2009 276:3 616-621
[13] Hitoshi Shimano, SREBPs: physiology and pathophysiology of the SREBP family. The FEBS Journal 2009 276:3 616-621
[14] Moon YA, Liang G, Xie X, Frank-Kamenetsky M, Fitzgerald K, Koteliansky V, Brown MS, Goldstein JL, Horton JD. The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals. Cell Metab. 2012 Feb 8;15(2):240-6
[15] Iichiro Shimomura, Robert E. Hammer, James A. Richardson, Shinji Ikemoto, Yuriy Bashmakov, Joseph L. Goldstein,Michael S. Brown
Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev. 1998 October 15; 12(20): 3182–3194.
[16] Karasawa T, Takahashi A, Saito R, Sekiya M, Igarashi M, Iwasaki H, Miyahara S, Koyasu S, Nakagawa Y, Ishii K, Matsuzaka T, Kobayashi K, Yahagi N, Takekoshi K, Sone H, Yatoh S, Suzuki H, Yamada N, Shimano H. Sterol regulatory element-binding protein-1 determines plasma remnant lipoproteins and accelerates atherosclerosis in low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2011 Aug;31(8):1788-95.
[17] Kurtak, K. Dietary and Nutritional Manipulation of the Nuclear Transcription Factors, PPAR’s and SREBP’s, as a Tool for Reversing the Primary Diseases of Premature Death and Aging. Rejuvenation Research 17-2. April 2014. P 140-44.
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Phenotype (fē-nō-tīp)
noun
The net result of the interaction of an organism’s genes with its environment.
In 1953, Watson and Crick’s discovery of DNA was a beacon of hope for understanding what causes human disease. Since then science and medicine have invested billions in research and man hours under the premise and promise that understanding our genetic code would lead us to answers and cures for the leading causes of disease and death. To our surprise, the results have not been so straightforward. As we’ve gained more and more information about our genetic programming, we’ve discovered that genetics plays only a small role in the development of many of the leading causes of chronic disease and premature death. Our antiquated belief that we are destined to fall victim to a disease that ended the life of our parents and/or grandparents has given way to the sometimes difficult realization that we have more influence over the future of our health and our lifespan than we could have imagined.
As more and more research has come online, we’ve discovered that many human diseases are largely a result of external factors that are potentially under our control. A study published in 2004 in The Lancet followed over 15,000 people assessing risk factors for heart attack. The authors identified nine non-genetic risk factors that “collectively accounted for 90-94% of cardiovascular disease and had the potential to prevent the majority of premature myocardial infarction1”. These risk factors were composed of external influences that can all be eliminated including “Abnormal lipids, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, consumption of fruits, vegetables, and alcohol, and regular physical activity[i]”.
A study appearing in JAMA in 2008 on 4883 people over the age of sixty-five concluded that 90% of DM2 cases are preventable using 5 lifestyle changes. Diabetes-related risk factors include physical activity level, dietary habits, adiposity, alcohol use, and smoking habits[ii].
As our understanding deepens, it is becoming apparent that perhaps these are not diseases at all but in fact what we call phenotypes.
Since 1998, the statistics regarding cancer risk, which were studied separately by the NIH and WHO, have remained surprisingly steady. Despite thousands of new studies every year the figures stood at approximately 80% environmental (a scientific term for external factors) and 20% genetic. This was concurred in 2014 by The American Cancer Society saying, “environmental factors (as opposed to heredity factors) account for an estimated 75%-80% of cancer cases and deaths in the US[iii]. On January 2nd 2015 this assessment came crashing down with the controversial Science article by Cristian Tomasette and Bert Vogelstein titled “Variation in Cancer Risk Among Tissues Can Be Explained by the Number of Stem Cell Division”[iv]. This was an elegant, groundbreaking study that shined a light on the novel idea that some cancers simply occur because of random mutations during stem cell division. Suddenly, part of the 80% environmental aspect had to be redefined. The authors’ unfortunate choice to assign a new value to the environmental influence in the absence of adequate data parameters was incendiary across the media and scientific community. Six of the top eleven most frequently occurring cancer types were not included in this study. Interestingly, each of the excluded cancer types have a huge body of scientific evidence demonstrating that each of them is highly influenced by environmental factors. Among these cancers were prostate, breast, uterine, urinary bladder, kidney and Non Hodgkin’s Lymphoma, collectively, responsible for nearly 20% or 1/5 of cancer deaths in the US in 2014 and their incidence rate an even higher contribution3. The environmental factors that influence their development include infectious agents[v], endogenous[vi] and exogenous hormones, xenobiotic compounds[vii], certain heavy metals[viii], certain pharmaceuticals, specific industrial and organic chemicals[ix], alcohol consumption[x], glycemic control[xi], and aflatoxin[xii].
One reason the scientific community raised such a fuss about the “bad luck” cancer study was that an inordinate amount of funding and resources is already dedicated to the diagnosis and treatment of cancer. The same goes for many other “diseases” including heart disease and diabetes. After all, each one forms a massive economic base that generates billions of dollars annually. Research funding directed towards the understanding and true prevention of these diseases contributes very little to monthly recurring revenues. Instead, it represents an ominous threat to the economic base of the medical industry as well as any industry whose products might be identified as a risk. Despite the hurdles, advances in our understanding of the processes that create these “diseases” has accelerated so fast that it has created a growing chasm where science and medicine no longer overlap but have diverged. The statistics about the environmental influences on “disease” have been well known in the scientific community for at least 15 years. However, they are poorly acknowledged by the medical industry and, as a result, have remained clandestine to the general public. Chemicals aside, imagine if society truly understood how they could prevent diabetes or delay the onset of heart disease simply by adopting a regimen of glycemic control as described in the studies above. What if it was not based on a drug but was based on reducing their consumption of excess sugar? This one change would have massive reverberations through multiple industries. On one side, there would be reduced “need” for medical services that manage the entire sequela of diseases that are known to be caused by poor glycemic control. This would translate into reduced doctor visits, reduced “need” for pharmaceuticals, fewer hospitalizations, fewer surgeries, lower consumption medical supplies, reduced need for assisted living and in home care, reduction of insurance costs etc. On the other side the industrial farming and food complex would also be widely affected. This includes farming equipment, GPS equipment, chemical fertilizers, pesticides, herbicides, fungicides, GMO seeds, all sugar-laden products, packaging, transportation and distribution, fuel consumption etc. As you can see, a significant base of the economy relies on a mutualistic relationship between Big Farma and Big Pharma. The current medical paradigm actually benefits from environmental problems and generally relegates efforts to fix this to the realm of environmental fundamentalism and quackery.
At what point do we embrace our responsibility of removing the known causes of disease? There are already billions of dollars and man-hours wasted on researching and treating diseases that are created by humans literally poisoning themselves. What is the sense? To continue to protect economic interests cloaked inside a societal dietary lexicon that has been hijacked by mass manipulation of naturally occurring, animalistic addictions through marketing, food additives and advertising? We must focus on removing the factors that create these disease phenotypes. Once this illusion has been cleared we can direct our resources towards novel drugs and therapies that will do the most good. Image a healthy, thriving society where disabled life expectancy is a thing of the past. Where companies and organizations like SENS, Calico and Human Longevity Inc. create drugs that don’t depend on illness but address the factors that are not under our control to produce meaningful lasting advances in health and longevity.
[i] Prof Salim Yusuf DPhil,Steven Hawken MSc,Stephanie Ôunpuu PhD,Tony Dans MD,Alvaro Avezum MD,Fernando Lanas MD,Matthew McQueen FRCP,Andrzej Budaj MD,Prem Pais MD,John Varigos BSc,Liu Lisheng MD,on behalf of the INTERHEART Study Investigators Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study
The Lancet – 11 September 2004 ( Vol. 364, Issue 9438, Pages 937-952) DOI: 10.1016/S0140-6736(04)17018-9
[ii] Dariush Mozaffarian, MD, DrPH; Aruna Kamineni, MPH; Mercedes Carnethon, PhD; Luc Djoussé, MD, ScD; Kenneth J. Mukamal, MD; David Siscovick, MD, MPH. Lifestyle Risk Factors and new Onset Diabetes Mellitus in Older Adults. Arch Intern Med. 2009;169(8):798-807. doi:10.1001/archinternmed.2009.21.
[iii] [iii] ACS (2014). Cancer Facts & Figures 2014, Atlanta. American Cancer Society, 2014. Available at: http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf
[iv] Cristian Tomasetti, Bert Vogelstein. Variation in Cancer Risk Among Tissues Can Be Explained by the Number of Stem Cell Divisions. Science 2 January 2015 Vol. 347 no. 6217 pp. 78-81. DOI:10.1126/science.1260825
[v] Yidya Vedham Ph. D., Mukesh Verma Ph. D. Cancer-Assoicated Infectious Agents and Epigenetic Regulation Cancer Epigenetics Methods in Molecular Biology Nov. 8, 2014 Vol. 1238, pp333-354 Doi: 10.1007/978-1-4939-1804-1_18
[vi] Tim Key; Endogenous Hormones Breast Cancer Collaborative Group Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: Reanalysis of eighteen prospective studies. Steroids. Oct. 7, 2014. Doi: 10.1016/j.steroids.2014.09.001
[vii] Hye-Rim Lee; Kyung-A Hwang; Kyung-Chul Choi. The estrogen receptor signaling pathway activated by phthalates is linked with transforming growth factor-β in the progression of LNCaP prostate cancer models. International Journal of Oncology. May 22, 2014. Pp595-602 Doi: 10.3892/ijo.2014.2460
[viii] García-Lestón, J; Roma-Torres, J; Vilares, M; Pinto, R; Prista, J; Teixeira, JP; Mayan, O; Conde, J; Pingarilho, M; Gaspar, JF; Pásaro, E; Méndez, J; Laffon, B. Genotoxic effects of occupational exposure to lead and influence of polymorphisms in genes involved in lead toxicokinetics and in DNA repair. Environ Int, 2012 vol. 43 pp. 29-36
[ix] Guo, H; Bassig, BA; Lan, Q; Zhu, Y; Zhang, Y; Holford, TR; Leaderer, B; Boyle, P; Qin, Q; Zhu, C; Li, N; Rothman, N; Zheng, T. Polymorphisms in DNA repair genes, hair dye use, and the risk of non-Hodgkin lymphoma. Cancer Causes Control, 2014 vol. 25(10) pp. 1261-70
[x] Qian Zhong, Ganggang Shi, Yanmei Zhang, Lei lu, Daniel Levy, Shuping Zhong. Alteration of BRCA1 Expression Affects Alcohol-induced Transcription of RNA Pol III-Dependent Genes. Gene Vol 556, Issue 1, Feb. 1, 2015 74-79.
[xi] Juhyun Park; Sung Yong Cho; Young Ju Lee; Seung Bae Lee; Hwancheol Son; Hyeon Jeong. Poor Glycemic Control of Diabetes Mellitus Is Associated with Higher Risk of Prostate Cancer Detection in a Biopsy Population. PLOS Sept. 18, 2014. Doi: 10.1371/journal.pone.0104789
[xii] Xi-Dai Long; Dong Zhao; Xiao-Qiang Mo; Chao Wang; Xiao-Ying Huang; Jin-Guang Yao; Yun Ma; Zhong-Hua Wei; Min Liu; Li-Xiao Zeng; Jian-Jun Zhang; Feng Xue; Bo Zhai; Qiang Xia. Genetic Polymorphisms in DNA Repair Genes XRCC4 and XRCC5 and Aflatoxin B1–related Hepatocellular Carcinoma. Epidemiology Sept 2013, Vol. 24 Issue 5 pp. 671-81. Doi: 10.1097/EDE.0b013e31829d2744
by Here is a link to my presentation. SENS6 Karen Kurtak
Hello all! This is my first presentation at a major international conference. It’s very technical but there are pieces that clarify in non-biochemical terminology . Here I present an argument for why the primary diseases of aging are not “diseases” at all but, in fact, phenotypes. I also discuss how the ketogenic diet alters signaling of DNA through nuclear transcription factors to stop, and sometimes reverse, the processes that ultimately lead to the primary “diseases” of aging including diabetes, heart disease, cancer, Alzheimer’s Disease. It was a lot of information to cover in 15 minutes but it offers a rough outline of the biochemical mechanism of action of the ketogenic diet. This took me literally over 1000 hours of sorting through science articles and plugging in the pieces until it all began to make sense. Along the way I found multiple journal articles that were completely wrong that led me down frustrating rabbit holes. Grrrr! For more extensive information please see my article that will be published in Rejuvenation Research Journal. Ultimately, this is just one example of the amount of information we already possess that is independent of clinical trials. Since I was limited to 2000 words in the article, I will be discussing each of these points in more detail in the coming months.
Thanks to Bill Andrews, who in his quest to cure aging or die trying, asked me a question that I couldn’t answer. Thank you to Aubrey de Grey for your vision that has created a firm foundation of understanding of the processes that lead to disease and aging. Thank you to all the humans of the Earth who have dedicated time and money towards uncovering truth and knowledge through science. Thank you to journals who don’t limit access of knowledge by creating pay walls. Elsevier, you guys are self-serving hijackers of knowledge. Thank you Markdavis and mmkroll for your open access photos on Flickr. Thanks to Nick, Robyn, my parents, Doreen, Bob, Michelle, Jordan, Michelle, Cliff, Darcie, Paula, Randi, Sue, Beth and Lara who supported me through multiple meltdowns and temporary possession by the Demon of OCD. Thank you Rozyln, William, Bill, (Bill’s brilliant wife whose name has escaped me), Dr. Cai, and everyone else who cheered for me before or during the conference!!!
Karen
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I seek to cure what’s deep inside, frightened of this thing that I’ve become.
-Toto
Around 20 years ago, both the National Institute of Health and The World Health Organization released separate, independent studies concluding that genetics only plays a minor role in the development of cancer. Most of us were completely surprised to find that environmental and lifestyle factors influenced over 80% of this outcome. Since then, several large studies have unveiled similar statistics including the development of heart disease and diabetes. The belief that we are mere victims to our genetic programing has given way to the realization that, with some accurate knowledge, we have incredible influence over our health as we move forward in our lives. In science, the term that describes the accumulation outside factors upon an organism’s genes is called “phenotype” (pronounced fee-no-type). What is your phenotype? What do you want it to be? Of course there are things that we cannot control. However, always remember, you have incredible influential powers to create and re-create your life and your future.
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