Life Extension Magazine February 2014
How Glucose Mediates Life And Death By Turning Genes On And Off
By Paul McGlothin and Meredith Averill
Averill. Activation of
longevity genes begins with
delicious foods and recipes
that help control glucose.
Are you happy with the color of your eyes? Your eye color and many other physical characteristics that give you your own distinctive look are determined by genes, inherited from your parents. Genes are powerful. They control how cells function and when those functions are carried out.1 While influencing all the genes that regulate cellular function is not yet possible, you can control many genes that affect your disease risk, as well as length of life – just by managing glucose (blood sugar) levels.2,3
The CR Way , the holistic lifestyle for living better and longer, calls for keeping blood glucose low for optimal health. Fasting glucose in the 80s (mg/dL) or below and postprandial (post-meal) glucose below 120 mg/dL are the goal levels.
Maintaining glucose in these lower ranges has long been suggested in the CR Way to Great Glucose Control classes and is strongly advocated by Life Extension.
What most doctors don’t yet know is that controlling glucose within these lower levels helps activate genes associated with longevity and reduced disease risk.4 Here we introduce some of these genes and explain how glucose and insulin mediate life and death by turning them on or off.
Some genetic activity can be altered beneficially by diet and lifestyle.5,6 When long-term, serious calorie-restricted humans were tested at Washington University School of Medicine, their fasting glucose and insulin levels were lower than sex- and age-matched cohorts of runners and of subjects who followed a standard western diet.7
A later study, made possible in part by the Life Extension Foundation®, found that long-term calorie restriction in humans activates longevity genes proven to be associated with the insulin/IGF-I pathway.8
Insulin is a well-known hormone. Most people think of it as part of managing glucose.9 However, it promotes the absorption of fatty acids and amino acids into cells, as well.9 Moreover, it facilitates cellular replication and, thus, growth.9
When blood glucose rises, usually after eating, pancreatic beta cells produce insulin.9 It circulates through the blood – binding to insulin receptors on cell surfaces, where it moves glucose into the cells. Insulin stimulates the body to store excess glucose as glycogen and promotes the synthesis of fatty acids which are stored in the fat cells of adipose tissues.9
People usually don’t think about managing their diet to keep glucose or insulin at healthful levels unless they develop diabetes. But by then it may be too late. Excess blood glucose causes unfavorable gene expression that can lead to excess insulin production, sustained activation of inflammatory pathways, and increased risk of developing disease complications.10-12
When glucose levels are kept within healthful levels in the bloodstream, genes that regulate insulin production are activated.12 Optimal function of these genes may provide some protection from diabetes.
Some of the following paragraphs will appear technical to the lay reader, but it is important for the scientists who rely on Life Extension magazine to understand the important genes influenced by blood glucose levels:12
Pdx-1 (pancreatic and duodenal homeobox-1) directly regulates signals that trigger insulin production.13 Pdx-1 also activates glucose transporter-2, which helps transport glucose from the blood into the cell.13 NeuroD1 (neurogenic differentiation 1) helps regulate brain cell differentiation and insulin release. Defects in NeuroD1 have been implicated in diabetes.14 MafA (Beta cell nuclear MusculoAponeurotic Fibrosarcoma oncogene family A) interacts with Pdx-1 and NeuroD1, and stimulates pancreatic B-cells to produce insulin – particularly when glucose levels are high.13
Genetic and other insulin-regulating signals can be turned “down or off” when exposed chronically to high glucose levels.15 This is thought to be a potential cause of type II diabetes.
Insulin And IGF-I
Like insulin, IGF-I regulates growth-related functions, which are essential for life.16 However, insulin and IGF-I levels are also linked to cancer and accelerated aging.17,18 Genetic manipulations that reduce the intensity of insulin and IGF-I signaling consistently extend life span in worms, flies, and mice.19
When insulin binds to its receptor, it activates a chain reaction of signals, beginning with the insulin receptor itself and including key enzymes involved in glucose homeostasis.20 These enzymes include Protein Kinase B (PKB/Akt), which regulates many signals, such as the FoxO (Forkhead box O) family of transcription factors (proteins that control whether a gene becomes active).18
FOOD → GLUCOSE → INSULIN
INSULIN → PKB/AKT → FOXO
FoxO transcription factors play a pivotal role in metabolism and life span. “Glucose reduction and/or calorie restriction causes FoxO factors to take over to determine the fate of a cell: long-term survival in a quiescent state, or programmed cell death.”21
When food is scarce, FoxO factors shuttle from the cytoplasm back into the nucleus and activate longevity genes, which help the organism make it through lean times until food is available. When food is plentiful, FoxO stays in the cytoplasm of the cell and thus cannot perform its longevity enhancement.22
One member of the FoxO family, FoxO3A, is associated with extended life span and has been identified in centenarian research.23
Preserving Cellular Energy Producers With SIRT3
Mitochondria, the cellular energy producers that provide the fuel for the cells’ function(s), are very vulnerable to age-related decline.24 Glucose restriction may slow age-related mitochondrial deterioration by activating the SIRT3 gene,25 a member of the sirtuin family of genes – known to protect against age-related hearing loss.26 SIRT3 hooks up with FoxO3A and the ancient enzyme and energy sensor, AMPK (AMP-activated protein kinase), to form an energy-producing complex in mitochondria.26 This facilitates the energy-enhancing formation of new mitochondria.27,28
Low Glucose: Different Reactions In Genes Of Healthy Vs. Cancer Cells
Cancer cells are glucose gluttons because they need this simple form of energy to fuel their rapid growth rates. So, making energy easily available by maintaining high glucose levels increases both cancer risk and rate of metastasis.29
Maintaining low glucose levels has been shown to extend the life span of healthy cells.30
Low blood glucose also provides the benefit of activating hTERT (human telomerase reverse transcriptase) an enzyme that keeps telomeres from shortening when cells divide. Longer telomeres are associated with increased life span in animal and human studies.31 Protection of mitochondria under mild stress is another important benefit of hTERT.32
Glucose And Dementia: Can One Gene Restore Memory?
As people age, they become increasingly vulnerable to dementia.33 This usually means memory loss, along with impaired judgment and/or reduced language skills.33 Loss of everyday skills, such as the ability to manage a bank account or drive safely, is demoralizing.
The RbAp48 gene became famous instantly when it was linked to memory restoration.34 Scientists at Columbia University knocked out RbAp48 in mice and found that they experienced memory loss. When the researchers increased the level of RbAp48 in old mice – their memories returned to the level of much younger mice!
Apparently, the dentate gyrus, a part of the hippocampus region of the brain, is important for memory formation and is targeted during aging. RbAp48 is less abundant in the dentate gyrus of older mammals versus younger ones.34 Moreover, the dentate gyrus is extremely sensitive to damage by high blood glucose levels, which may result in dementia.35
Making dietary mistakes that send glucose and insulin soaring is easy to do. So living a lifestyle that is fun, easy to follow, and known to activate longevity genes that are associated with longer life makes a big difference. This drove the development of the CR Way, which emphasizes delicious, low-calorie meals that help control glucose and insulin levels. Published and soon-to-be-published studies indicate that the CR Way approach to calorie restriction activates genes, associated with longer life and reduced disease risk.8,36
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
- Available at: http://ghr.nlm.nih.gov/handbook/howgeneswork?show=all. Accessed November 13, 2013.
- Cabarcas SM, Hurt EM, Farrar WL. Defining the molecular nexus of cancer, type 2 diabetes and cardiovascular disease. Curr Mol Med. 2010 Nov;10(8):744-55.
- Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J Med. 2013; 369:540-8.
- Yamaza H, Chiba T, Higami Y, Shimokawa I. Lifespan extension by caloric restriction: an aspect of energy metabolism. Microsc Res Tech. 2002 Nov 15;59(4):325-30.
- Niculescu MD, Lupu DS. Nutritional influence on epigenetics and effects on longevity. Curr Opin Clin Nutr Metab Care. 2011 Jan;14(1):35-40.
- Mathers JC, Strathdee G, Relton CL. Induction of epigenetic alterations by dietary and other environmental factors. Adv Genet. 2010;71:3-39.
- Fontana L, Meyer TE, Klein S, HolloszyJO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci U S A. 2004 Apr 7; 101(17):6659-63.
- Mercken EM, de Cabo R, Fontana L, et al.Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile. Aging Cell. 2013 Aug;12(4):645-51.
- Gowthamarajan K, Kulkarni GT. Oral insulin - fact or fiction? Possibilities of achieving oral delivery for insulin. Resonance. May 2003: 36-46.
- Cooper ME, El-Osta A. Epigenetics: mechanisms and implications for diabetic complications. Circ Res. 2010 Dec 10;107(12):1403-13.
- Brasacchio D, Okabe J, Tikellis C, et al. Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes. 2009 May;58(5):1229-36.
- Andrali SS, Sampley ML, Vanderford NL, Ozcan S. Glucose regulation of insulin gene expression in pancreatic beta-cells. Biochem J. 2008 Oct 1;415(1):1-10.
- Chin Chen, Eric Sibley, Expression profiling identifies novel gene targets and functions for Pdx1 in the duodenum of mature mice. Am J Physiol Gastrointest Liver Physiol. 2012 February; 302(4): G407–19.
- Available at: http://www.ncbi.nlm.nih.gov/gene/4760. Accessed November 14, 2013.
- Shilpa K, Dinesh T, Lakshmi BS. An in vitro model to probe the regulation of adipocyte differentiation under hyperglycemia. Diabetes Metab J. 2013 Jun;37(3):176-80.
- Delafontaine P, Song YH, Li Y. Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels. Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):435-44.
- Kaaks R. Nutrition, insulin, IGF-1 metabolism and cancer risk: a summary of epidemiological evidence. Novartis Found Symp. 2004;262:247-60; discussion 260-8.
- Anversa P. Aging and longevity: the IGF-1 enigma. Circ Res. 2005 Sep 2;97(5):411-4.
- van Heemst D. Insulin, IGF-1 and longevity. Aging Dis. 2010 October; 1(2): 147–57.
- Shin DJ, Joshi P, Hong SH, Mosure K, Shin DG, Osborne TF. Genome-wide analysis of FoxO1 binding in hepatic chromatin: potential involvement of FoxO1 in linking retinoid signaling to hepatic gluconeogenesis. Nucleic Acids Res. 2012 Dec;40(22):11499-509.
- Burgering BM, Medema RH. Decisions on life and death: FoxO Forkhead transcription factors are in command when PKB / AKT is off duty. J Leukoc Biol . 2003 Jun;73(6):689-701.
- Calnan DR, Brunet A.The FoxO code. Oncogene. 2008 Apr 7;27(16):2276-88.
- Anselmi CV, Malovini A, Roncarati R, et al. Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuvenation Res. 2009 Apr;12(2):95-104.
- Gómez LA, Hagen TM. Age-related decline in mitochondrial bioenergetics: does supercomplex destabilization determine lower oxidative capacity and higher superoxide production? Semin Cell Dev Biol. 2012 Sep;23(7):758-67.
- Peserico A, Chiacchiera F, Grossi V, Matrone A, Latorre D, et al. A novel AMPK-dependent FoxO3A-SIRT3 intramitochondrial complex sensing glucose levels. Cell Mol Life Sci. 2013 Jun;70(11):2015-29.
- Someya S, Yu W, Hallows WC, et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell. 2010 Nov 24;143(5):802-12.
- Kong X, Wang R, Xue Y, et al. Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS One. 2010 Jul 22;5(7):e11707.
- Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011 Sep 2;13(9):1016-23.
- Dang CV. Links between metabolism and cancer. Genes Dev. 2012 May 1;26(9):877-90.
- Yuanyuan Li, Liang Liu, Trygve O. Tollefsbo. Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression. FASEB. 2010 May;24(5):1442-53.
- Bakaysa SL, Mucci LA, Slagboom PE, et al. Telomere length predicts survival independent of genetic influences. Aging Cell. 2007 Oct;6(5):709-13.
- Ahmed S, Passos JF, Birket MJ, et al. Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. J Cell Sci. 2008 Apr 1;121(Pt 7):1046-53.
- Available at: http://www.who.int/features/factfiles/dementia/dementia_facts/en/index.html. Accessed November 14, 2013.
- Pavlopoulos E, Jones S, Kandel ER, et al. Molecular mechanism for age-related memory loss: the histone-binding protein RbAp48. Sci Transl Med. 2013 Aug 28;5(200):200ra115.
- Kerti L, Witte AV, Winkler A, Grittner U, Rujescu D, Flöel A. Higher glucose levels associated with lower memory and reduced hippocampal microstructure. Neurology. 2013 Nov 12;81(20):1746-52.
- Mercken EM, Majounie E, Ding J, et al. Age-associated miRNA alterations in skeletal muscle from Rhesus Monkeys reversed by caloric restriction. Aging (Albany NY). 2013 Sep;5(9):692-703.