Life Extension Magazine®

Woman making low-calorie meal for the CR Way lifestyle to control glucose and insulin levels

How Glucose Mediates Life And Death By Turning Genes On And Off

The CR Way is a lifestyle that emphasizes delicious, low-calorie meals designed to help control glucose and insulin levels. Studies now indicate that the CR Way approach to calorie restriction activates genes that are specifically associated with longevity.

Scientifically reviewed by: Dr. Crystal M. Gossard, DCN, CNS, LDN, in August 2023. Written by: Paul McGlothin and Meredith Averill.

William Faloon
Paul McGlothin and Meredith
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

Glycogen Generation and Storage, Fat Storage
Cell Division and Growth and Sometimes Cancer

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

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


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

What You Need To Know
Glucose And Your Genes

Glucose And Your Genes

  • Genes exert powerful control over how cells function and when those functions are carried out.
  • Some genetic activity can be altered beneficially by diet and lifestyle.
  • 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.
  • Genetic and other insulin-regulating signals can be turned “down or off” when exposed chronically to high glucose levels.
  • Low blood glucose provides the benefit of activating hTERT (human telomerase reverse transcriptase) an enzyme that keeps telomeres from shortening when cells divide.
  • Maintaining low glucose levels has been shown to extend the life span of healthy cells.

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

The CR Way to Great Glucose Control Helps Lower Glucose Naturally
The CR Way to Great Glucose Control Helps Lower Glucose Naturally

Offered in partnership with the Life Extension Foundation®, this adult education course features foods, recipes, and unique meal plans that provide glucose guidance for every hour of your day, giving you lots of opportunities to lower your glucose. It includes two friendly classes via live teleconference with Paul McGlothin, Meredith Averill, and others who share your passion for healthful living.

To find out more about The CR Way To Great Glucose Control Program and The CR Way Optimal Health Membership, please visit

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® Wellness Specialist at 1-866-864-3027.


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