Juvenon Health Journal volume 3 number 8 august 2004
By Benjamin V. Treadwell, Ph.D.
Recent studies have demonstrated an association between impaired mitochondria (the power plants inside our cells) and dementia, such as is characteristic of patients with Alzheimer’s Disease (AD). Furthermore, there appears to be an increased incidence of Alzheimer’s in patients with type 2 diabetes, and evidence indicates that the mitochondria may play a role in this connection.
Why should type 2 diabetics, who suffer from a disease characterized by high blood glucose and impaired insulin regulation, have an increased incidence of dementia?
Obesity is associated with type 2 diabetes (a disease more prevalent as we age), and as described below an additional risk factor for dementia. It appears the hormone insulin, and another related growth factor, IGF-1, block an enzyme involved in saving an injured cell from death. This enzyme was first isolated from yeast, and now has been demonstrated to be present in mammals including humans. The enzyme is a member of a family of related enzymes with different jobs to perform in the cell. For simplicity, only one member will be discussed below. This enzyme is known as SIRT1 in humans (silent information regulator T1).
SIRT1 (SILENT INFORMATION REGULATOR T1)
SIRT1 appears to be the connection between, obesity, insulin, IGF-1, and cell death. One can envision SIRT1 as the protagonist in cellular health, and the preceding three of the antagonists. Evidence indicates that when a cell is injured, as from a free radical attack, a message is sent to other parts of the cell that ultimately determines whether the cell should be destroyed, and discarded, or repaired. SIRT1 normally channels the cell toward a repair pathway, and thus saves its life. Insulin, on the other hand, promotes fat synthesis by increasing the size of the individual fat cell. Large fat cells, in turn, churn out hormones and inflammatory cytokines that have detrimental effects on the tissues of the body. They act to stimulate inflammation of tissues and the production of destructive oxidants, or free radicals. Finally, the large fat cell-stimulated production of free radicals injures cells and activates a self-destruction or a suicidal pathway.
SIRT1 seems almost too good to be real! It has been shown in cell-culture studies to have a number of interesting properties. Two of them help the cell avoid the death trap described above.
First, SIRT1 acts to inhibit the insulin-IGF-1-promoted fat synthesis pathway and to stimulate fat release from fat tissue. It appears that SIRT1 stimulates fat metabolism (the burning of fat for energy) and depletes the age-associated accumulation of bloated fat-cells that is common to diabetic patients.
Second, if the cell is injured by a free radical, and the injury sets in motion the built-in cell-suicide pathway, SIRT1 puts up a roadblock. It turns out that one key protein in the cell cytoplasm (bax) moves into the mitochondria when it is acetylated and sets in motion the cell-suicide pathway. However, if SIRT1 gets to acetylated bax immediately to remove its acetyl group, bax is once again immobilized in the cytoplasm…and the cell survives!
OK, I do realize the above is a bit confusing; let me summarize it as follows:
High intake of food increases the production of insulin, which in turn increases the production of fat tissue, a condition associated with type 2 diabetes. Large bloated fat cells, the product of increased fat synthesis, in turn activate the synthesis of hormones and inflammatory cytokines. Inflamed tissue spews out oxidants, such as free radicals, which, in turn, damage cells, and set in motion a specific cell-suicide pathway (bax gets acetylated). If SIRT1 is present, it can deacetylate bax and block the pathway.
What is the basis for the AD-Type II diabetes connection?
The propensity to develop diabetes increases with age. It is associated with an increase in a specific type of fat, that which forms around our organs and is known as white adipose fat (as opposed to the healthier subcutaneous fat that in fact decreases as we age). Because elevated blood insulin promotes inflammation, it is no surprise that several adverse complications result, such as atherosclerosis and heart disease. Experimental evidence indicates that inflammation may be a factor promoting AD. This may be one of the reasons for the apparent increased incidence of this disease in patients with diabetes.
How can we increase levels of SIRT1 in our cells?
Fortunately, the two opposing pathways, the cell-death pathway and the SIRT1 pathway, can be adjusted or optimized for a happy long life. By keeping the intake of calories to a reasonable level, one can lower the blood level of insulin-IGF-1, and raise that of SIRT1. One sure method to maximize SIRT1 is through caloric restriction, or the consumption of food high in nutrients but minimal in calories—eating enough to just maintain a minimum healthy weight.
There are other potential methods to improve the synthesis of SIRT1. The compoundresveratrol, present in red wine, has been shown to be a potent stimulator of SIRT1, and has been shown to activate its activity in yeast, in mammals, and more recently in human cells in culture. There is also evidence that SIRT1 may be involved in prolonging life.
The cumulative effect of cell loss over time is thought to be an important contributor to aging. At the same time,caloric restriction has been shown to increase lifespan. The relationship between cell loss and caloric restriction has therefore piqued the interest of scientists. A recent research study explored this topic and spells out the work of silent information regulators in the detailed biochemical mechanisms at work in this process. For technical details on the results of this research, visit ScienceMagazine.
“Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase.”
Science 16 July 2004: 390-392.
This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.
Dr. Treadwell answers your questions about Juvenon™ Cellular Health Supplement
QUESTION: Does the Juvenon team have an answer for why the body produces less of the chemicals contained in Juvenon as it ages? Could there possibly be some positive benefit in having less of these chemicals?
B.E., via email
ANSWER: Our research indicates that these compounds decrease in concentration in the tissues of our body as a result of impaired synthesis. The enzymes involved in their synthesis are not as active in old cells.
We have shown in animal studies that increasing the concentration of these two components by supplementing their diets improves cellular health. It also improves the mental acuity (as determined by a water maze test) and physical energy of the animals.
To date we have not seen any negative effect from the compounds contained in the Juvenon™ Cellular Health Supplement when given to humans, animals and cell culture studies.
Benjamin V. Treadwell, Ph.D., is a former Harvard Medical School associate professor and member of Juvenon’s Scientific Advisory Board.