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Calorie Restriction Mimetic number 1: Metformin
One of the most important CRM's is the anti-diabetic drug metformin, which modulates insulin action. In order to reduce blood glucose, insulin has to be produced in sufficient amounts, but it also has to bind to insulin receptors on the cells in the body. Aging causes an increased difficulty in the smooth operation of this process, and there is a situation whereby insulin cannot effectively bind to the receptors, therefore it does not perform its duties properly. This is called 'increased peripheral resistance' to insulin, and it is a cardinal sign in diabetes and aging. Drugs which help mitigate this problem have existed for several years, and new ones are being studied at present.
Metformin (brand name Metforal®), is a drug which has been in use for over 40 years against diabetes. It is considered to be a receptor sensitizer, because it enhances the sensitivity of insulin receptors on the surface of muscle and fat cells (12). In addition, it also increases the actual numbers of receptors. While other anti-diabetic drugs stimulate the pancreas to produce more insulin, metformin only increases the sensitivity to insulin and does not influence its secretion. The upside of this, is that metformin does not usually cause insulin-dependant hypoglycaemia. When the insulin receptors are as sensitive to insulin as possible, the levels of circulating glucose falls, fat metabolism becomes more balanced and the weight of the patient is reduced (13). Apart from being a receptor sensitizer, metformin also reduces glucogenesis, (glucose production by the liver) and inhibits excessive absorption of glucose by the gut, (14) thus contributing to the overall glucose-lowering effect.
Specifically, French researchers from the Laboratory of Endocrinology, Metabolism and Development in Paris, have confirmed that metformin is able to activate genes which reduce the production of glucose by the liver, thus reducing the risk of glycosylation and other age-related damage. Chemical agents such as lactate, pyruvate, alanine and galactose can be used by the liver to create new molecules of glucose. Metformin can alter the expression of genes which make this conversion possible, thus reducing glucose concentration as a whole and, especially, reducing the concentration of toxic by-products of glucose. In addition, metformin can reduce the gene expression for enzymes which increase oxidation of fatty acids. These enzymes, (such as palmitoyltransferase I) contribute to the oxidation of fats resulting in cell membrane disruption and eventual cell death. But the formation of these enzymes is blocked by metformin which ultimately saves the cell from an untimely death. At the same time, genes which encode for proteins that modulate glycolysis, (destruction of glucose) are activated by metformin.
In the French experiment, expression of genes encoding for glucokinase and liver-type pyruvate kinase, (two enzymes which are involved in glycolysis) was increased by 250% following treatment with metformin (15). It is worth remembering that CR also results in modulation of genes, (16) which affect glucose formation in the liver (high when needed, and low when not needed), influence glycolysis (i.e. glucose elimination, which is high when energy is needed by the rest of the body, and low when not needed), containment of the glycolysis by-products which may contribute to glycosylation, and reduction of tissue levels of AGEs, as well as a reduction in fatty acid oxidation, all of which correspond to the same actions of metformin genetic effects. Therefore, the case for metformin being a CRM is strengthened further.
As mentioned above, using GeneChips is a quick way to test the status of several thousand genes which may affect aging. In an experiment, scientists tested (on mice) four compounds known to affect glucose metabolism. They tested the status of 12422 genes and found that metformin was twice as effective as the other compounds in mimicking the effects of CR. It affected a total of 63 genes, particularly those involved in energy production, protein formation and degradation, cell growth, and detoxification (17).
Metformin works along several different pathways, in order to control glucose activities, modulate insulin action and reduce cell death, eventually increasing life-span. But metformin does not always operate directly via glucose and insulin modulating pathways. It has many other 'glucose-independent' activities. With reference to Hormesis, (see footnote 1) metformin is able to modulate the stress response, in other words, it takes part in adjusting the cellular activities following mild stress. A specific biochemical pathway is through activation of AMPK. This is a protein kinase (an enzyme) which is normally active within the cell following multiple stresses. AMPK stands for 'Adenosine Mono Phosphate- activated protein Kinase', and is, as the name suggests, activated by Adenosine Mono Phosphate (AMP), an energy-rich molecule (18). Normally AMPK is switched on by stresses such as hypoxia (low oxygen), glucose deprivation, ischaemia or muscle contractions (which increase the energy demands). Once activated, AMPK initiates biochemical activities which prevent and repair cell damage, by leading to a sudden bout of energy production and by switching off any energy-demanding processes which are not directly essential for the survival of the organism. For example, it blocks the long-term production of complex proteins, lipids and carbohydrates which are not needed for the immediate survival of the cell, i.e. it behaves as if the body is in 'survival mode.' (But when the presence of these proteins/lipids/carbohydrates becomes essential at a later stage, when the emergency is over, then other mechanisms take over to start creating them again at the right amounts and concentrations so that to keep the cells multiplying again). This is exactly what happens during CR when the body is in 'survival mode' and when the nutritional stress of low a calorie diet activates pathways which increase cell repair.
Metformin, and another anti-diabetic drug rosiglitazone were shown to activate AMPK (whereas insulin blocks AMPK) and, as a result, glucose metabolism and cell repair are kept in balance. This is important because a healthy AMPK status reflects an optimal heart function (19). It was also suggested that, by keeping AMPK active, metformin contributes to the beneficial effects of exercise seen in the treatment of diabetes (20). In addition, when metformin activates AMPK in the liver, the production of enzymes which help form new lipid molecules is reduced (21). In other words, metformin through the AMPK process blocks the accumulation of fat.
Summary of AMPK
CR causes a mild nutritional stress with low energy available to the cells. This stressful event activates AMPK which aims to rebalance the process of energy formation, and repairs any cell damage, (including any coincidental age-related cell damage) while switching off any processes not necessary for immediate survival. Therefore, the cell survives and the organism ultimately lives longer. Metformin, being a mimetic of CR, results in the same effect by directly activating AMPK which confers the above benefits to cell repair. The main point here is that it may not be necessary to have to undergo a period of CR to achieve cell repair, when metformin can do this itself by working on the same mechanisms as those involved in CR.
Metformin use
Patients with significant kidney or liver disease, or those with heart failure should avoid taking it. Common and mild side effects are nausea, vomiting or abdominal bloating. The normal anti-diabetic dosage for metformin is 500 mg twice a day, or 850 mg daily. This can be increased as necessary to a maximum of 3000 mg a day. However, the dose required for calorie restriction mimetic effects has not been calculated formally. In mice, a dose of 300 mg/kg/day has been shown to reduce body temperature (a CR mimetic effect). But this cannot be extrapolated to humans, as it will mean 21000 mg for an average male. Further research is needed to clarify this point. Healthy people who take metformin for its general anti-ageing benefits use 500 mg twice a day.
It is important to keep an eye on the blood biochemistry during metformin treatment. Tests commonly performed are fasting glucose and lipid status, liver and kidney function and haemoglobin A1c which is a glycosylated haemoglobin indicating the effectiveness of glucose control in the body. A low A1c means that the level of glucose (and therefore, indirectly, the level of glycosylation damage) in the body is well-controlled. Normal levels are those below the value of 5%. People who drink alcohol excessively should avoid metformin, or at least take it only under expert medical supervision.
One of the most important CRM's is the anti-diabetic drug metformin, which modulates insulin action. In order to reduce blood glucose, insulin has to be produced in sufficient amounts, but it also has to bind to insulin receptors on the cells in the body. Aging causes an increased difficulty in the smooth operation of this process, and there is a situation whereby insulin cannot effectively bind to the receptors, therefore it does not perform its duties properly. This is called 'increased peripheral resistance' to insulin, and it is a cardinal sign in diabetes and aging. Drugs which help mitigate this problem have existed for several years, and new ones are being studied at present.
Metformin (brand name Metforal®), is a drug which has been in use for over 40 years against diabetes. It is considered to be a receptor sensitizer, because it enhances the sensitivity of insulin receptors on the surface of muscle and fat cells (12). In addition, it also increases the actual numbers of receptors. While other anti-diabetic drugs stimulate the pancreas to produce more insulin, metformin only increases the sensitivity to insulin and does not influence its secretion. The upside of this, is that metformin does not usually cause insulin-dependant hypoglycaemia. When the insulin receptors are as sensitive to insulin as possible, the levels of circulating glucose falls, fat metabolism becomes more balanced and the weight of the patient is reduced (13). Apart from being a receptor sensitizer, metformin also reduces glucogenesis, (glucose production by the liver) and inhibits excessive absorption of glucose by the gut, (14) thus contributing to the overall glucose-lowering effect.
Specifically, French researchers from the Laboratory of Endocrinology, Metabolism and Development in Paris, have confirmed that metformin is able to activate genes which reduce the production of glucose by the liver, thus reducing the risk of glycosylation and other age-related damage. Chemical agents such as lactate, pyruvate, alanine and galactose can be used by the liver to create new molecules of glucose. Metformin can alter the expression of genes which make this conversion possible, thus reducing glucose concentration as a whole and, especially, reducing the concentration of toxic by-products of glucose. In addition, metformin can reduce the gene expression for enzymes which increase oxidation of fatty acids. These enzymes, (such as palmitoyltransferase I) contribute to the oxidation of fats resulting in cell membrane disruption and eventual cell death. But the formation of these enzymes is blocked by metformin which ultimately saves the cell from an untimely death. At the same time, genes which encode for proteins that modulate glycolysis, (destruction of glucose) are activated by metformin.
In the French experiment, expression of genes encoding for glucokinase and liver-type pyruvate kinase, (two enzymes which are involved in glycolysis) was increased by 250% following treatment with metformin (15). It is worth remembering that CR also results in modulation of genes, (16) which affect glucose formation in the liver (high when needed, and low when not needed), influence glycolysis (i.e. glucose elimination, which is high when energy is needed by the rest of the body, and low when not needed), containment of the glycolysis by-products which may contribute to glycosylation, and reduction of tissue levels of AGEs, as well as a reduction in fatty acid oxidation, all of which correspond to the same actions of metformin genetic effects. Therefore, the case for metformin being a CRM is strengthened further.
As mentioned above, using GeneChips is a quick way to test the status of several thousand genes which may affect aging. In an experiment, scientists tested (on mice) four compounds known to affect glucose metabolism. They tested the status of 12422 genes and found that metformin was twice as effective as the other compounds in mimicking the effects of CR. It affected a total of 63 genes, particularly those involved in energy production, protein formation and degradation, cell growth, and detoxification (17).
Metformin works along several different pathways, in order to control glucose activities, modulate insulin action and reduce cell death, eventually increasing life-span. But metformin does not always operate directly via glucose and insulin modulating pathways. It has many other 'glucose-independent' activities. With reference to Hormesis, (see footnote 1) metformin is able to modulate the stress response, in other words, it takes part in adjusting the cellular activities following mild stress. A specific biochemical pathway is through activation of AMPK. This is a protein kinase (an enzyme) which is normally active within the cell following multiple stresses. AMPK stands for 'Adenosine Mono Phosphate- activated protein Kinase', and is, as the name suggests, activated by Adenosine Mono Phosphate (AMP), an energy-rich molecule (18). Normally AMPK is switched on by stresses such as hypoxia (low oxygen), glucose deprivation, ischaemia or muscle contractions (which increase the energy demands). Once activated, AMPK initiates biochemical activities which prevent and repair cell damage, by leading to a sudden bout of energy production and by switching off any energy-demanding processes which are not directly essential for the survival of the organism. For example, it blocks the long-term production of complex proteins, lipids and carbohydrates which are not needed for the immediate survival of the cell, i.e. it behaves as if the body is in 'survival mode.' (But when the presence of these proteins/lipids/carbohydrates becomes essential at a later stage, when the emergency is over, then other mechanisms take over to start creating them again at the right amounts and concentrations so that to keep the cells multiplying again). This is exactly what happens during CR when the body is in 'survival mode' and when the nutritional stress of low a calorie diet activates pathways which increase cell repair.
Metformin, and another anti-diabetic drug rosiglitazone were shown to activate AMPK (whereas insulin blocks AMPK) and, as a result, glucose metabolism and cell repair are kept in balance. This is important because a healthy AMPK status reflects an optimal heart function (19). It was also suggested that, by keeping AMPK active, metformin contributes to the beneficial effects of exercise seen in the treatment of diabetes (20). In addition, when metformin activates AMPK in the liver, the production of enzymes which help form new lipid molecules is reduced (21). In other words, metformin through the AMPK process blocks the accumulation of fat.
Summary of AMPK
CR causes a mild nutritional stress with low energy available to the cells. This stressful event activates AMPK which aims to rebalance the process of energy formation, and repairs any cell damage, (including any coincidental age-related cell damage) while switching off any processes not necessary for immediate survival. Therefore, the cell survives and the organism ultimately lives longer. Metformin, being a mimetic of CR, results in the same effect by directly activating AMPK which confers the above benefits to cell repair. The main point here is that it may not be necessary to have to undergo a period of CR to achieve cell repair, when metformin can do this itself by working on the same mechanisms as those involved in CR.
Metformin use
Patients with significant kidney or liver disease, or those with heart failure should avoid taking it. Common and mild side effects are nausea, vomiting or abdominal bloating. The normal anti-diabetic dosage for metformin is 500 mg twice a day, or 850 mg daily. This can be increased as necessary to a maximum of 3000 mg a day. However, the dose required for calorie restriction mimetic effects has not been calculated formally. In mice, a dose of 300 mg/kg/day has been shown to reduce body temperature (a CR mimetic effect). But this cannot be extrapolated to humans, as it will mean 21000 mg for an average male. Further research is needed to clarify this point. Healthy people who take metformin for its general anti-ageing benefits use 500 mg twice a day.
It is important to keep an eye on the blood biochemistry during metformin treatment. Tests commonly performed are fasting glucose and lipid status, liver and kidney function and haemoglobin A1c which is a glycosylated haemoglobin indicating the effectiveness of glucose control in the body. A low A1c means that the level of glucose (and therefore, indirectly, the level of glycosylation damage) in the body is well-controlled. Normal levels are those below the value of 5%. People who drink alcohol excessively should avoid metformin, or at least take it only under expert medical supervision.
