|LE Magazine June 2003|
BioMarker Pharmaceuticals Develops
By Saul Kent, Director, Life Extension Foundation
Anti-cancer mechanisms induced by CR
BioMarker has found changes in gene expression in CR mice that suggest several anti-cancer mechanisms induced by CR. One is the reduction of endoplasmic reticulum chaperone gene levels. Most proteins require the action of chaperone genes for biosynthesis, maturation, processing, transport and degradation. Chaperones are involved in the building (folding) and repair (refolding) of proteins, which helps to maintain the integrity of cells that counter the damage caused by heat, oxidative, ischemic and inflammatory stress.
|Fig. 3. Representation of the results of longevity studies conducted by BioMarker. The black line shows the life span of control mice who consumed a normal number of calories. The red line shows the life span of mice subjected to caloric restriction starting in old age. The blue line shows the life span of mice subjected to caloric restriction, starting very early in life. A major finding is that CR extended the remaining life span by the same proportion in both experimental groups.|
However, elevated chaperone expression, which occurs during aging, decreases apoptosis, a key mechanism that causes aberrant cells to self-destruct (commit suicide). There is evidence that chaperones increase the secretion of proteins that inhibit apoptosis and reduce apoptotic responsiveness to stress.[15,16] Apoptosis plays an important role in getting rid of cancer cells and other aberrant cells, including cells injured during the aging process. In every tissue, a balance must be struck between the need to maintain cell number and function, and the need to eliminate damaged, potentially toxic cells, including cancer cells. CR reduces chaperone levels in mouse liver, which increases apoptosis. This may be one of the reasons CR prevents cancer in organs such as the liver, which feature dividing cells. In contrast, in non-dividing cells, such as neurons, CR appears to induce chaperone expression, which enhances cell survival and may delay the onset of neurologic disorders of aging, including Alzheimer's disease, Parkinson's disease and stroke.
Is Growth Hormone an
Anti-Aging or Pro-Aging Therapy?
Growth hormone (GH) and growth-hormone-releasing agents have been actively promoted as anti-aging therapies. Release of GH from the pituitary declines with advancing age and reduced levels of GH (and IGF-1) almost certainly contribute to age-related loss of muscle mass, increase of body fat, loss of bone minerals and impairment of cognitive function.
These declines in function can be reduced or reversed by GH therapy. The use of GH in anti-aging medicine is further supported by evidence that, in GH-deficient individuals, treatment with GH has a positive effect on several measures of psychological well-being and the quality of life.
On the other hand, there is considerable evidence that excess GH can contribute to age-related diseases and shorten life span, and that life span-extending models such as caloric restriction (CR) and dwarfism triggered by gene mutation cause a decline in GH levels. These findings suggest that GH therapy might have pro-aging effects.
The apparently opposite effects of GH on aging and diseases are not necessarily conflicting because they refer to different actions of GH and to different stages of life. The anti-aging actions of GH refer to its effects on body composition and function in elderly persons, rather than its role in determining life expectancy. The anti-aging effects of GH therapy are typically observed after short-term treatment in GH-deficient subjects, however there is evidence that chronically elevated GH levels increase the incidence of cancer, cardiovascular disease, diabetes and kidney disease.
It may be that short-term administration of GH in aging GH-deficient patients can effectively rejuvenate them, while GH given to persons with normal or above-normal GH levels has negative effects, including, perhaps, shortened life span. It’s also possible that restoring other age-related hormone deficiencies in addition to GH can produce beneficial effects on health and longevity, while long-term administration of GH alone has deleterious effects. Clearly, further research is needed. BioMarker Pharmaceuticals will be exploring these critical issues by assessing the effects on gene expression in animals and humans receiving growth hormone (and other hormone) therapies.
Other anti-disease mechanisms induced by CR
Another mechanism linked to cancer and other diseases associated with aging is inflammation. Researchers have found changes in gene expression linked to the development of age related pathologies in the liver, muscle and brain.[12, 21, 22] BioMarker's gene chip studies in mouse liver have found that aging is associated with other gene expression changes consistent with disease processes. The company found several gene expression changes involved in inflammation, which increases with advancing age, and has been associated with the development of several chronic diseases. BioMarker found that caloric restriction suppressed the age-related increase in inflammatory and stress response genes, which may be another reason for the ability of CR to prevent cancer and diminish the severity of autoimmune and inflammatory diseases in mice.
The liver is one of the primary organs involved in metabolizing, detoxifying and excreting potentially damaging chemicals and drugs. A decline in these functions in the liver has been found in aging mice, rats, monkeys and humans. For example, cytochrome P450 activity, which plays a major role in the detoxification process, decreases 30% in humans after 70 years of age. In rodents, there is compelling evidence for a decline in similar critical enzyme activities.
In the BioMarker studies, aging decreased the expression of xenobiotic metabolism genes. This finding is likely responsible in part for the age-related decline in the metabolizing capacity of the liver, which is a recognized source of adverse drug reactions in aging mammals and may contribute to the increase in cancer with age in mice. Both short-term and long-term caloric restriction reversed the decrease in the expression of these genes, which may be another reason for the anti-cancer and anti-aging effects of CR.
The liver plays a major role in maintaining glucose (blood sugar) homeostasis, which is controlled by hormones such as insulin, glucagon, growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Elevated levels of glucose and insulin are implicated in many age-related diseases, such as type 2 diabetes, hypertension, heart disease and stroke, and are a hallmark of mammalian aging.
Caloric restriction reduces blood glucose and insulin levels in rodents, monkeys and humans.[6,27,28] Diseases associated with elevated glucose are reduced or eliminated entirely by CR. BioMarker's gene chip studies showed that the expression of genes associated with glucose and insulin were shifted to a more youthful profile. This result is consistent with the finding that CR mice are four times more insulin sensitive than normally-fed mice.
The most valuable breakthrough
The most valuable breakthrough made by BioMarker is the finding that a majority of the changes in gene expression caused by long-term CR (over two years) occur (in the liver) in only two to four weeks after placing mice on a CR diet. Traditionally, scientists have regarded CR as a slow process that incrementally prevents the accumulation of deleterious age-related changes in physiology and gene expression.
BioMarker's finding that short-term CR rapidly shifts the gene expression profile of mice toward that of longterm CR is a profound paradigm changer. It introduces for the first time the idea that drugs can be rapidly assayed for their ability to mimic the anti-aging, anti-disease, life span-extending effects of long-term CR. Previously, it was thought that the drugs would have to be administered over an animal's lifetime to produce evidence that they can slow or reverse aging. Now, with the use of BioMarker's proprietary technology, it is possible to screen for anti-aging drugs in a matter of weeks.
BioMarker's use of high-density microarrays, which measure the expression levels of thousands of genes at a time makes it possible to conduct the screening process for anti-aging drugs 25 times faster than any other technique currently available. The ability to measure the expression of thousands of genes at a time generates a huge amount of data per experiment.
This makes it possible to obtain enormous insights into aging and longevity with a few mice per drug in less than a month.
Rejuvenating the elderly
BioMarker's finding that CR can produce anti-aging, anti-disease and life span-extending effects in old mice just as it can in young mice means that anti-aging drugs discovered with its technology should be effective in old people as well as young and middle-aged people. It gives the elderly hope for a longer, healthier life span, even if they are highly advanced in age.
BioMarker's research suggests it is possible that the ability of CR to extend life span in old animals occurs because it may be able to reverse aging and rejuvenate the elderly, not just slow down the aging process. If this is so, then drugs that mimic the effects of CR should be able to achieve both these objectives. This is of critical importance not just for the elderly, but for anyone over age 30, who has already begun to experience the degenerative effects of aging.
Quick screening for anti-aging drugs
The ability to screen for anti-aging drugs quickly and inexpensively is an enormous breakthrough. Pharmaceutical companies spend billions of dollars in their efforts to improve upon the largely inadequate therapies currently available for cancer, heart disease, stroke, Alzheimer's disease and other killers. They usually have to conduct lengthy, highly expensive studies on thousands of drugs in order to find even one promising new drug candidate.
BioMarker can save these companies huge amounts of money and time with its unique technology. The company can help them discover new drugs to combat aging and degenerative disease, as well as new uses for already approved drugs. BioMarker has been in contact with several large pharmaceutical companies, which have expressed strong interest in forging strategic alliances with the company.
BioMarker has also embarked on its own research program to search for anti-aging drugs. The power of the company's revolutionary technology has already been demonstrated in its first series of experiments. Five drugs were evaluated for their ability to mimic the gene expression profile of CR in the liver of mice using Affymetrix gene chips. Four of the compounds tested were glucoregulatory agents that produce a marked reduction in blood glucose and insulin and enhance insulin sensitivity in tissues, as CR does. The fifth agent tested was a cancer chemopreventive agent.
The effects of the drugs were tested by feeding them to elderly mice as part of their diet. A normal control group and short-term CR and long-term CR groups were also included in the study. After a few months, the gene expression profiles of 12,422 genes were determined. The control group and the mice on long-term CR and short-term CR were compared to the drug treated groups to determine the extent to which the drugs reproduced the effects of CR. Gene expression changes were verified by quantitative PCR and Northern Blot analysis.
Metformin stands out from the pack
|Fig. 4. The ability of drugs to mimic the gene expression effects of caloric restriction. BioMarker scientists found that metformin was most effective at reproducing the gene expression biomarkers of CR. Metformin's ability to do so is represented at 100% by the lowest bar in the chart, with the other drugs represented according to their lesser ability to mimic CR relative to metformin.|
The BioMarker scientists found that all the glucoregulatory agents reproduced some of the gene expression effects of CR, but that metformin was the undisputed star of the group, being twice as effective as the others in reproducing the effects of CR. The chemopreventive agent reproduced almost none of the effects of CR. Fig. 4 summarizes the gene expression changes. The overlap between the drug-induced gene expression profiles and those of CR is represented by the length of the colored bars.
The genes that were altered in expression by both metformin and CR are linked to drug metabolism and detoxification; energy metabolism; protein biosynthesis and degradation; cell growth and proliferation and the cytoskeleton. These findings suggest that metformin has more beneficial effects than the reduction of blood glucose and insulin, and that it may be an authentic anti-aging therapy.
Metformin extends life span
Further evidence that metformin is an anti-aging therapy is a study conducted by scientists at the National Institute on Aging (NIA) showing that metformin extended the life span of mice by 20%. The results of this study were presented in November 2002 at an NIA-sponsored meeting at the Mayan Ranch in Bandera, Texas. BioMarker is now conducting a life span study with metformin to see if the company can reproduce these results.
There have been no human studies to identify the optimal dose of metformin that is needed to duplicate the beneficial gene expression effects that are described in this article.
For people who want to derive the many proven health benefits of metformin, it might be prudent to follow the dosage schedule used by Type II diabetics. According to the Physician's Desk Reference, the starting dose should be 500 mg of metformin twice a day. (An alternative option is 850 mg of metformin once a day).
After one week, increase the dose of metformin to 1000 mg as the first dose of the day and 500 mg as the second dose. After another week, increase to 1000 mg of metformin two times a day. The maximum safe dose described in the Physician's Desk Reference is 2550 mg a day (which should be taken as 850 mg three times a day).
According to the Physician's Desk Reference, clinically significant responses in Type II diabetics are not seen at doses below 1500 mg a day of metformin. Anti-aging doctors, on the other hand, have recommended doses as low as 500 mg twice a day to healthy non-diabetics who are seeking to obtain metformin's other proven benefits such as enhancing insulin sensitivity and reducing excess levels of insulin, glucose, cholesterol and triglycerides in the blood.
It could be the dosage range is highly individualistic in healthy people, meaning some may benefit from 500 mg twice a day, while others may need 1000 mg twice a day for optimal effects. Blood tests to ascertain if the dose of metformin you are taking is improving glucose/insulin metabolism would be:
- Hemoglobin A1c
- Fasting insulin
- CBC/Chemistry panel that includes glucose, cholesterol
triglycerides and indicators of liver and kidney function
A hemoglobin A1c test measures the average amount of sugar in your blood over the last 3 months. Metformin helps lower hemoglobin A1C to safe low levels (below 5-6%).
Aging and overweight people often suffer from metabolic disorders that manifest in the blood as excess serum insulin, glucose, cholesterol and triglycerides. Metformin often helps correct all of these metabolic disturbances that can lead to the development of numerous degenerative diseases. The CBC/Chemistry test provides readings on cholesterol, glucose and triglycerides and can also warn you of underlying liver-kidney impairment that would make you ineligible for metformin. The fasting insulin test indicates if metformin is adequately lowering levels of serum insulin to a safer range of below 5 (micro IU/ML).
Check back at the www.lef.org web site for dosage recommendation updates on metformin.
Precaution: There was a drug that was very similar to metformin, called phenformin, which was removed from the market by the FDA in 1976. Some physicians gave this drug to patients with kidney or liver problems, or congestive heart failure. Some of these patients died due to lactic acidosis build-up because a healthy kidney and liver were needed to metabolize the drug. It is not recommended that people who have liver or kidney problems, or congestive heart failure, use metformin due to the drug's similarities to phenformin. Those who drink excessive amounts of alcohol should not take metformin.
In the late 1970s, Dilman and Anisimov at the N.N. Petrov Research Institute of Oncology in Leningrad (now St. Petersburg), Russia found that the life-long administration (2 mg/day) of phenformin-a glucoregulatory drug similar to metformin that causes more side effects-increased the life span of female C3H/Sn mice by 23%, while reducing the incidence of mammary tumors and other cancers in these animals. The scientists proposed that phenformin delays the aging process, and that its effects may be similar to those caused by caloric restriction.
Finding key anti-aging gene changes
One of BioMarker's major challenges is to find which gene expression changes are the keys to the anti-aging, life span-extending effects of CR. The use of microarrays has given BioMarker a powerful tool to map the gene changes involved in extending life span, but further research is needed to pinpoint which gene changes are critical in the process. BioMarker scientists believe that there may be a few regulatory gene changes that trigger most of the other gene changes that occur after animals are placed on CR, and that these changes may be among the earliest changes caused by CR. The company is conducting research to find these key gene changes.
There is now significant scientific evidence that aging can be retarded and life span extended by manipulating a small number of genes. Studies in yeast, worms and flies have shown that silencing or overexpressing certain genes can double or even triple the maximum life span of these forms of life.
A single gene change extends life span in mice
Since the mid 1990s, studies have generated evidence that a single gene change can radically extend the life span of mice. First, it was shown by Andrzej Bartke of Southern Illinois University and others that adult Ames dwarf mice (which are one-third the weight of normal Ames mice) live much longer than their normal counterparts.[32,33] Then a comparable extension in life span was detected in Snell dwarf mice by Kevin Flurkey of The Jackson Laboratory in Bar Harbor, Maine and Richard A. Miller of the University of Michigan in Ann Arbor.[34,35] The life spans of these mice were extended by 40% to 70%!
These mouse models have a single mutation-at the Prop-1 locus in Ames dwarf mice and the Pit-1 locus in Snell dwarf mice-which interferes with anterior pituitary development, which causes deficiencies in growth hormone (GH), prolactin (PRL) and thyroid-stimulating hormone (TSH). It has been found that the deficiency of PRL is probably not involved in extending the life span of these mice, that the deficiency of TSH may be involved to a small degree, but that the deficiency of GH (and insulin-like growth factor-1, which is made in response to GH) may be a primary reason these mice live so much longer. One finding that suggests this is that mice who cannot respond to growth hormone because their GH receptor gene has been knocked out, live up to 55% longer than normal mice.
|Project Director, Senior Scientist Joseph Dhahbi, M.D., Ph.D. (left) and Stephen R. Spindler, Ph.D., Head of Technology of BioMarker discuss recent findings by the company.|
In addition to the radical extension of life span in these mice, there is other significant evidence that Ames and Snell dwarf mice age more slowly than normal mice. These include findings that there is no age-related decline in cognitive function in Ames dwarf mice; that the activity of two protective antioxidant enzymes (superoxide dismutase and catalase) in the liver, kidney and brain is higher-than-normal in Ames dwarf mice;[38,39] that Ames dwarf mice develop cancer later in life than normal; that plasma glucose and insulin levels are reduced and insulin sensitivity increased in both Ames and Snell dwarf mice; that Snell dwarf mice exhibit diminished osteoarthritis of the knee joint; and that long-lived dwarf mice retain youthful immune function and connective tissue elasticity as they grow older.
Dwarf mice as a model of extended life span
BioMarker is using dwarf mice as a second model of extended life span in its search for authentic anti-aging therapies. The company has been collaborating with Drs. Andrezej Bartke and Richard A. Miller to conduct microarray studies of gene expression in the tissues of dwarf mice in order to learn more about the genes involved in longevity.
|Fig. 5. Survival plots of Ames dwarf (DF) and normal (wild-type, WT) mice fed ad libitum (AL) or restricted to 70% of normal calorie intake (calorie restriction, CR). (Reproduced from Bartke A, Wright JC, Mattison JA, et al. Extending the life span of long-lived mice, Nature, 414:412, 22 Nov. 2001)|
The gene mutation in Ames and Snell dwarf mice is the only known way of producing anti-aging and life span extending effects comparable to caloric restriction. The dramatic life span extension effect (up to 70%) found in these animals makes it clear that, as in CR, we are dealing with a method of retarding the aging process. The fact that only a single genetic change can extend life span so radically in mammals is strong evidence that there may only be a few key genes involved in longevity.
There is also evidence that the life span extension found in dwarf mice is somewhat different than in CR. Recently, Bartke, Miller and others showed that Ames dwarf mice, which live 50% longer than normal Ames mice, had their life span extended another 25% by CR. The scientists divided 45, two-month-old Ames dwarf mice and 53 of their normal siblings into two groups, which were subjected either to CR (70% of normal food intake) or unrestricted feeding. These two groups were then followed until the animals were more than two years of age.
The CR mice had a maximum life span about 300 days longer than the unrestricted mice; the dwarf mice lived a bit longer than the CR mice; while the dwarf mice on CR lived about 500 days longer than the unrestricted mice. The survival curves in Fig. 5 show that, although both CR and dwarfism extended life span, CR reduced the rate of age-related mortality, while dwarfism shifted the age at which the age-dependent increase in mortality first became appreciable. Thus, CR appears to decelerate aging, while dwarfism appears to delay it. The scientists concluded that: "Our results indicate that long-lived Ames dwarf mice are not merely mimics of CR mice, and show that the pathways responsible for extending life span in the dwarf and CR animals are not identical."
BioMarker's preliminary gene chip results show that gene expression in the tissues of long-lived dwarf mice is similar in some respects as in the tissues of CR mice, but different in others. The company is investigating gene expression in the tissues of dwarf mice on CR. The availability of a second model of radical life extension in mammals will give BioMarker new tools in its quest to discover authentic anti-aging therapies that can also fight age-related diseases. If, as it appears, CR and dwarfism, are different in their mechanisms of action, the company will, eventually, develop anti-aging therapies that are more potent than CR mimetics alone.
Among the projects BioMarker is carrying out are the following:
1. Further research to explore the anti-aging, life span extending effects of metformin, including life span studies, studies to determine the optimal dosage and administration of the drug, the search for analogs of metformin that are more potent with fewer side effects, and the combining of metformin with other drugs.
2. Research to discover other promising anti-aging, antidisease therapies, with the same or other mechanisms of action than metformin.
3. Gene chip anti-aging research in mice, monkeys and humans. BioMarker has already started such research in monkeys and is formulating plans to do so in humans.
4. Research to pinpoint the critical anti-aging genes involved in prolonging health and extending life span.
5. Further research to determine the differences in gene expression in normal aging, delayed aging caused by CR and delayed aging caused by dwarfism, with the use of these findings to search for new and better anti-aging therapies.
6. Establishing research contracts with pharmaceutical and nutraceutical companies to test their compounds for effects on aging and age-related diseases.
7. Forming strategic alliances with major pharmaceutical companies to develop new anti-aging drugs and to discover new applications for existing drugs.
BioMarker Pharmaceuticals is the first company with a patented scientific method to measure the effects of drugs on aging in mammals (including humans). Its revolutionary technology is enabling its scientists to develop new breakthrough anti-aging therapies rapidly and inexpensively. Thus far, it has been funded exclusively by Life Extension.
For further information about BioMarker contact:
BioMarker Pharmaceuticals, Inc.,
900 East Hamilton Ave., Suite 100,
Campbell, California 95008.
Tel: 408-257-2000; Fax: 408-356-6661
Web Site: www.biomarkerinc.com
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