The Pain and the Spin Stops Here

By: Gerald A. Bruno Ph.D.

February 3, 2010

The following is an account of the commercial development of a totally different approach to dealing with the pain and stiffness associated with osteoarthritis (OA). When this story began, the only available options were trying the glucosamine/chondroitin supplements or opting for a surgical joint replacement. Ten years later, these are still the options promoted by mainstream medicine, along with periodic intra-articular injections of hyaluronic acid. As a result of my having to deal with the debilitating effects of OA, and the unattractiveness of the available options, a natural product has been developed and commercialized that offers a real alternative for people dealing with debilitating joint pain.

An Unwelcome Introduction and Intrusion

I was introduced to osteoarthritis about 10 years ago, when I was in my early 60’s. The introduction was subtle and forgettable, a slight stiffness in my right knee after playing a few games of racquetball. Within a few years, the slight stiffness progressed to extreme pain and stiffness after a single game. Not really understanding the nature of the problem and being optimistic that it was a temporary problem that I could “play through”, I succeeded in precipitating a major flare-up that had me on crutches and physical therapy 3 times per week. After an X-ray of my knee, I was told that there was essentially no cartilage between the bones in my knee, and I would have to live with debilitating pain and stiffness until I cried “uncle” and had my knee replaced.

Because of my stubborn nature, and a basic mistrust of medical advice, I continued to walk, run, and play racquetball with the aid of knee braces, routine icing, and occasional NSAID use. I was severely limited in my activities, including entering and exiting a car, and driving for more than 30 minutes without severe knee pain.

At about this time, I became involved with a startup nutraceutical company and had my first conscious exposure to dietary supplements and alternative medicine. The Dietary Supplement Health and Education Act (DSHEA) had been passed in 1994, and many enterprises were being established to capitalize on the rapid growth of this new industry. With a degree in pharmaceutical science and a 15-year stint in pharmaceutical industry research, I saw an opportunity to apply more rigorous scientific scrutiny to the natural substances that could be sold under DSHEA. Despite being well into retirement age, I decided to start a dietary supplement company (Ethical Alternative Products) that focused on natural substances with a strong scientific basis for their use in restoring a healthy balance.

Fish Oil and Rosehips: The Beginning of the Answer

As I immersed myself in the world of natural healing, the constant pain in my right knee served to heighten my attention to articles dealing with osteoarthritis. When I came across a reference that suggested a synergistic benefit to taking a combination of fish oil and rosehips, I immediately started taking these products, and after a few weeks I started to feel a reduction in pain and stiffness. Being sensitive to the possibility of a placebo effect, I shared the remedy with a few friends with knee pain, and they experienced the same improvement in symptoms.

The improvement in pain and stiffness are believed to result from the anti-inflammatory properties of the omega-3’s in fish oil, and the anti-inflammatory and anti-oxidative processes attributable to the vitamins, carotenoids and galactolipids in the rosehips. The apparent synergistic effects of fish oil and rosehips were not explained.

Improving on a Good Thing

Over the next few years, I continued taking fish oil and rosehips, and continued to see the beneficial effect on pain and stiffness in my knee. I also continued my search for other natural joint supplements, and found convincing scientific and clinical evidence that krill oil, collagen type II, and pine bark extract are beneficial in reducing joint pain and stiffness. I tested these substances individually and in various combinations, until a final combination containing the five ingredients was found that profoundly reduced the pain and stiffness symptoms. The biological properties of the krill oil, collagen type II, and pine bark extract were both overlapping and complementary to the actions of the fish oil and rosehips. These ingredients added substantial anti-inflammatory and anti-oxidative activity, and also introduced the lubricating properties of hyaluronic acid (BioCell Collagen Type II contains 10% HA) and the chondrocyte stimulating properties of type II collagen.

It was fully recognized that the sample size was small, but the elimination of pain and stiffness was so dramatic, that it was decided to evaluate formulation of these five substances in a single dose capsule.

Sharing the Answer

The decision to develop a commercial joint health product was based on a large amount of scientific data on the individual ingredients and a small amount of clinical data on the efficacy of these ingredients in combination. A commercial formulation was ultimately developed that allowed the five ingredients to be filled into a single softgel capsule. The commercial product, called OmniFlex, was introduced to the market in mid-2009. Since that time it has been used by a larger number of people, and a broader database of clinical results is being tabulated. To facilitate this process, a special feedback questionnaire (based on the WOMAC osteoarthritis index), was developed and provided to users in hard-copy and website based format. Early returns have confirmed the pre-marketing clinical experience, and include some reports of dramatic reductions in pain and stiffness after taking the product for 2 – 3 weeks.

Lost in the Hype

I recently came across an article in which the CEO of a successful company was quoted as being driven by the motto “after finding the answer, you need to sell the benefits.” I think this is sound advice, but is a particularly difficult task in the natural products marketplace. The natural products consumer is continually bombarded with advertising messages that promise every imaginable health benefit. Both educated and naive consumers are at a loss to decide whether the latest product offering will help restore their health.

In this type of environment, there are two primary ways to gain attention for a product with real health benefits. Both approaches are exceedingly expensive, and generally beyond the financial capability of the typical entrepreneurial enterprise. The first approach involves spending large sums of money on advertising and promotion, so that the product becomes familiar to the consumer after repeated exposure. Since the consumer is generally incapable of separating clinical relevance from pseudo-scientific extrapolation (hype), this approach is commonly employed by enterprises that cannot demonstrate clinical product utility.

The second approach involves spending even larger sums of money to conduct controlled clinical studies, that will hopefully demonstrate the safety and efficacy of the product for the intended purpose. Depending on the intended use, controlled clinical studies can be relatively straight-forward or impossibly complex. Testing products for their effect on joint pain fits into the straight forward category, but can still cost millions of dollars. For example, a 2009 NIH-sponsored multi-center study on glucosamine/chondroitin that involved 1,583 patients at 16 rheumatology research centers cost $12.5 Million. Even though the study concluded that there was no difference between using glucosamine/chondroitin or a placebo, these products are still used by a vast number of people, confirming the effectiveness of expensive advertising.

A Small Step

Lacking the resources or inclination to pursue either of the above methods of “selling the benefits” of our new product, Ethical Alternative Products has chosen to perform a clinical study of the OmniFlex product through participation of the product users in an open-label clinical feedback program. Physicians and consumers who are using the product are being asked to complete a modified WOMAC scoring assessment that will be continuously tabulated and reported to the general public. Progress on this approach has been slow, as users tend to be reluctant to take the time to record their experience over an 8-week period, but will hopefully prove successful as use of the product spreads.

It’s Personal

I decided to take the somewhat unorthodox approach of sharing my personal experience in developing a joint health product, because the product has had a profound impact on the quality of my life. Contrary to conventional wisdom, I have been able to maintain a very active lifestyle, without resorting to surgical replacement of my knee joint. I fully recognize that this story will be perceived by some as another form of over-selling the benefit of a new supplement product, but I challenge the doubters to try the product for 2 to 3 weeks and add your experience to our clinical database. I spent a number of years optimizing the formulation and I am happy to share the answer with fellow sufferers for the expenditure of much less effort.

New OmniFlex Nourishes Joints in Convenient, Effective Doses

Ethical Alternative Products has launched OmniFlex, a unique joint support formula combining five highly researched ingredients shown specifically to positively impact joint structure and function in easy-to-swallow soft-gel capsules.

According to Gerald Bruno, Ph.D., President of Ethical Alternative Products, OmniFlex is not only unique in its combination, but affords customers an economically friendly dietary supplement. “The concept of combining these five ingredients is based on outstanding portfolios of research demonstrating the efficacy of each for supporting joint health. We are quite confident in the viability of use, efficacy, of this particular combination that we will be investing in a pilot clinical trial with others planned in the future to validate the results of OmniFlex.”

Bruno and his team also surveyed buying habits in health food stores and pharmacies and took away with them the undisputable knowledge that consumers interested in addressing joint health and maintenance through supplementation are averse to taking several individual supplements to achieve desired effects. “A majority of consumers sought combination products, which also are less expensive than purchasing several individual supplements”, said Monica Adametz, CFO.

The five ingredients in OmniFlex are marine-derived Omega 3 EFAs, rose hips and krill oil, all which help mediate inflammatory response to address pain; Biocell collagen type II, which stimulates collagen biosynthesis to support cartilage structure; and Toyo-FVG Pine Bark Extract abundant in oligomeric proanthocyanidins, a potent antioxidant.

“The launch of OmniFlex is timely for consumers as more people are wary of prescription COX-2 inhibitors,” Bruno asserts. “OmniFlex is an attractive choice for its targeted mechanisms of action, its convenience and its cost.”

OmniFlex is available in 60-count bottles, and retailers will receive free literature for bag stuffers. Retailers can learn more by calling (800) 861-0492 or visiting www.gotoeap.com.

About Ethical Alternative Products
Ethical Alternative Products is a dietary supplement supplier that is focused on the research and manufacturing of a select group of scientifically sound, broad-use supplement products. The company objectives are to develop and produce high-value supplements, employing innovative formulations and highest quality raw materials. Products initially developed include the ThioGel products containing solubilized alpha lipoic acid, and the unique triple antioxidant ThioGel-L combination product for protection of the liver. The formulation science employed in the ThioGel products yields enhanced absorption and bioavailability, and enhanced anti-oxidant performance.

Impact of Obesity and Knee Osteoarthritis on Morbidity and Mortality in Older Americans

Background: Obesity and knee osteoarthritis are among the most frequent chronic conditions affecting Americans aged 50 to 84 years.

Researchers offer first direct proof of how osteoarthritis destroys cartilage

Goal: preventative medicine for the leading cause of US disability

ALA featured on Max News

How Age-Damaged Mitochondria Cause Your Cells To Age-Damage You

Methuselah Foundation
Free radicals, and reactive oxygen species (ROS) in particular, play an important part in aging. These are (usually small) molecules lacking an electron needed for stability; they will steal an electron from the first thing they bump into. Like pulling a cog out from clockwork, stealing an electron from a protein or enzyme is usually not good for the finely-tuned biochemical machinery of our cells. The free radical might be rendered safe in the process, but it has left some form of chaos and damage in its wake.

Free radicals are sufficiently dangerous to biochemical machinery that some of our body’s defenders use bursts of free radicals as a kill mechanism.

Scientists generally concur that accumulated damage throughout the body due to free radicals is one important root cause of age-related degeneration – but the devil is in the details. The vast, overwhelming majority of those free radicals are generated by your own metabolism as an unavoidable byproduct. The rate of free radical generation increases greatly with age as the basic mechanisms of your of metabolism are themselves damaged by the free radicals they created. This is not a one-step process, however. I’ll try to walk through it at a high level, cribbing from the mitochondrial free radical theory of aging proposed by Aubrey de Grey and working its way into general acceptance.

Within each of your cells are many mitochondria, tiny biochemical power plants that convert chemicals from food to ATP, the basic fuel molecule used by your cells to provide energy for life.

Mitochondria were once a separate organism that came to live in symbiosis with ancestral cells. As such, they brought their own DNA to the party; some of it still remains within our mitochondria, separate from the DNA we carry in chromosomes in the cell nucleus.
Mitochondria have a couple of ways of generating ATP. The more efficient of these methods – oxidative phosphorylation (OXPHOS) – generates some amount of free radicals as a natural byproduct, and requires the proteins coded in the mitochondrial DNA to function. It is the predominant way by which healthy cells generate their power.

A great deal of work is needed to make this happen, even with today’s biotechnology. But if you don’t get started, you’ll certainly never finish! Generous donations to the Methuselah Foundation help to fund the first steps in this direction.

Free radicals created through OXPHOS within a mitochondrion are most likely to damage that mitochondrion; they’re very reactive, so they won’t get far before sabotaging something. The components that really matter are (a) a membrane that helps organize the movement of various chemicals in the process of generating ATP, and (b) the mitochondrial DNA.
Sufficient free radical damage to mitochondrial DNA shuts down OXPHOS within that mitochondrion, as the necessary proteins can no longer be produced. The mitochondrion switches over to using a less efficient method of producing power, one that doesn’t produce free radicals, but has to run at a much higher rate to produce the same level of ATP.

Mitochondria, like most cellular components, are recycled on a regular basis. Components called lysosomes are directed around the cell in response to various signals, engulfing and breaking down damaged or worn components. After the herd has been culled, surviving mitochondria within a cell divide and replicate, much like bacteria, to make up the numbers.
The signal to break down a mitochondrion is triggered by sufficient damage to its membrane: a sign that it’s old, leaky, inefficient and needs to be replaced with a shiny new power plant.

BUT: if a mitochondrion has had its DNA damaged to the point of stopping OXPHOS, it will no longer be producing free radicals that can damage its membrane. So it will never get broken down by a lysosome. When the time comes to divide and replicate, it will replicate its damaged DNA into new mitochondria. None of those new mitochondria will be producing free radicals via OXPHOS, and so will not be recycled either.

One DNA-damaged, non-OXPHOS mitochondrion will eventually take over the entire mitochondrial population of a cell in this way. At that point, the trouble really gets started.
By the time you hit late life, perhaps 1% of your cells are in this state of being taken over by non-OXPHOS mitochondria. As for any neighborhood or city, it only takes a small proportion of dangerous criminals to make life really unpleasant for the rest of us.

Non-OXPHOS mitochondria have the unfortunate effect of depleting a needed molecule used in many cellular processes, NAD+. This is a carrier molecule in the OXPHOS process, given an electron (and turned into NADH in the process) to port between point A and point B within the mitochondria. Once the electron is delivered, the NADH becomes NAD+ again. But without a working OXPHOS process to return NAD+ into circulation, the cell would quickly build up a deadly excess of NADH, run out of NAD+ and die.

Fortunately for the cell, and unfortunately for us, there is another way to recycle NADH into NAD+. Since NADH is just NAD+ with an electron stuck to it, all the cell has to do is export those unwanted electrons.

In a form of chemical waste dumping, this is just what the cell does. Structures on the cell membrane known as the plasma membrane redox system (PMRS) export electrons from NADH, recycling it into NAD+. This process is only very active in cells which have been taken over by DNA-damaged, non-OXPHOS mitochondria, but their outer surfaces are little hotspots of electron dumping.

What do these electrons do? Well, for one, they combine with oxygen molecules – which are abundant in any of our living tissue – to create reactive oxygen species (ROS): more free radicals. So you have the Rube Goldberg system outlined above whereby a few free radicals have caused a cell to become an ongoing, major exporter of free radicals into the surrounding environment. These will make life unpleasant for surrounding cells, but that is most likely not the real problem. ROS just can’t travel far enough to explain how a corrupt 1% of our cells can cause a large fraction of the difference between being young and being old.

A more likely target for all the newly created ROS is cholesterol. Cholesterols, such as low-density lipoproteins (LDL) are used everywhere in the body and travel widely. If ROS reacts with nearby LDL – and there will always be nearby LDL – to form damaged, oxidized cholesterol, that damaged cholesterol can then be incorporated into and further damage biochemical processes throughout the body. For example, its effects on our arteries is well known:

In conditions with elevated concentrations of oxidized LDL particles, especially small LDL particles, cholesterol promotes atheroma formation in the walls of arteries, a condition known as atherosclerosis, which is the principal cause of coronary heart disease and other forms of cardiovascular disease.

There are many other ways in which accumulations of oxized cholesterol can send biochemical processes awry. This, then, seems to be a good candidate for the plausible, systematic method by which a small number of cells can work such varied damage upon your entire body.

Aubrey de Grey has proposed an engineering solution to this problem, based upon this way of looking at it. That is to go straight to the root, and get the OXPHOS process working again by (a) moving mitochondrial DNA into the nucleus, and (b) ensuring that the necessary proteins can make it from the nucleus back into the mitochondria where they are needed.

As usual, we’re lucky – evolution has done the hardest part of this for us already. Mitochondria are very complex — there are about 1000 different proteins in them, each encoded by a different gene. But nearly all of those genes are not in the mitochondrion’s DNA at all! — they are in the nucleus. The proteins are constructed in the cell, outside the mitochondrion, just like all non-mitochondrial proteins. Then, a complicated apparatus called the TIM/TOM complex (no kidding…) hauls the proteins into the mitochondrion, through the membranes that make its surface. Only 13 of the mitochondrion’s component proteins are encoded by its own DNA.

This gives us a wonderful opportunity: rather than fixing mitochondrial mutations, we can obviate them. We can make copies of those 13 genes, modified in fairly obvious ways so that the TIM/TOM machinery will work on them, and put these copies into the chromosomes in the nucleus. Then, if and when the mitochondrial DNA gets mutated so that one or more of the 13 proteins are no longer being synthesised inside the mitochondria, it won’t matter — the mitochondria will be getting the same proteins from outside. Since genes in our chromosomes are very, very much better protected from mutations than the mitochondrial DNA is, we can rely on the chromosomal copies carrying on working in very nearly all our cells for much longer than a currently normal lifetime.

A Vital Part of Healthcare Reform

John Neustatdt, ND

One aspect of healthcare reform that hasn’t received nearly enough media attention is the need to reform the primary care medical education system. The current system teaches disease management and symptom suppression, which is insufficient to meet our healthcare needs. A reformed system needs a new paradigm that stresses health promotion and treatments that attempt to correct the underlying causes of disease.

Primary care physicians are on the front lines of healthcare. They are the first doctors people see, and the ones they return to for long-term care. One trait that tends to draw people into primary care medicine is the desire to develop lasting relationships with their patients. This frequently means that these doctors end up treating entire families, and in the process learning intimate details of a person’s family dynamics and medical conditions. These relationships provide opportunities to help and affect individuals and families in profound ways.

I have the privilege of working with primary care docs all over the country. Many report to me with frustration that their education doesn’t give them the tools they need to provide the highest possible care. While no one can dispute that these professionals work exceedingly hard, they are hampered by two major failings of conventional medical education philosophy: 1) it focuses on suppressing symptoms with drugs, which are considered the primary and only legitimate treatment modality; and 2) it doesn’t teach how to treat the underlying causes of disease.

I believe that the symptom-suppression model of healthcare provides great insight into why our healthcare system is failing. If people are depressed, prescribe antidepressants such as Prozac or Welbutrin. If they have anxiety, prescribe benzodiazepines such as Klonipin. If they can’t sleep, prescribe sleeps aid such as Ambien. While these medications can be extremely effective and necessary in some cases, they are frequently unnecessary and carry their own risks of side effects. Training doctors to uncover and treat the underlying causes of disease could eliminate much of the unnecessary reliance on pharmaceuticals and reduce their devastating, and sometimes deadly, side effects.

In many cases, the underlying causes of disease are biochemical in nature. Biochemistry is how the body uses vitamins, minerals, fats and proteins to do its job, and how things like infections, allergies and environmental toxins interfere with proper biochemistry to cause symptoms and disease. In other words, if you weren’t sick last year or last month, and you are now, something has changed in your biochemistry. Determining where a person’s biochemistry has gone haywire and then correcting it through targeted nutritional therapies is called medical biochemistry or functional medicine.

While bringing these concepts together into a coherent medical philosophy is relatively new, the underlying clinical observations, basic research and clinical trials are more than 100 years old. This approach has even shown in rigorous clinical trials that genetic diseases that were once considered untreatable — such as phenylketonuria (a metabolic disease that can cause mental retardation and seizures) — can be treated successfully with targeted nutrient therapies.

Let’s go back to depression. As far back as 1951, researchers discovered that a deficiency in any one of 10 different amino acids (the building blocks for proteins) can cause symptoms of lack of appetite, extreme fatigue and irritability — all symptoms of depression and anxiety. Those schooled in functional medicine also know that deficiencies of other nutrients that can cause, or are associated with, depression include vitamin B12, folic acid, magnesium, vitamin B6, omega-3 fatty acids and iron. No one ever has a deficiency of Prozac or Welbutrin. So why should that be the first line of therapy? Instead, primary care doctors should know how to diagnose nutrient deficiencies through sophisticated and comprehensive biochemical tests, and how to correct them for optimal body function.

Clinical trials show unambiguously that targeted nutrient therapy can be safe and effective, and in the hands of skilled clinicians, this approach often times can be more successful, more cost-effective and safer than the pharmacologic approach. Take vitamin K2 and osteoporosis, for example. Since 1995 in Japan, MK4 (a form of vitamin K2) has been approved for the treatment of osteoporosis. Clinical trials show that taking 45 mg MK4 daily with calcium and vitamin D3 can decrease fracture risk by more than 80%, compared with about 45-50% for Fosamax, Actonel and Boniva. But MK4 can’t be patented, so there is no financial incentive for the pharmaceutical industry to bring this to market. Luckily, it’s available in osteoporosis supplements in the US.

But in discussing the benefits of MK4 with doctors, many of them become concerned that it will cause blood clots. This is because the only role for vitamin K that most doctors have heard of is to promote blood clotting. Since they aren’t educated in nutritional medicine, they don’t know that vitamin K is used for many processes in the body, including bone building. Once the body has enough vitamin K for proper blood clotting, the biochemical pathways responsible for creating blood clots are saturated and the left-over vitamin K is used for other processes, such promoting bone health. The safety of MK4 is proven in studies using more than one hundred milligrams daily that didn’t show any tendency towards increased blood clotting, and in fact, the US Institute of Medicine (IOM) has deemed that vitamin K is safe at all doses.

There are so many more examples. Six hundred milligrams daily of the nutrient alpha lipoic acid can decrease pain experienced by people with diabetes when they walk, called diabetic peripheral neuropathy. Clinical trials using zinc have been shown to promote improved self-image and weight gain in girls and women with anorexia nervosa. Supplementation with magnesium and vitamin B6 significantly reduced PMS symptoms in women in another clinical trial. There is a multitude of other studies and data, literally hundreds of thousands of citations indexed by the National Library of Medicine on the healthful effects of nutrients. Unfortunately this research is ignored by the general medical community.

In addition to the studies supporting this approach, this paradigm provides a rational philosophy that is sorely lacking in medicine. The next time you see your healthcare provider, ask him or her which philosophy of medicine they were taught. Likely he or she will tell you, “First do no harm.” But what does that mean? Deaths from correctly prescribed and taken medications in this country are now the fourth leading cause of death. Therefore, the “first do no harm” philosophy is not working. And that’s because conventionally trained doctors aren’t taught any way of conceptualizing, evaluating or treating disease except through the very narrow perspective of drugs and surgery. There is another way and another, more expansive and physiologically appropriate philosophy based on the way the body’s biochemistry works, and how we can restore health.

While we reform our health care system, let’s make sure a part of that is the education in our medical schools. Currently, conventional medical schools in the US don’t require courses in nutritional medicine. Yet the more our primary care doctors know about medical biochemistry — nutritional deficiencies and how to correct them — the more efficient, efficacious and cost-effective our medical system will be. The conventional medical establishment needs to take a page out of naturopathic medical training and shift their philosophy to healthcare that “treats the cause.” Doing no harm is no longer good enough.

John Neustadt, ND is medical director of Montana Integrative Medicine and the co-founder, with Steve Pieczenik, MD, PhD, of Nutritional Biochemistry, Incorporated (NBI) and NBI Testing and Consulting Corp (NBITC).

HUFFINGTON POST

Alpha Lipoic Acid. An Alternative Treatment for Diabetic Neuropathy

Alpha Lipoic Acid. An Alternative Treatment for Diabetic Neuropathy

Alpha Lipoic Acid- Fountain of Youth, Fountain of Health

Cindy Bruno

ALA is perhaps the magic bullet to not only a long lifespan, but more importantly, a great “healthspan,” that is, the number of years of good health and freedom from degenerative disease one can expect. Alpha Lipoic Acid has myriad positive effects on the cellular level and it just may be the key to feeling great for years to come.

Cindy Bruno is a freelance writer who specializes in medicine, psychology and nutrition. Previously she was a writer/producer for the Food Network for 10 years.

Source: http://ezinearticles.com/?expert=cindybruno

Scientists Find Molecular Trigger That Helps Prevent Aging and Disease

ScienceDaily (Nov. 18, 2009) — Researchers at Mount Sinai School of Medicine set out to address a question that has been challenging scientists for years: How does dietary restriction produce protective effects against aging and disease? And the reverse: how does overconsumption accelerate age-related disease?
An answer lies in a two-part study led by Charles Mobbs, PhD, Professor of Neuroscience and of Geriatrics and Palliative Medicine at Mount Sinai School of Medicine, published in the November 17 edition of the journal PLoS Biology. The study examines how dietary restriction and a high-caloric diet influence biochemical responses.
Dr. Mobbs and his colleagues unraveled a molecular puzzle to determine that within certain parameters, a lower-calorie diet slows the development of some age-related conditions such as Alzheimer’s disease, as well as the aging process. How the diet is restricted — whether fats, proteins or carbohydrates are cut — does not appear to matter. “It may not be about counting calories or cutting out specific nutrients,” said Dr. Mobbs, “but how a reduction in dietary intake impacts the glucose metabolism, which contributes to oxidative stress.” Meanwhile, a high calorie diet may accelerate age-related disease by promoting oxidative stress.
Dietary restriction induces a transcription factor called CREB-binding protein (CBP), which controls the activity of genes that regulate cellular function. By developing drugs that mimic the protective effects of CBP — those usually caused by dietary restriction — scientists may be able to extend lifespan and reduce vulnerability to age-related illnesses.
“We discovered that CBP predicts lifespan and accounts for 80 percent of lifespan variation in mammals,” said Dr. Mobbs. “Finding the right balance is key; only a 10 percent restriction will produce a small increase in lifespan, whereas an 80 percent restriction will lead to a shorter life due to starvation.”
The team found an optimal dietary restriction, estimated to be equivalent to a 30 percent caloric reduction in mammals, increased lifespan over 50 percent while slowing the development of an age-related pathology similar to Alzheimer’s disease.
The first part of the study looked at C. elegans, a species of roundworm, that were genetically altered to develop Alzheimer’s disease-like symptoms. Dr. Mobbs and his team reduced the roundworms’ dietary intake by diluting the bacteria the worms consume. In these types of roundworms, human beta amyloid peptide, which contributes to plaque buildup in Alzheimer’s disease, is expressed in muscle, which becomes paralyzed as age progresses. This model allowed researchers to readily measure how lifespan and disease burden were simultaneously improved through dietary restriction.
The researchers found that when dietary restriction was maintained throughout the worms’ adulthood, lifespan increased by 65 percent and the Alzheimer’s disease-related paralysis decreased by about 50 percent.
“We showed that dietary restriction activates CBP in a roundworm model, and when we blocked this activation, we blocked all the protective effects of dietary restriction,” said Dr. Mobbs. “It was the result of blocking CBP activation, which inhibited all the protective effects of dietary restriction, that confirmed to us that CBP plays a key role in mediating the protective effects of dietary restriction on lifespan and age-related disease.”
In the second part of study, Dr. Mobbs and his team looked at the other end of this process: What happens to CBP in a high-calorie diet that has led to diabetes, a disease in which glucose metabolism is impaired? Researchers examined mice and found that diabetes reduces activation of CBP, leading Dr. Mobbs to conclude that a high-calorie diet that leads to diabetes would have the opposite effect of dietary restriction and would accelerate aging.
Dr. Mobbs hypothesizes that dietary restriction induces CBP by blocking glucose metabolism, which produces oxidative stress, a cellular process that leads to tissue damage and also promotes cancer cell growth. Interestingly, dietary restriction triggers CBP for as long as the restriction is maintained, suggesting that the protective effects may wear off if higher dietary intake resumes. CBP responds to changes in glucose within hours, indicating genetic communications respond quickly to fluctuations in dietary intake.
“Our next step is to understand the exact interactions of CBP with other transcription factors that mediate its protective effects with age,” said Dr. Mobbs. “If we can map out these interactions, we could then begin to produce more targeted drugs that mimic the protective effects of CBP.”
Journal Reference:
1. Zhang et al. Role of CBP and SATB-1 in Aging, Dietary Restriction, and Insulin-Like Signaling. PLoS Biology, 2009; 7 (11): e1000245 DOI: 10.1371/journal.pbio.1000245