The Life Extension FoundationMay 2007
By Dave Tuttle
The Life Extension Foundation supports groundbreaking research on therapies to extend the healthy human life span. While commercial companies fund research to develop profitable drugs, the Foundation seeks out projects that have the maximum potential to extend our lives radically, committing its research dollars in areas that would be difficult or impossible to fund with government dollars, institutional grants, or commercial financing sources.
Recent projects include studies to determine the genetic basis of why we age and what can be done to slow or reverse it. The Foundation also funds tissue and organ cryopreservation research, which one day will lead to banks of compatible tissues for transplants to treat aging and diseased patients. Another project funded by the Foundation is identifying less toxic methods of delivering chemotherapy drugs to cancer patients.
These and other areas of study are helping scientists to better understand the mechanisms of aging and disease—bringing the Life Extension Foundation closer than ever to its objective of extending the healthy human life span indefinitely.
In this article, we bring readers up to date on the latest and most promising Foundation-funded research projects.
The Promise of “Longevity Genes”
One of Life Extension’s most important initiatives is determining the molecular mechanisms of aging and the retardation of aging, and understanding how longevity genes are altered by interventions that mimic the effects of caloric restriction, a method that has been shown to significantly extend life span in mammals. This is the primary research objective of BioMarker Pharmaceuticals, an organization funded almost exclusively by Life Extension.
“We are developing therapeutic interventions to extend the healthy life span,” says Dr. Zhao-Wilson, BioMarker’s CEO and lead scientist. “Longevity genes identified in yeast, worms, flies, and rodents are directly relevant to humans. BioMarker is seeking to develop products that mimic both the gene expression and life-span-extending effects of caloric restriction. Our objective is to slow and reverse aging, and to prevent the diseases of aging.
“The average American now spends the last 10 years of life in a disabled state,” adds Dr. Zhao-Wilson. “By slowing aging and preventing disease and disability, we should be able to extend the average human life span to over 100 years. We also aim to extend maximum life span in humans to 150 years or above.”
Proven Benefits of Caloric Restriction
While BioMarker has conducted a variety of gene-expression studies of caloric restriction, two stand out as being particularly important.
BioMarker scientists discovered that caloric restriction stimulates a rapid response in gene expression and in the organism itself.1 This study showed that when caloric restriction was initiated in 19-month-old mice, it increased the mean time to death by 42% and prolonged the mean and maximum life spans by 4.7 and 6.0 months, respectively—within only two months. Tumors as a cause of death decreased from 80% to 67%.
Another study examined caloric restriction’s benefits for the heart.2 Once again, mice responded quickly to a regimen of caloric restriction. Eight weeks of restricted food intake reproduced 19% of the gene-expression changes associated with long-term restriction. Heart remodeling and fibrosis were reduced, while contractility and energy production were enhanced. Smaller cardiomyocytes were seen in the left ventricle of the older mice, suggesting reduced age-related cell death. The improvements proved to be short lived—just eight weeks after the calorie-restricted animals went back on the control diet, fully 97% of the genes returned to their previous expression levels.
Clearly, these studies indicate that you are never too old to begin a program of caloric restriction, and that it is likely that therapies that mimic the benefits of caloric restriction will work even late in life.
BioMarker uses a technology that can check the impact of a nutrient or drug on all 45,000 gene probe sets, representing a complete set of over 34,000 genes of the mouse genome. The company is now working to apply this technology to humans. The first goal is to develop a method to test for changes in gene expression that would enable doctors to determine the biological age of a person rather than just relying on his or her chronological age. The second goal is to study the impact of nutrition and specific nutrients on gene transcription and protein expression. This will eventually lead to the development of nutrigenomics, in which a person’s genetic expression will be used to personalize care to help prevent aging and disease.
“The human body is a complicated circuit, and its pathways interact,” explains Dr. Zhao-Wilson. “It is hard to believe that such a sophisticated system can be switched on and off by a single chemical compound, especially when there are several diseases present. Life Extension’s funding will help us to dissect these chronic diseases at the molecular level. No one size fits all, which is why standard drugs can have differing effects on different people. We will take an approach to evaluate how genes are responding to intervention, and also look at nutrients that Foundation members can use to assist this process. This will help determine which health interventions are most appropriate, so we can live longer, healthier lives.”
BioMarker investigated the benefits of Life Extension’s grape extract with resveratrol and found that it protects mitochondrial function and prevents protein oxidation in vitro. Whole grape has a complex mixture of nutrients, such as resveratrol, quercetin, and proanthocyanidins—each of which has diverse biological activities. Moreover, BioMarker’s in vitro and in vivo studies on rodents have shown a statistically significant overlap between the benefits of caloric restriction and the use of grape extract.
BioMarker is also looking at the benefits of a combination of ginkgo biloba, grape extract, and green tea. Scientists have already completed in vitro and in vivo animal studies on this combination, and the company is now conducting a randomized, double-blind, placebo-controlled human study, with results due later this year.
These research efforts will have a dramatic effect over time, helping reveal the true causes of aging and how to slow the aging process.
Creating a Tissue and Organ Transplant Bank
When a person’s kidney, heart, or other organ gives out, doctors try to find a replacement organ. Currently, the only available resource is an organization that acts as a broker, trying to find an organ donor who is compatible with the patient in need. Even if such donors can be found, often there are only poorly compatible organs available, and many times individuals waiting for an organ transplant die before one can be found. There are long lists of patients waiting for kidney, heart, and liver transplants. Moreover, today’s limited technology dictates that even patients who receive organ transplants must take expensive anti-rejection drugs—with serious side effects—for the rest of their lives.
“With successful cryopreservation methods, complex tissues and organs could be stored on a long-term basis in banks, which would increase the time that doctors would have to get organs,” notes Dean Barry, CEO of 21st Century Medicine, another California-based company funded by the Life Extension Foundation. “Transplants could become standard procedures instead of emergency surgery. There would be better matches because of greater availability, and less need for anti-rejection drugs that have side effects.”
Several companies and university laboratories are working on ways to overcome the rejection problem of transplanted tissues and organs. Once scientists develop a successful technology to overcome rejection, it will become possible to transplant almost every organ and tissue in the body (including many portions of the brain) to treat age-related diseases such as atherosclerosis, maturity-onset diabetes, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (Lou Gehrig’s disease), as well as manifestations of aging such as wrinkled skin, cross-linked collagen, weakened bones, sexual dysfunction, energy depletion, and muscular debilitation.
When methods to cryopreserve complex tissues are perfected, it will become possible to store virtually every tissue in the body—whether taken from human donors, grown in the laboratory from stem cells, or combined with artificial components to form bioartificial organs. Such banks will be used to cure diseased or severely injured patients and to reverse aging in humans. These efforts will be guided by much greater knowledge of the mechanisms of aging, as discovered by BioMarker and other laboratories.
With Life Extension funding, 21st Century Medicine now has six scientists working on an ice-free preservation technique known as vitrification, in which water in cells is replaced with cryoprotectant solutions that do not freeze but instead preserve tissue in a glass-like state, with little or no structural damage. To date, the company has vitrified human kidneys, corneas, blood vessels, ova, ovaries, brain slices, and cartilage, as well as rat hearts and testes. It has made considerable progress toward perfecting the vitrification of these organs and tissues.
21st Century Medicine’s most advanced research project involves the vitrification of corneas. It has worked on several hundred corneas, transplanting them into animals after they have been preserved for months. Despite the time lag, these corneas have had outstanding clarity, thickness, and endothelial function. The company is now ready to begin transplanting vitrified corneas into humans in emergency situations. The vitrified cornea will act as a “patch” to save the sight of an eye, if a standard cornea transplant is not available. 21st Century Medicine is now establishing relationships with several teaching universities to launch this project.