The giant monoliths of Easter Island are worn, but they have endured for centuries. New research suggests that a compound first discovered in the soil of the South Pacific island might help us stand the test of time, too.

In the journal Nature, The University of Texas Health Science Center at San Antonio and two collaborating centers reported that the Easter Island compound - called “rapamycin” after the island’s Polynesian name, Rapa Nui - extended the expected lifespan of middle-aged mice by 28 percent to 38 percent. In human terms, this would be greater than the predicted increase in extra years of life if cancer and heart disease were both cured and prevented.

The rapamycin was given to the mice at an age equivalent to 60 years old in humans.

The studies are part of the National Institute on Aging (NIA) Interventions Testing Program, which seeks compounds that might help people remain active and disease-free throughout their lives. The other two centers involved are the University of Michigan at Ann Arbor and Jackson Laboratory in Bar Harbor, Maine.

The Texas study was led by scientists at two institutes at the UT Health Science Center: the Institute of Biotechnology (IBT) and the Barshop Institute for Longevity and Aging Studies.

“I’ve been in aging research for 35 years and there have been many so-called ‘anti-aging’ interventions over those years that were never successful,” said Arlan G. Richardson, Ph.D., director of the Barshop Institute. “I never thought we would find an anti-aging pill for people in my lifetime; however, rapamycin shows a great deal of promise to do just that.”

Versatile compound

Discovered in the 1970s, rapamycin was first noted for its anti-fungal properties and later was used to prevent organ rejection in transplant patients. It also is used in stents, which are implanted in patients during angioplasty to keep coronary arteries open. It is in clinical trials for the treatment of cancer.

The new aging experiments found that adding rapamycin to the diet of older mice increased their lifespan. The results were the same in Texas, Michigan and Maine.

“We believe this is the first convincing evidence that the aging process can be slowed and lifespan can be extended by a drug therapy starting at an advanced age,” said Randy Strong, Ph.D., who directs the NIA-funded Aging Interventions Testing Center in San Antonio. He is a professor of pharmacology at the UT Health Science Center and a senior research career scientist with the South Texas Veterans Health Care System.

The findings have “interesting implications for our understanding of the aging process,” said Z. Dave Sharp, Ph.D., director of the Institute of Biotechnology and professor and chairman of the Health Science Center’s Department of Molecular Medicine.

“In addition,” Dr. Sharp said, “the findings have immediate implications for preventive medicine and human health, in that rapamycin is already in clinical usage.”

Molecular pathway

Aging researchers currently acknowledge only two life-extending interventions in mammals: calorie restriction and genetic manipulation. Rapamycin appears to partially shut down the same molecular pathway as restricting food intake or reducing growth factors.

It does so through a cellular protein called mTOR (mammalian target of rapamycin), which controls many processes in cell metabolism and responses to stress.

A decade ago, Dr. Sharp proposed to his colleagues that mTOR might be involved in calorie restriction. “It seemed like an off-the-wall idea at that time,” Dr. Richardson said.

In 2004, a year after the launch of the NIA Interventions Testing Program, Dr. Sharp submitted a proposal that rapamycin be studied for anti-aging effects. The proposal was approved, and testing centers in San Antonio and elsewhere began to include rapamycin in the diets of mice.

The male and female mice were cross-bred from four different strains of mice to more closely mimic the genetic diversity and disease susceptibility of the human population.

Dr. Strong soon recognized a problem: Rapamycin was not stable enough in food or in the digestive tract to register in the animals’ blood level. He worked with the Southwest Research Institute in San Antonio to improve the bioavailability of the compound through a process called microencapsulation. The reformulated drug was stable in the diet fed to the mice and bypassed the stomach to release in the intestine, where it could more reliably enter the bloodstream.

Older mice

The original goal was to begin feeding the mice at 4 months of age, but because of the delay caused by developing the new formulation, the mice were not started until they were 20 months old - the equivalent of 60 years of age in humans. The teams decided to try the rapamycin intervention anyway.

“I did not think that it would work because the mice were too old when the treatment was started,” Dr. Richardson said. “Most reports indicate that calorie restriction doesn’t work when implemented in old animals. The fact that rapamycin increases lifespan in relatively old mice was totally unexpected.”

Added Dr. Strong: “This study has clearly identified a potential therapeutic target for the development of drugs aimed at preventing age-related diseases and extending healthy lifespan. If rapamycin, or drugs like rapamycin, works as envisioned, the potential reduction in overall health cost for the U.S. and the world will be enormous.”

Source:
Will Sansom

University of Texas Health Science Center at San Antonio

Treatment with the angiogenesis inhibitor bevacizumab improved hearing and alleviated other symptoms in patients with neurofibromatosis type 2 (NF2). In a paper to appear in the July 23 New England Journal of Medicine, which is receiving early online release, researchers from Massachusetts General Hospital (MGH) report that bevacizumab treatment successfully shrank characteristic tumors in a small group of NF2 patients, the first reported successful NF2 treatment not involving surgery or radiation.

“This kind of treatment response is unprecedented,” says Scott Plotkin, MD, PhD, of the Pappas Center for Neuro-Oncology in the MGH Cancer Center, lead author of the NEJM paper. “Our study is the first to provide evidence that a drug can shrink vestibular schwannomas - benign tumors on the balance and hearing nerves - and the first to show that patients’ hearing can be improved.”

NF2 is an inherited genetic disorder in which benign tumors develop throughout the nervous system. Vestibular schwannomas are the most common NF2-associated tumors, and although they grow slowly, they usually cause patients to lose all or most of their hearing by young adulthood or middle age. The tumors can be removed surgically or treated with radiation, but in patients with vestibular schwannomas on both sides, which is typical in NF2, such treatment usually leads to complete hearing loss. Growing vestibular schwannomas can also press on the brainstem, leading to headaches, difficulty swallowing and other serious neurologic symptoms.

Since vestibular schwannomas are benign tumors, it was believed that they did not stimulate formation of new blood vessels as malignant tumors do. However, when the researchers studied tissue samples from NF2-related schwannomas, sporadic tumors not caused by NF2 and normal spinal nerves, they found evidence of excess blood vessel development and increased expression of angiogenesis-related molecules in both NF2-associated and sporadic vestibular schwannomas. With this suggestion that angiogenesis was involved in these tumors, members of the research team offered treatment with bevacizumab (Avastin), which is FDA-approved for treatment of several forms of cancer, to NF2 patients in danger of complete hearing loss or other significant neurological damage.

Among the first ten NF2 patients to receive bevacizumab, treatment led to tumor shrinkage in nine, and six had 20 percent or greater reduction in tumor size. In those six patients, tumor shrinkage lasted from 11 to 16 months, longer than the four months typically seen in bevacizumab treatment of malignant brain tumors. Of seven patients who had started to lose their hearing before treatment, four experienced some hearing restoration - two returning to work or school as a result - improvement that has also lasted for up to 16 months. In one patient without significant tumor shrinkage or hearing improvement (he had lost all hearing prior to treatment), treatment alleviated headaches and nausea caused by brainstem compression, allowing him also to return to school.

“This study has opened a new approach to research and understanding of these tumors,” says Emmanuelle di Tomaso, PhD, the study’s senior author, formerly with the Steele Laboratory of Tumor Biology in the MGH Department of Radiation Oncology. “There had been a dogma that these tumors do not produce edema and are not angiogenic, concepts that now need to be reevaluated.” She adds that the study also suggests that VEGF - the angiogenesis factor blocked by bevacizumab - may have a role in nerve physiology beyond the stimulation of blood vessel growth.

Plotkin notes, “Based on the results of this study, we have just opened the first formal clinical trial of a drug treatment for NF2. We are testing an exciting new, oral VEGF inhibitor that will be easier for patients to take - bevacizumab is administered intravenously - and may have fewer side effects.”

Notes:
Plotkin is an assistant professor of Neurology at Harvard Medical School (HMS). Formerly an assistant professor of Radiation Oncology at HMS, di Tomaso recently joined the Novartis Institutes for BioMedical Research. Additional co-authors of the NEJM report are Anat Stemmer-Rachamimov, MD, MGH Pathology; Fred Barker, MD, MGH Neurosurgery; Timothy Padera, PhD, Alex Tyrrell, PhD, and Rakesh Jain, PhD, MGH Radiation Oncology; Gregory Sorensen, MD, MGH Radiology, and Chris Halpin, PhD, Massachusetts Eye and Ear Infirmary.


The study was supported by the HMS Center for Neurofibromatosis and Allied Disorders, Neurofibromatosis Inc. New England, Children’s Tumor Foundation, the Department of Defense, the National Institutes of Health, and the MGH Executive Committee on Research. No support was provided by Genentech, which produces and markets bevacizumab under the brand name Avastin.

Source:
Katie Marquedant

Massachusetts General Hospital

View drug information on Avastin.

Transplant patients rely on drugs to prevent graft rejection, but at the cost of serious side effects. The class of immunosuppressive drugs known as calcineurin inhibitors (examples are cyclosporine and tacrolimus) can damage patients’ kidneys and lead to high blood pressure, among other problems.

A combination of treatments can effectively replace calcineurin inhibitors in preventing graft rejection when kidney transplants are performed on monkeys, scientists at the Emory Transplant Center have shown. The non-human primate research was conducted at the National Institutes of Health and Yerkes National Primate Research Center, Emory University.

The results are published in the July issue of Nature Medicine.

The finding opens the door to less-toxic post-transplant treatment that could be administered once a week rather than a dizzying mound of pills every day, says senior author Allan Kirk, MD, PhD, scientific director of the Emory Transplant Center and a Georgia Research Alliance Eminent Scholar.

“Both of the drugs used in this regimen are already used separately in humans, thus a clinical trial could be developed quickly,” Kirk notes.

One key ingredient in the combination is an experimental therapy called a costimulation blocker, designed to interfere with the T cells that cause graft rejection without affecting other organs. Costimulation refers to one of two signals T cells need from other cells (antigen presenting cells) to become fully activated.

The other key ingredient — a protein called alefacept — subdues memory T cells, a variety of T cells that allow the immune system to respond faster and stronger to an infectious agent or vaccine upon second exposure.

Costimulation blockers are sufficient for allowing mice to tolerate a transplanted kidney, but not monkeys or people, Kirk says. Memory cells appear to prevent costimulation blockers from working as well in monkeys as they do in mice.

“One of the big differences we’ve found between mice and both monkeys and people is that we primates have more exposure to infections that require us to develop immunological memory,” he says. “Memory cells are quicker to become activated and don’t need costimulation as much, so blocking costimulation doesn’t slow them down.”

By themselves, neither costimulation blockers (in this case, a molecule called CTLA4-Ig) or alefacept could prevent rejection in monkeys after the eight week treatment period, Kirk and his colleagues found. They had more success by combining costimulation blockers, alefacept and the transplant drug sirolimus. Under this regimen, monkeys could last for months after treatment ended without developing rejection or self-reactive antibodies.

CTLA4-Ig mimics a molecule found on T cells (CTLA4) and acts as a decoy. CTLA4-Ig is now used as an FDA-approved therapy for rheumatoid arthritis.

A similar drug called belatacept is now in phase III kidney transplant clinical trials, but current studies use it in combination with conventional immunosuppressive drugs.

Alefacept targets memory T cells via a molecule on their surfaces called CD2, the authors found. Alefacept was approved by the FDA for treatment of psoriasis in 2003. It is also being tested in a kidney transplant clinical trial in combination with conventional drugs.

Both CTLA4-Ig and alefacept are proteins and must be administered intravenously or possibly subcutaneously. However, their stability means they don’t need to be taken every day - once a week is enough, Kirk says.

Notes:
The paper’s first author is Tim A. Weaver, and other co-authors are Ali H. Charafeddine, Avinash Agarwal, Alexandra P. Turner, Maria Russel, Frank V. Leopardi, Robert L. Kampen, Linda Stempora, Mingging Song and Christian P. Larsen. The research was supported by the National Institutes of Health.


Reference: T.A. Weaver et al. Alefacept promotes costimulation blockade-based allograft survival in primates. Nature Medicine. 15, 746-749 (2009)

Source:
Holly Korschun

Emory University