Council Minutes - February 2001

NATIONAL INSTITUTES OF HEALTH, NATIONAL INSTITUTE ON AGING

Summary Minutes: The Eighty-First Meeting

National Advisory Council on Aging

September 27, 2000

National Institutes of Health
Building 31, Conference Room 6
Bethesda, Maryland 20892

CONTENTS

Overview

1. Review of Applications
2. Call to Order
3. Review of Behavioral and Social Research Program
4. Working Group on Program
5. Presentation: Osteoarthritis Initiative
6. Presentation: Opportunities for Research in Complementary and Alternative Medicine in Aging Americans
7. Program Highlights
8. Comments from Retiring Members
9. Adjournment
10. Certification

Attachment A - Roster of the National Advisory Council on Aging
Attachment B - Director's Status Report

Overview

The 81 st meeting of the National Advisory Council on Aging (NACA) was convened on Wednesday, September 27, 2000, at 10:00 a.m. in Building 31, Conference Room 6, National Institutes of Health (NIH), Bethesda, Maryland. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA), presided.

In accordance with the provisions of Public Law 92-463, the meeting was open to the public on Wednesday, September 27, from 10:00 a.m. to 4:20 p.m. The meeting was closed to the public on Wednesday, September 27, from 8:00 to 10:00 a.m. for the review, discussion, and evaluation of grant applications in accordance with the provisions set forth in Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code, and Section 10(d) of Public Law 92-463. (1)

Council Participants

Dr. Dennis Ausiello Dr. Mary S. Harper
Dr. John Cambier Dr. John Rowe
Dr. Judith Campisi Dr. Dennis Selkoe
Dr. Rose Dobrof Dr. Ilene Siegler
Dr. Fred Gage Dr. James Vaupel
Dr. Patricia S. Goldman-Rakic Dr. Jeanne Wei
Dr. Richard Goldsby Dr. Myron Weisfeldt

Ex-Officio Participants

Dr. Saadia Greenberg, AoA

Absent

Dr. Elizabeth Barrett-Connor Dr. Phyllis Wise
Senator Mark Hatfield LTC Dr. George F. Fuller
Dr. David Wise Dr. Judith Salerno

The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as Attachment A .

Members of the Public Present

Nancy Aldrich, Aging Research and Training News

Shirley V. Brown, Gerontology News
Ann Harrison Clark, Population Association of America
Lauren Hafne, F-D-C Reports
Cathy Fomous, Council for Responsible Nutrition
Tim McCaffrey, Cornell Medical
Sharon Moss, ASHA
Angela Sharpe, Consortium of Social Science Associations

In addition to NIA Staff, other Federal employees attending were:

Virginia Hartmuller, ORWH/NIH
Gayle Lester, NIAMS/NIH
Michael Martin, CSR/NIH
Michael Micklin, CSR/NIH
Paula Skedsvold, OBSSR/NIH

1. Review Of Applications

This portion of the meeting was closed to the public in accordance with the determination that it was concerned with matters exempt from mandatory disclosure under Sections 552b(c)(4) and 552b(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix). (2)

A total of 591 applications requesting $397,680,837 for all years was reviewed. Council recommended 402 for a total of $290,979,458 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.

2. Call To Order

Dr. Hodes called the meeting to order at 10:20 a.m. and welcomed members. He also noted the death of former Advisory Council member Dr. George Myers and commented that Dr. Myers had made enormous contributions to research in aging.

Director's Status Report

As yet, no appropriations bill has been passed. Speculation is optimistic that an appropriation will be passed in October. Until that time, NIH is expected to operate under a continuing resolution.

Dr. Hodes summarized trends in number and costs of awards following the recent 15% budget increase. He explained that average costs of awards increased approximately 50 percent from FY 1998-1999 and approximately 10 percent from FY 1999-2000. At the same time, although the NIA budget increased substantially in FY 1999 and FY 2000, success rates decreased from 28 percent in FY 1998 to 27.7 percent in FY 1999 and to an estimated 24.4 percent in FY 2000. It is likely that a portion of the cost increases relate to the nature of research supported, e.g., clinical trials, population studies, and complex multi-component research projects. Still, there is concern that low success rate limits opportunity to support meritorious research and also that low success rate can become a disincentive for principal investigators to apply for NIA support. As a consequence, rather than continuing to fund applications at the level recommended by study section, staff will adjust budgets so that more projects can be supported. The NIA funding policy for FY 2001 can be seen on NIA's Home Page .

In discussion, Council inquired whether the same trend, increased costs and decreased success rates, is being experienced by other Institutes. Dr. Hodes replied that NIH-wide average costs have increased and success rates have not increased in proportion to the budget. However, NIA increases are more extreme than average increases NIH-wide.

Dr. Hodes commented on the departure of Dr. Terrie Wetle, NIA's Deputy Director, who, he stated, had been an outstanding resource to the Institute and to aging research nationally and internationally. Dr. Wetle has accepted a new position that will provide a good opportunity to continue her work in the field of aging. He requested that Council members help in recruitment of a successor with scientific credibility and judgment, administrative skills, and a voice to the outside public. The Deputy can make a real and important impact by influencing the inner workings of the Institute as well as interfacing with the research community.

Future Meeting Dates

• February 6-7, 2001 (Tuesday-Wednesday)
• May 22-23, 2001 (Tuesday-Wednesday)
• September 24-25, 2001 (Monday-Tuesday)
• January 29-30, 2002 (Tuesday-Wednesday)
• May 21-22, 2002 (Tuesday-Wednesday)
• September 24-25, 2002 (Tuesday-Wednesday)

Consideration of Minutes of Last Meeting

The minutes of the May 27, 2000 meeting were approved as submitted.

3. Review Of The Behavioral And Social Research Program

Drs. James Vaupel and Ilene Siegler co-chaired the Behavioral and Social Research (BSR) Program Review Committee and presented the Committee's report. They commented that the materials prepared for the review informed the committee and were of excellent quality. The charge to the review committee was to advise on planning, organizational structure and program priorities; and to provide input on future directions.

The committee made four recommendations:

1. That the organizational structure of BSR be more fluid, flexible, and horizontal in order to maintain excellence and develop innovative targets of research in cross-cutting substantive research areas;
2. That a position be added for a Deputy Associate Director who would have strong managerial abilities and broad interests that would complement existing staff;
3. That special attention be given to integrative cross-cutting research areas where researchers from both traditional and emerging behavioral and social science disciplines are making important contributions;
4. That the Associate Director set priorities and make choices on some areas that need to be pruned and others that need to be added.

The committee expressed high regard for Dr. Suzman's vision for BSR and confidence in the BSR staff, and emphasized that the program has a broad trans-NIA and NIH role in investigating lifestyle and behavioral factors that are important in disease processes.

Dr. Hodes thanked the committee for their work and extensive deliberations. He indicated he had discussed the report with Dr. Suzman and recruitment for a Deputy will be immediate in response to the recommendation. Dr. Suzman and his staff will soon generate a list of priorities for initiatives and will welcome feedback about those initiatives at the next Council. A few of the priority areas will be: health disparities, cognitive psychology (following publication of The Aging Mind ), and a small initiative to look at the social and ethical impact of the interaction between genes and environment.

Dr. Suzman commented that the report reflected many of the ideas BSR staff originally presented to the review committee. He expressed his belief that BSR funds some of the best social and behavioral science in the world. He observed that BSR has become more central to and integrated with other programs at NIA and added that staff continue to welcome applications from investigators in any of the broad areas represented in BSR's mandate. Dr. Suzman thanked Drs. Vaupel and Siegler for their hard work as co-chairs.

Council inquired as to how many initiatives the committee had advised Dr. Suzman to cut back. There were approximately 40 to 50 program announcements and initiatives issued within the past three years with new ones being planned. Initiatives have been added but not subtracted. Drs. Suzman and Hodes reiterated that the identification of priorities should not be interpreted as a limitation of scope--it relates to focus of staff activities, not to restrict the ingenuity of investigators. BSR staff will continue to work with these investigators across the full breadth of the science. The committee and Council members also recommended that BSR recruit senior research scientists to help develop initiatives.

Council accepted the report of the May 2000 BSR Program Review as submitted.

4. Working Group On Program

Dr. Fred Gage, Chair of the Working Group on Program (WGOP), presented the report of the meeting which took place from 12 noon to 3:00 p.m. on the day prior to Council.

Discussion of the NIA's Strategic Plan To Address Health Disparities was led by Dr. J. Taylor Harden. The Strategic Plan To Address Health Disparities is part of a trans-NIH initiative mandated by the Principal Deputy Director of the NIH in support of the White House and Secretary's initiatives to reduce and ultimately eliminate health disparities. Development of the NIA Strategic Plan to Address Health Disparities was started with the goal of addressing health disparities in older Americans. The plan focuses on three major areas: (1) research, (2) research infrastructure, and (3) public information, outreach and education, and includes ongoing and future initiatives. The plan is composed of over 60 activities to help the NIA advance research and better understand health disparities among ethnic and racial older adults:

1. Research to advance understanding of the development and progression of diseases and disabilities that contribute to health disparities in older persons and populations as well as research to develop new or improved approaches for disease and disability detection, diagnosis, prevention, delay and treatment.
2. Research Infrastructure to train a skilled and diverse research workforce and provide support for institutional resources that facilitate health disparities research.
3. Public Information, Outreach and Education to sustain a diverse workforce and a professional environment that supports and encourages excellence in aging research by developing research-based information resources, communicating information to increase public awareness, and transferring knowledge to health professionals.

The NIA Strategic Plan to Address Health Disparities , together with the NIA Strategic Plan for Aging Research and the recently completed Review of Minority Aging Research by the National Advisory Council on Aging, present a vision and approach to redress health disparities in older adults.

Discussion in the Working Group focused on how the plan would be assessed: What benchmarks would indicate progress or success? Members pointed out that more problems will likely be noticed as more attention is paid to health disparities. The Working Group agreed that eliminating health disparities is a long-term goal and that intermediate goals are to build an infrastructure, and to develop a process and plan to address the reduction of health disparities.

Council noted that major contributors to morbidity and mortality in diverse populations are not reflected in the document and expressed concern about disease orientation. For example, the NIA has a specific mandate to support and conduct research on Alzheimer's disease even though cardiovascular disease results in substantially greater morbidity and mortality. Council members also pointed out that attention needs to be paid to understanding behavioral determinants of illnesses, such as lifestyle and generational differences, as well as to development of culturally appropriate assessment instruments, to the quality of available services and to reasons that available services are or are not used by targeted population groups. Council expressed appreciation to Dr. J. Taylor Harden and the Programs for work on the complex task of developing the plan.

The Work Group next discussed increases in average cost of grants. The Director reported earlier in the meeting that NIA received substantial budget increases in recent years and that average grant costs have increased while success rate has fallen. Members discussed whether the decrease in success rate is a trend or a transient phenomenon and speculated that some of the changes may be caused by increased costs in program projects, modular grants, more epidemiologic and clinical studies, and salaries. Council members recommended further study to help understand observed increases in average costs of grants. The Institute's plan to control costs was shared with Council and is posted on the NIA Home Page.

The third topic of discussion was advisory meetings and workshops. The first of two meetings discussed in depth was an NIA Repository Oversight Committee meeting planned for Spring, 2001. NIA supports a number of studies that collect and store biospecimens. These resources might be used by other investigators if specimens are stored in repositories that have good information about the nature of the specimens, how they are collected and stored, data on the populations from which they were obtained, and policies and agreements in place governing their use. The planned meeting would consider the best type of repository arrangement for currently ongoing NIA-supported studies with repositories: storage of specimens in a central repository through which specimen distribution is administered; a distributed repository in which specimens are stored at the institutions that collect them but specimen distribution is administered by the Repository Oversight Committee; or virtual repositories that contain and administer their own specimen collections. The staff believes that the advantages of a repository to the research community outweigh difficulties in coming to an agreement on how to proceed and the costs involved. The Working Group was asked to consider the types of expert advice needed for an oversight committee and to recommend individuals with appropriate expertise. Members suggested that expertise in longitudinal research and ethics be included. The planned meeting was approved by the Working Group.

Next, a second workshop on Primate Models of Menopause was discussed. A purpose of this workshop is to determine the current status of research on hormonal changes across the perimenopause in non-human primates. It will target physiologic changes leading to increased incidence of hot flashes, bone loss, cardiovascular and cognitive function. The NIA will request recommendations from an advisory committee regarding future research directions. The Working Group approved a follow-up meeting.

Following the 2000 World Congress on Alzheimer's Disease held in Washington, DC, the President announced a commitment of significant funds to support new research, including research to develop and test a vaccine for Alzheimer's disease. In response, the Institute is developing new initiatives for release in FY 2001. Two priority areas were identified that are fully consistent with NIA's planning. One stems from reports that vaccination relative to the expression of amyloid in transgenic animals might be a potential therapy for reduction of amyloid burden in animals. The other is in the area of secretases; how the protein is being cleaved and targeting of drugs to influence the activity of these enzymes. The Working Group agreed that research in both areas is important and timely. Dr. Hodes commented that the attention received by NIA-supported research in the Presidential statement increased the American public's awareness in this area.

As new business, Council members discussed the peer review of aging research grant applications. Some Council members expressed concern about the quality of reviewers, the composition of review groups, and about the adequacy of review of particular types of applications, for example longitudinal studies and multidisciplinary applications. Dr. Michael Martin, Center for Scientific Review (CSR), provided an overview of CSR's efforts to modify and evaluate review processes and to improve them. A Council sub-committee was formed to gather information related to NIA's review of grant applications. The sub-committee will lead a discussion at the February or May 2001 Working Group meeting on how Council might contribute to ongoing efforts to improve peer review processes and increase the awareness and fairness of the review procedure. The sub-committee invited Council members from other disciplines to communicate by e-mail so their input can be considered.

The Working Group expressed sadness at the departure of Dr. Terrie Wetle, NIA's Deputy Director, and asked staff to prepare a statement of appreciation acknowledging Dr. Wetle's contributions to NIA and NIH.

5. Presentation: Osteoarthritis Initiative
   

Dr. Hodes and Dr. Stephen I. Katz, Director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), described the NIH Osteoarthritis Initiative Public-Private Consortium (OAI). The concept for the initiative was formulated in a series of meetings attended by NIH, FDA and potential private sector collaborators. The initiative will sponsor the development and management of a research resource to support the discovery and evaluation of biomarkers and surrogate endpoints for osteoarthritis clinical trials. The project's goal is to create a public archive of data, biological samples, and joint images that will be a critical prerequisite for evaluating and validating osteoarthritis biomarkers. It is hoped that these biomarkers will provide public and private sector investigators new opportunities to develop disease-modifying therapies as well as diagnostic and patient management methods.

The seven-year, longitudinal, population-based study will be sponsored by the NIA and NIAMS and several corporate partners. The NIH hopes the initiative, projected at yearly costs of $10 million ($3 million Federal funds and $7 million private), will be a model for interaction between NIH, academia, and the private sector. The funds will be administered by the Foundation for NIH. According to

Dr. Katz, the public-private efforts of the SNP (single nucleotide polymorphisms) consortium, a collaborative venture supported by companies and institutions integral to the sequencing of the human genome, have served as a model for OAI. Pharmaceutical companies understand that generating surrogate markers will ultimately be of use to them in generating drug and intervention therapies. NIH will provide access to the data as early as is feasible.

Four to six clinical centers will recruit, evaluate, and conduct follow-up studies with a targeted enrollment of 5,000 people. MRI and radiographic techniques will be used to assess joint structural markers of the knee as potential surrogate disease endpoints. A data coordinating center will design and implement bioinformatic protocols to manage data generated by the clinical centers and will serve as a repository for biospecimens. Pharmaceutical sponsors will be represented on a consortium steering committee that will include principal investigators from the clinical and data coordinating centers and the NIH program official.

Council members cautioned that universities might be wary of private-sector interests taking advantage of their research outcomes. Dr. Hodes responded that NIH is aware of such concerns and has been consulting with the Association of American Medical Colleges. He assured Council that appropriate policies will govern distribution of limited biospecimens, intellectual property rights to tools developed by the OAI, and licensing restrictions for databases. He believes that the OAI will be a prototype for the development of resources, and indicated that NIA has held preliminary discussions about other disease models.

6. Presentation: Opportunities For Research In Complementary And Alternative Medicine In Aging Americans
   

Dr. Hodes introduced Dr. Steve Straus, Director, National Center for Complementary and Alternative Medicine (NCCAM), who spoke about complementary and alternative medicine (CAM) and the approaches NCCAM is taking to study popular and controversial practices. NCCAM is developing an approach sensitive to complementary and alternative practices that draws on the expertise of mainstream biomedical science. He defined complementary and alternative medicine by exclusion, as diverse healthcare modalities that people choose themselves and that are not extensively incorporated into training or practice of conventional American medicine. CAM practice is extensive and increasing. In the US, it is estimated to be used by 40 percent of people and to have increased in use by 30 percent during the last 10 years. Many people use CAM practices in addition to conventional medicine to improve wellness or to relieve symptoms associated with chronic degenerative or fatal diseases. The majority of CAM use is not disclosed to physicians.

Dr. Straus described five CAM domains: alternative medical systems (oriental medicine, Ayurvada, Native-American Medicine, homeopathy and naturopathy), mind-body interventions (meditation, dance, music and art therapy, prayer, mental healing), biologically-based treatments (herbal therapies, special diets, orthomolecular therapies, other biological therapies), manipulative and body-based methods (chiropractic, osteopathic manipulation, massage), and energy therapies (Qi gong, Reiki, Therapeutic touch, electroacupuncture, magnetic field therapies).

Dr. Straus offered examples of how conventional scientific methods can be useful to investigate alternative / complementary practices. He described a study (Philipp, et al., Brit Med J 319: 1534; 1999) in which St. John's Wort, an herb used to treat depression, was compared to placebo and Imipramine. The study reported improvement in the placebo arm but statistically superior effect with Imipramine or St. Johns Wort, with the two active substances about equal in effect. However, in another study Piscitelli, S., et al., ( Lancet 355: 547; 2000) had administered Indinavir, an HIV protease inhibitor, and found reduced viral loads. When they added an effective dose of St. John's Wort to the Indinavir regimen, they found that blood levels of the drug fell because St. John's Wort accelerated hepatic clearance of Indinavir. Thus, well-designed studies successfully demonstrated positive and negative uses of an herbal substance. CAM practices are increasingly available and are sometimes reimbursed by insurance companies. Since some practices may sustain and improve health and others may not, research on which practices are safe and effective can contribute to public health.

In 1998, Congress mandated that NIH establish a center to conduct and support basic and applied research, research training, and others programs to identify, investigate, and validate complementary and alternative treatments, diagnostic and prevention modalities, disciplines and systems (PL105-277). Since its inception, NCCAM has developed a strategic plan and a research program to conduct a full range of research including clinical trials when warranted on the basis of smaller studies and using the array of NIH support mechanisms. Five NCCAM-supported random controlled clinical trials now in progress include: St. John's Wort (hypercium) for treatment of depression compared with placebo and a serotonin reuptake inhibitor (with NIMH); adjunctive therapy with shark cartilage for lung cancer (with NCI); acupuncture for osteoarthritis pain (with NIAMS); glucosamine-chondroitin sulfate for osteoartritis (with NIAMS). With NIA, the NCCAM is supporting a placebo controlled study of ginkgo biloba to prevent dementias, especially Alzheimer's disease. This last study will assess changes in cognitive function, incidence of cardiovascular disease, and mortality in 3,000 adults age 75 and over. Dr. Straus pointed out that both positive and negative outcomes will result in useful information: in the first case, a preventive treatment and, in the second, information on the natural history of cognitive decline in an otherwise healthy older group. In addition to clinical trials, the NCCAM is launching studies on CAM approaches to end-of-life care and on treatments of many diseases and conditions that affect older persons.

In addition to funding research, research training and career development, NCCAM is supporting the development of medical/nursing school model curricula. The Center also mounted a public communications program.

Council members thanked Dr. Straus for his presentation and raised several issues. One was the challenge of selecting what to study when findings are few. Dr. Straus responded that public health implications and level of evidence play a role in deciding priorities and level of support. Small placebo controlled studies that resulted in encouraging evidence are prerequisite to decisions about major investments. Council members pointed out that much of medicine is not evidence-based. A second issue is the power of the placebo and the importance of studying it. Dr. Straus responded that a November meeting will take place on placeboes. He added that he is interested in understanding the placebo as a therapeutic tool. A third issue was whether the NCCAM is interested in studying components of botanicals to identify effective parts. Dr. Straus responded that the Center is likely to study the whole plant or the whole in relation to its parts while other ICs, in complementary studies, might study constituent parts. Other discussion issues included the nature of collaboration with Native American groups, public health communication, and demographic characteristics of CAM users.

7. Program Highlights

A. Dr. Fred Gage, of the Laboratory of Genetics at the Salk Institute in La Jolla and a member of the National Advisory Council on Aging, was introduced by Dr. Marcelle Morrison-Bogorad, Associate Director of the Neuroscience and Neuropsychology of Aging Program. Dr. Gage spoke about age- and injury-related neuronal atrophy, and the reversal of neuronal dysfunction by specific cell nutrients called neurotrophic factors. He also addressed the translation of basic science findings into clinical science.

Dr. Gage began with an overview of the consequences of injury to a neuron (Horner, P.J. and Gage, F.H., Nature 407:963-970; 2000). Injury can induce a loss of the myelin sheath that wraps around neuronal processes, retraction of neuronal axons in a process called retrograde degeneration, and neuronal cell death. In addition to consequences to the neuron, injury can also activate another cell type in the nervous system, the astrocyte, which through the production of various molecules plays a role in the overall degenerative process. The remainder of the talk focused on basal forebrain cholinergic neurons and their response to aging and disease processes.

The basal forebrain cholinergic neurons make connections with neurons in the hippocampus and cortex, brain areas involved with learning, memory, and other higher cognitive processes. These cholinergic neurons were one of the first neurotransmitter systems shown to be deficient in Alzheimer's disease, and existing therapeutic treatment of Alzheimer's disease is based on drugs that enhance the functioning of the cholinergic system. Numerous studies have described a family of neurotrophic factors that provide nourishment for cholinergic neurons. Nerve growth factor (NGF), the best characterized of these neurotrophic factors,has been shown to promote the survival and maintain optimal functioning of basal forebrain cholinergic neurons. If cholinergic neurons are disconnected from their target cells so that they are deprived of NGF, the neurons become dysfunctional and atrophy, a response that can be prevented by NGF. Considered a potent "rescue factor" for damaged cholinergic neurons, NGF prevents cholinergic neuron death after injury, reverses atrophy of cholinergic neurons in aging, augments cholinergic neuron function, and improves memory perfomance in aged or lesioned rodents.

These basic research findings have prompted the use of NGF in human clinical trials, but the first clinical trials indicated that direct injection of NGF resulted in significant side effects, particularly pain syndromes in the periphery. Due to the clinically-relevant biological activity of NGF, alternative ways of providing NGF to dysfunctional cells, such as local delivery to the site of action, are being explored. Dr. Gage described the concept of gene therapy as a way of delivering proteins to selected populations of cells (Gage F.H., Nature 392:18-24; 1998). There are two approaches to gene therapy, direct and indirect. The direct approach involves inserting the gene of interest into a viral-based vector and then injecting the vector into the organism. The indirect method involves inserting the gene of interest into cells and then transplanting the genetically altered cells into tissues of the organism. Dr. Gage and others are using autologous cells in which cells from a particular individual are obtained, grown in culture, transfected with the gene of interest, and then transplanted back into the same individual. This approach avoids immunological rejection of the transplanted cells by the host immune system.

The approach was used to deliver NGF to the brains of aged rats and rhesus monkeys. In rats, transplantation of NGF-producing autologous cells into the brain reversed the age-related decline in the number and size of basal forebrain cholinergic neurons. NGF-producing cell grafts also improved spatial learning and memory performance of aged rats. These studies have been extended to the aged monkey brain. Aging in monkeys is associated with extensive atrophy of basal forebrain cholinergic neurons as evidenced by decreases in the number and size of cells labeled with specific cholinergic cell markers (Smith D.E., et al., Proc Natl Acad Sci USA 96:10893-10898; 1999). Skin biopsies were obtained from aged monkeys, skin cells were grown in culture and the human NGF gene inserted into the cells. Transplantation of these NGF-producing skin cells into the basal forebrain region of aged monkeys reversed the atrophy of the cholinergic cells. Transplantation of control cells, i.e., genetically modified but not producing NGF, failed to reverse the cholinergic cell atrophy.

These results, and others, formed the basis for a recently approved clinical trial to test the safety and efficacy of NGF-producing autologous cells in patients with Alzheimer's disease. This safety-trial will be a dose escalation study in eight patients in which there will be four cell doses with two patients per dose. The patients will be monitored by magnetic resonance imaging (MRI) and will undergo neuropsychological testing at defined intervals after cell transplantation.

Dr. Gage concluded his presentation with a summary of the traditional views of death and plasticity of the central nervous system, and how emerging findings are challenging these views. For example, the adult brain retains a significant capacity for regeneration and self-repair. Cell replacement may even be possible by stimulation of the self-renewing properties of the nervous system.

Discussion raised questions on whether the neurons that apparently disappear or atrophy become un-differentiated or proliferative, on what happens to the transplanted skin cells over time, on the response of the host brain to the transplanted cells, on the need for inducible or regulatable vectors in which the gene of interest could be turned on or off as needed, and on aspects of the upcoming clinical trial using genetically modified cells for transplantation in Alzheimer's disease.

B. Dr. MaryFran Sowers, Professor of Epidemiology at the University of Michigan, was introduced by Dr. Evan Hadley, Associate Director of the Geriatrics Program (GP). Objectives of her talk were to present findings relevant to emergent osteoarthritis at midlife and what it represents.

Osteoarthritis (OA) may be described from a physiological or functional perspective. Physiologically, OA is a condition of the softening, fibrillation, ulceration, and loss of articular cartilage. It is characterized by bony osteophyte formation, the presence of bony cysts, and ultimately, the exposure of the subchondral bone. Functionally, it is the substantial pain, disability, and limitations in physical function associated with OA that lead to its diagnosis and treatment. Treatment can range from self-management, alleviating pain through pharmaceutical means, to surgical strategies. Although established risk factors include increasing age, body size/obesity, joint injury, and female sex, the pathophysiology of OA remains elusive.

Because OA has been considered a disease of the elderly, few population-based studies have examined the frequency and characteristics of OA in persons under age 55 and consequently the time course and natural history for the development of OA is poorly understood. Until recently, only one other study, of the Zoetermeer population (from The Netherlands), has evaluated younger individuals (van Saase, J.L., et al., Ann Rheum Dis 48:271-80; 1989). Furthermore, few studies have also focused on non-Caucasian populations.

In Dr. Sowers' work, two study populations of pre- and perimenopausal women were evaluated to determine the prevalence of osteoarthritis. One study, the population-based Michigan Bone Health Study (MBHS) includes 602 women who were aged 25-45 at baseline in 1992 and had subsequent follow-up visits in 1996, 1998, and 2000. The second population-based study evaluates women from the Michigan site (in Ypsilanti and Inkster) of the Study of Women's Health Across the Nation (SWAN) where examination of osteoarthritis and related changes in physical functioning is a site-specific study component assessed in 1996, 1998, and 2000. The SWAN group of 319 African American and 227 Caucasian women, who were aged 42 to 52 at baseline in 1996, include hand and knee films protocols consistent with those of the MBHS (Sowers MF., et al., Osteoarthritis Cartilage 8:69-77; 2000). Because these two studies used the same measures at comparable time intervals, the values can be pooled to yield a population of over 1000 women in a relatively restricted age range.

In the combined cohort, the prevalence of OA, defined radiographically, of the knee and hand in women between 27 and 39 was less that 1.5 percent. However, there was a steep increase in the 40-44 year age group such that the prevalence jumps to 15 percent in the knee and 14 percent in the hand. The prevalence of OA increased with age in both African Americans and Caucasians with the suggestion that beyond age 50, African American women may be at greater risk of this condition. These studies strongly suggest that radiographically-defined OA of the hand and knee is common in women soon after the age of 40 and that OA emerges rapidly between 35 and 40 years in both African-American and Caucasian women.

Since OA affects a substantial proportion of women at midlife, primary prevention of OA should be considered earlier, in young adulthood, to curtail the emergence of OA at mid-life. Further efforts are needed to identify sensitive risk factors and to improve risk assessment and diagnosis earlier in life. Future avenues of exploration include the use of state-of-the-art technologies such as MRI and the identification of new, sensitive biomarkers such as C-reactive protein and other pro-inflammatory products.

In discussion, Council asked for clarification on how C-reactive protein can be a marker of both cardiovascular disease and osteoarthritis since those two diseases must overlap significantly for that to be true. Dr. Sowers said that it is known to be an acute phase marker, an inflammation marker that tracks with a risk factor for OA. It predicts OA apart from obesity and suggests that a condition never before thought of as being an inflammatory one has a more measurable inflammatory component than previously thought.

C. Dr. Becca Levy, Assistant Professor in the Department of Epidemiology at Yale University, who is working at the intersection of social psychology and epidemiology, was introduced as the next speaker by Dr. Richard Suzman, Associate Director of the Behavioral and Social Research Program. Dr. Levy presented her research on the impact of stereotypes on health and functioning (Levy, R. R., et al., J Gerontol:Psych Sci 55B : 205-213; 2000).

The overall question guiding the research asks if aging self-stereotypes, or older individuals' beliefs about the elderly, have a direct impact on their health, particularly on physiological function. The study included a positive age stereotype intervention and a negative age stereotype experimental condition. In both, the words were presented subliminally. Using words generated by older adults, the positive age stereotype intervention included words such as wisdom or insightful, whereas the negative intervention included words such as senility and dependence.

In earlier research using this intervention, it was found that positive age stereotypes improved memory performance, walking speed, control of handwriting, will to live, and self-efficacy. Those in the negative stereotype condition showed declines in these measures. In previous studies of young and older adults, effects were found on the old and not on the young.

Dr. Levy focused on whether aging self-stereotypes may influence cardiovascular response to stress because cardiovascular disease is common in old age and because of research suggesting that the cardiovascular system may be particularly sensitive to psycho-social variables. A cardiovascular response to stress paradigm was used with 54 individuals between the ages of 62 and 82, and baseline measures were taken in systolic blood pressure, diastolic blood pressure, heart rate and skin conductance. Participants were randomly assigned to either a positive age stereotype group or a negative age stereotype group, stress was induced with mathematical and verbal challenges, and then follow up measurements were taken. The change from baseline to follow-up in systolic blood pressure indicated a significant difference between those who were exposed to the positive age stereotypes and those who were exposed to the negative age stereotypes, with the negative stereotypes showing a significantly heightened cardiovascular response to stress.

Moreover, multiple cardiovascular measures were taken during the study, and Dr. Levy found that most of the effect occurred during the initial exposure to the negative age stereotypes, before participants were given mathematical and verbal stressors. It appears the negative age stereotypes alone were bringing about the cardiovascular response. There was a similar pattern for skin conductance. One cognitive measure was included and a significant difference in performance between the groups was found. The measure of self-efficacy also varied significantly between the groups.

It appears that aging self-stereotypes may influence physiological function, even when older adults are not aware of their exposure to them. Negative aging self-stereotypes seem to act as direct cardiovascular stressors and positive aging self-stereotypes seem to reduce cardiovascular stress.

In discussion, Council asked how the study clearly established a link between what was described and an age-based self-stereotype. Dr. Levy explained that this response was found only in the old and not in the young in the experimental studies. A similar pattern was found in cross-cultural research. Another question from Council was whether the findings might indicate a response to stress--that perhaps exposure to words like love and affection versus war and conflict would have the same result. Dr. Levy commented that she thought age stereotypes themselves are effective but that the suggestion could be pursued in a follow-up study.

D. Dr. Timothy McCaffrey, Associate Professor of Medicine at the Joan and Sanford I. Weill Medical College, New York, was introduced by Dr. Huber Warner, Associate Director of the Biology of Aging Program. Dr. McCaffrey spoke about his research on TGF beta 1 receptors in restenosis and aging.

Advancing age is the most significant factor in the development of atherosclerosis. More than 40 percent of the 300,000 elderly patients treated by angioplasty for coronary atherosclerosis develop a fibroproliferative lesion that reoccludes the artery within 6 months. The mechanism of this restenosis is unknown, and thus, it has been resistant to therapy.

An age-related defect has been identified in the proliferative capacity of vascular smooth muscle cells (SMC) related to the specific loss of Type II receptors for transforming growth factor-ß1 (TGF-ß1) due to a loss of the mRNA for the Type II TGF-ß1 receptor in atherosclerotic SMC. The lesion-derived cells show no growth inhibitory response to TGF-ß1. Transfection of Type II receptor cDNA corrects the aberrant behavior of the lesion-derived cells. In some patients, the loss of the Type II receptor is due to frame-shift mutations in replication error-prone regions of the Type II receptor gene (McCaffrey, T.A. et al., J Clin Invest 100:2182-2188 (1997). Because TGF-ß1 is overexpressed in fibroproliferative vascular lesions, such as restenosis after balloon angioplasty, this selective loss of growth inhibitory response to TGF-ß allows the SMC to grow in a slow, uncontrolled fashion, and strongly favors extracellular matrix accumulation.

Atherosclerosis and restenosis could result from a 'failure to die' by vascular repair cells, but the mechanism that protects them is unknown. As described above, an age-related defect has been documented in the response of vascular smooth muscle cells to TGF-ß1. In vivo , old rats show an excessive, and more persistent neointimal hyperplasia in response to injury. In vitro, SMC derived from old rats show enhanced serum-independent growth compared to cells from young rats. This can be explained by a loss of the antiproliferative response to TGF-ß1, an autocrine growth inhibitor. This resistance to TGF-ß is due to loss of the TGF-ß Type II receptor (TßR-2), which is required to convey an antiproliferative signal.

It was further established that cells derived from human atherosclerotic lesions are also resistant to TGF-ß1. As in the aged rat, the acquired resistance is due to decreased expression of TßR-2. Transfection of TßR-2 cDNA partially restores the antiproliferative response. Although a subset of patient cell lines express mutations in the receptor, it is believed that in most cases the receptor is transcriptionally suppressed.

Dr. McCaffrey's group screened the following using cDNA arrays: (1) old versus young rat arteries, (2) human lesions versus adjacent media, and (3) lesion-derived versus medial-derived cells, for factors that might suppress TßR-2 transcription. The results identified Egr-1, a zinc-finger transcription factor, as one candidate factor that was highly expressed in lesions compared to the adjacent media. The most recently published work demonstrates that Egr-1 potently suppresses transcription of TßR-2, and thus, may be the underlying cause of resistance to TGF-ß in lesion cells (McCaffrey, T.A., et al., J Clin Invest 105: 653-662; 2000).

The 'failure to die' phenotype results from acquired resistance to growth inhibitors and apoptotic factors, such as TGF-ß. This acquired resistance results from transcriptional suppression of one of the TGF-ß receptors. Thus, while the prior model was based on the concept that receptor loss was a passive defect that conferred resistance, the new data indicates that TGF-ß receptors are actively suppressed by Egr-1, or related factors. This active resistance appears to extend beyond just TGF-ß, and thus, it is potentially a powerful explanation for the aberrant behavior of cells in the lesion. Future studies will use high-throughput screening (HTS) to identify the nature of TGF-ß resistance.

Dr. McCaffrey and his colleagues took a similar approach in studying the in vitro and in vivo aging of the artery. Acquired resistance to TGF-ß and glucocorticoids had been identified in cells from the aorta of aged rats (20 mo old Fisher 344). Cells from young rat aortas are initially sensitive to TGF-ß, showing both an antiproliferative response and an apoptotic response. As these cells are subpassaged, they acquire resistance to both TGF-ß and glucocorticoid-induced inhibition and apoptosis. Using genomic arrays, a 28-fold increase in nur77 (NGFI-B), a factor closely related to Egr-1 (NGFI-A), was identified. In addition, a number of other genetic changes were identified that were consistent with active resistance to apoptosis in these cells. Uninjured, young versus old F344 rat aortas were recently examined by genomic arrays (Clontech 1200 gene). Again, among the most elevated genes were

Egr-1, which had a 1.5-fold increase in steady-state levels.

The resistance of lesion cells to inhibitory factors may be a key determinant of their pathological behavior. By selectively manipulating particular genes, it is hoped that the defect can be recreated, or conversely, corrected. The ability to alter the behavior of the lesion cells should lead to natural wound repair after vascular injury, and may encourage regression of existing atherosclerotic lesions.

In discussion, Council expressed interest that two apparently distinct mechanisms degenerate the same regulated endpoint. Dr. McCaffrey explained that he showed only the two parts that are known to be causally related--but the phenotype of resistance is related to an entire family of factors which modulate the sensitivity to apoptosis. Council inquired about eventual application in clinical circumstances.

Dr. McCaffrey said it is possible that by attacking the multidrug resistance in some cells, those cells can be made sensitive to therapies that have formerly proven ineffective.

8. Comments From Retiring Members

Dr. Patricia Goldman-Rakic commented that NIA is a model Institute and that it has been a privilege to be on this Council which is exemplary in its capacity as a working Council, that the level of professionality and scholarship of the NIA staff is outstanding, and the involvement of the Director at all levels of interaction with the staff and with Council is especially unusual. She said serving on the Council has been very enriching and that the people of this country and world-wide are fortunate to have such a group working in this extraordinary way.

Dr. Richard Goldsby agreed with Dr. Goldman-Rakic and added that it had been an extraordinary privilege to be on Council and that the taxpaying public needs to know this is a place where there is absolutely no concept of a 40-hour week.

Dr. Jack Rowe commented on how remarkable it has been that the NIA has carved a fundamental niche in the panoply of NIH and identified its agenda; that its agenda is built from the science up and that, in many ways, NIA has led the way at NIH in communicating with society, fostering interdisciplinary activities, and communicating and partnering with other Institutes. He added that it had been a privilege to be associated with the Institute and a great pleasure to see it grow and prosper.

9. Adjournment

The 81 st meeting of the National Advisory Council on Aging was adjourned at 4:20 p.m. on September 27, 2000. The next meeting is scheduled for February 6-7, 2001.

10. Certification

I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete. (3)

Richard J. Hodes, M.D.
Chairman, National Advisory Council on Aging
Director, National Institute on Aging

Prepared by Miriam F. Kelty, Ph.D.

Attachment A

MEMBERSHIP ROSTER, NATIONAL ADVISORY COUNCIL ON AGING

Richard J. Hodes, M.D., Chair
Director
National Institute on Aging
National Institutes of Health
Bethesda, Maryland 20892

Ausiello, Dennis A., M.D. (2003)
Chief, Medical Services
Massachusetts General Hospital
Boston, Massachusetts

Barrett-Connor, Elizabeth L., M.D. (2000)
Professor
Department Family and Preventive Medicine
School of Medicine
University of California - San Diego
La Jolla, California

Cambier, John D., Ph.D. (2003)
Ida and Cecil Green Professor and Chairman
Department of Immunology
University of Colorado Health Sciences Center and National Jewish Medical & Research Center
Denver, Colorado

Campisi, Judith, Ph.D. (2002)
Senior Scientist
Division of Cell and Molecular Biology
Lawrence Berkeley Laboratory
University of California
Berkeley, California

Dobrof, Rose, DSW (2002)
Brookdale Professor of Gerontology
Brookdale Center on Aging
Hunter College of the City of New York
New York, New York

Gage, Fred H., Ph.D. (2001)
Professor
Laboratory of Genetics
The Salk Institute
La Jolla, California

Goldman-Rakic, Patricia S., Ph.D. (2000)
Professor of Neuroscience
Department of Neurobiology
Yale University School of Medicine
New Haven, Connecticut

Goldsby, Richard A., Ph.D. (2000)
Professor
Department of Biology
Amherst College
Amherst, Massachusetts

Harper, Mary S., Ph.D. (2001)
Geropsychiatric Research Consultant and Distinguished Adjunct Professor
The University of Alabama
Tuscaloosa, Alabama

Hatfield, Mark O. (2001)
Retired U.S. Senator
Portland, Oregon

Rowe, John W., M.D. (2000)
President and CEO
Mount Sinai - NYU Medical Center & Health System
Mount Sinai Medical School
New York, New York

S iegler, Ilene C., Ph.D., MPH (2003)
Professor of Medical Psychology
Department of Psychiatry & Behavioral Sciences
Duke University
Durham, North Carolina

Footnotes

1. For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions, or (b) in which a conflict of interest may have occurred. This procedure only applied to applications that were discussed individually, not to "en bloc" actions.

2. For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions or (b) in which a conflict of interest may have occurred. This procedure only applied to applications that were discussed individually, not to "en bloc" actions.

3. These minutes will be approved formally by the Council at the next meeting on February 7, 2001, and corrections or notations will be stated in the minutes of that meeting.