Council Minutes - September 2002

National Advisory Council on Aging

Summary Minutes: The Eighty-Seventh Meeting

September 24-25, 2002

CONTENTS

1. Review of Applications
2. Comments from the Director, NIH
3. Call to Order
4. Report: Task Force on Minority Aging Research
5. Report: Working Group on Program and Clinical Investigators Working Group
6. Comments from the Floor
7. Comments from Retiring Members
8. Program Highlights
9. Adjournment
10. Certification

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

The 87th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, September 24, 2002, at 3:00 p.m., in Building 31, Conference Room 10, 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 closed to the public on Tuesday, September 24, from 3:00 p.m. to 5:00 p.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] The meeting was open to the public on Wednesday, September 25, from 8:00 a.m. to 12:25 p.m.

Council Participants:

Dr. Dennis Ausiello
Dr. John Cambier
Dr. Judith Campisi
Dr. Rose Dobrof
Dr. David Espino
Dr. Lewis Kuller
Dr. Stanley Prusiner
Ms. Judith Riggs
Dr. Ilene Siegler
Dr. Phyllis Wise

Ex-Officio Participants:

Dr. James Burris (VA)
Dr. George Fuller (USUHS)
Mr. John Wren (AoA)
Dr. Elias Zerhouni (NIH)

Absent:

Dr. Myron Weisfeldt
Dr. David Wise

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

Members of the Public Present:

Dr. Robert Butler, International Longevity Center
Ms. Angela Clear, Analytical Sciences, Inc.
Dr. Michael Gloth, Victory Springs Senior Health Care Ms. Linda Harootyan, Gerontological Society of America
Ms. Sara Keitt, Society for Womens' Health Research
Dr. Rose Maria Li, Analytical Sciences, Inc.
Dr. Jeanne Mandelblatt, Georgetown University
Ms. Carol Schutz, Gerontological Society of America
Dr. James Smith, RAND Corporation
Dr. Leon Thal, University of California, San Diego
Ms. Tamara Thompson-Johnson, American Association of Colleges of Osteopathic
Medicine (AACOM)
Dr. Herman Vandenburgh, Brown University

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

Mr. Donald Grantt, AoA
Ms. Janet Gregory, NIDDK
Dr. K. Krishnan, CSR
Ms. Nancy Miller, OD, OSP
Dr. Elliott Postow, CSR
Dr. Sherry Stuesse, CSR

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 590applications requesting $512,094,087 for all years underwent initial review. Council recommended 393for a total of $364,525,671 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. Comments from the Director, NIH

Dr. Hodes introduced the new NIH Director, Dr. Elias Zerhouni. He described Dr. Zerhouni as someone who represents a unique combination of scientist and administrator, and who has brought a very thoughtful and inclusive but evidence-based process to challenge in a positive way not only the science that NIH supports, including the identification of scientific priorities, but also the way that NIH conducts its business.

Dr. Zerhouni began his comments by underscoring the key role of Advisory Councils to the work of NIH. He credited two important reasons for NIH success: (1) the peer-review and funding system and the investigator-initiated process, which allows science to adapt continuously; and 2) the reliance on so many participants at NIH Councils, peer-review sections, and other groups to set the agenda and aid NIH in promoting biomedical research. Every year, about 21,000 people help NIH by reviewing grants, participating in ad hoc groups, and providing advice. Few, if any, government agencies solicit advice, seek counsel, and remain in touch with communities as NIH does. Dr. Zerhouni expressed appreciation to Council members for their help, guidance, and hard work, and proceeded to share some of the challenges facing NIH.

Given the economic challenges today—declines in the stock market, federal deficits replacing federal surpluses, and new emergency requirements that have been imposed by defense and bioterrorism initiatives—Dr. Zerhouni remarked that NIH will need to be especially good at making decisions, setting priorities, and continuing the momentum in science. There is also demand for accountability about how NIH has spent its doubled budget and for justifications for continued investment in NIH. Noting the renewal of threats emerging and reemerging, the data on diabetes and obesity, and the incredible growth in health care expenditures, Dr. Zerhouni concluded that the mastery of life sciences is a top priority of the century if we are to succeed in containing the federal budget and maintaining the integrity of our social fabric. Dr. Zerhouni acknowledged that this is no small challenge, but curtailing investment in knowledge would be foolish. Dr. Zerhouni called on the Council members and staff not to lose sight of life sciences as one of the last frontiers of knowledge to master, despite remarkable progress.

Dr. Zerhouni understands that NIA focuses not on a disease but on a phase of life. As a result, NIA needs to stimulate research across other institutes and Council may benefit from coordination with other Institute Councils. He observed that there is a need for more formal trans-Council interactions and coordination across the NIH, and recognized Dr. Hodes as supportive of greater efforts at integration.

Dr. Zerhouni outlined three challenges for continuing scientific progress: (1) the complexity of research today, requiring strategies for reinforcing scientific teams and their components and for how new technologies will be conceived; (2) access to enabling resources for the biomedical sciences, including biocomputing, libraries of molecules and complete series of reagents to perform experiments, and the ability to analyze the results; and (3) strengthening the system of clinical research, requiring a strategy to reduce the currently prohibitive costs of correlating phenotype and genotype on a large scale, creating databases interoperable between trials, and looking at the diverse populations across the United States to identify trends early.

He then invited Council members to share their views. The Council members introduced themselves individually to Dr. Zerhouni before the question and answer period.

In response to a question about the implications of smaller increases in the NIH budget,
Dr. Zerhouni echoed his sentiment that the unsolved challenge remains life sciences. He would like to present the evidence that investing in NIH has paid dividends and noted that even though the budget has doubled, the purchasing power of research has not doubled. Institutions have made huge investments in research space and faculty, and abrupt changes in investments cannot be good policy. Dr. Zerhouni stated that we cannot expect 15 percent increases forever, and we need to make strong arguments for continued investments in NIH research. A Council member observed that NIH went through a growth period in the 1990s, and the growth of biotechnology rode the wave of the information technology boom, making careers in biotechnology more and more attractive. But now with the stock market going down, he expressed concern that biotechnology is on the decline, which is frightening to the whole biomedical enterprise because biotechnology is as important as academic biomedical research. Dr. Hodes underscored
Dr. Zerhouni's points that we need to make our arguments as compelling as possible for maintaining support for biomedical research.

A Council member raised the issue of NIH's need to adjust to the complexity of research today and to encourage discussion of cross-cutting issues. Dr. Zerhouni acknowledged that a “silo” effect exists across the biomedical training enterprise. The first step is to encourage schools to create joint programs of new emerging disciplines and pathways, particularly because the convergence in science makes it difficult to identify to which department particular work belongs. Council members added that it is important to bring in people from the fringes and to promote interdisciplinary dialogue among researchers in such fields as engineering, physics, chemistry, mathematics, and biology. Council members stated that NIH should advocate for the importance of such interdisciplinary interactions, and the Council could discuss possible mechanisms for this.

In addressing a question about how well NIH evaluates innovative research, Dr. Zerhouni agreed that there are some problems, but he believes that peer review has served NIH well. He suggested we consider creating a different path for high-impact research. Arguing for shorter applications, a council member noted that Larry Ellison, the CEO of Oracle, has put $100 million into aging research with innovation as the highest priority, and the applications are short and simple. European grants also tend to be short and concise at 10 pages. It can be difficult to grasp innovation when wading through 25 pages. Dr. Zerhouni stated that we need to be vigilant about promoting innovation, but he also recognized that there is great variety in the types of research supported. As a field matures, the requirements for rigor increase. For a young field, three to five pages might suffice; for more mature fields, perhaps more details are required. Another member related his difficulties in advocating for innovative applications in study sections and suggested that study sections should be reminded about the importance of innovation in review. Members added that the issue is a difficult one to solve because real innovation is only recognized after the fact. Publication record could be a main criterion. Study section members can and do get excited about innovation, but excitement can be dampened by reading background information. It is important not to stamp out creativity, but equally important not to frustrate applicants by limiting the pages in which they can make their case. Dr. Zerhouni concurred that a good track record from published works can provide sufficient indication of rigor. A member observed that the Council is faced with a similar problem: sometimes applications that fare poorly in the study section are brought to the Council because of innovation, but if we believe in the peer–review system, it is difficult to second guess the study section and be fair to everyone in the process.
Dr. Zerhouni suggested that instead of a half–page summary abstract, a three–page executive summary could be used to highlight innovation.

A member suggested that programs across institutes get together to address a specific problem rather than segmenting research by institute. In working with the AIDS groups, for example, he described total confusion about which Institute/Center (IC) supports which part of the research program.

Coming from the perspective of someone at an organization that works with Congress on NIH issues, a member praised NIA as a model for maximizing effective use of resources and encouraging collaborations across external groups, and stated that NIA needs to make the value of this activity clear to Congress. We need to be careful to show a seamless progress in facilitating how good science comes together. Examples of success stories can be effective ways to communicate this. Dr. Zerhouni acknowledged that coordination and integration is an inherent challenge in a growing and complex organization such as NIH.

3. Call To Order

Dr. Hodes called the meeting to order at 8:10 a.m. on Wednesday, September 25, 2002, and welcomed members.

Director's Status Report

Dr. Hodes highlighted a number of pressing issues at NIH. The NIH Director, Dr. Elias Zerhouni, has initiated a planning process to identify priority areas. Dr. Zerhouni asked five IC directors to convene a meeting of about 20 people to discuss topics ranging from research infrastructure to clinical research challenges. The groups' recommendations are to be combined, common themes identified and these will be used to guide the FY2004 budget process. The process reflects Dr. Zerhouni's intent to gather diverse input in the planning process.

Dr. Hodes turned to the topic of the administrative re-organization of the NIH. Consolidating many of NIH's administrative functions is a visible topic for this administration, beginning first with human resources. Several human resources (personnel) offices will be consolidated to promote greater efficiency and consistency. NIH leaders are doing their best to effect a smooth transition. Other areas are being discussed for similar consolidation.

The Institute of Medicine (IOM) has renewed efforts to look at the organization of the NIH now that an NIH director has been appointed. The IOM will make recommendations on whether the organization and grouping of ICs within the NIH is optimal, and if not, how the NIH should be reorganized.

Turning to personnel, Dr. Hodes reported on a number of IC director vacancies and appointments. There are ongoing searches to identify new directors for the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Drug Abuse (NIDA), and the National Institute of General Medical Sciences (NIGMS). Recently, Dr. Roderic Pettigrew was named as the new director of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), Dr. Thomas Insel was selected to lead the National Institute of Mental Health (NIMH), and Dr. Ting-Kai Li was named to head the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

Dr. Hodes updated the Council on the NIA budget situation. The NIA FY2002 budget was $893 million. The President's proposed FY 2003 budget for NIA is $950 million, a 6 percent increase from FY2002. It is unclear if the Senate's recommended 10.7 percent increase will be sustained. It seems likely that the NIH will be operating at the beginning of FY2003 under continuing resolutions (CR) of uncertain duration. Under this scenario, NIA will operate as if funded at the FY2002 level. The terms of the CR are at the discretion of Congress. At times, this has delayed new research initiatives. The extent to which programs are disrupted depends on how “new initiative” is defined. Although a CR is not expected to impair operations in October or November, a longer period without an appropriation could be challenging. The upcoming elections may further delay the budget deliberation process.

Comments in Honor of Florence Mahoney

Dr. Robert Butler, founding director of NIA, gave a tribute to Florence Mahoney. The tribute was part of a formal ceremony to name the NIA conference room in honor of Ms. Mahoney.

Dr. Butler said that it was a pleasure to speak about this visionary and activist who, at 103, is a national treasure. He began his tribute by giving a brief biography of Ms. Mahoney, noting that she was born Florence Sheets near Muncie, Indiana. As a girl, she was interested in medicine but did not go to medical school. Instead, she married Daniel Mahoney, who was from a Miami journalist family. From 1946 to 1956, Ms. Mahoney wrote a Sunday column on women's issues. She felt strongly that women's issues were not receiving enough quality attention. She persuaded the newspaper to focus more on health and biomedical issues. Along with her friend and fellow activist, Mary Lasker, she enjoyed discussing science and mobilizing Congress to address these issues. For example, Ms. Mahoney led the effort to establish the NIA, and also founded the Alzheimer's Association. Dr. Butler commended Ms. Mahoney as a woman who had the brilliant intuition to recognize the uniqueness of aging and the importance of understanding the underlying biology. At the same time, she was lauded as a master of friendship and a woman to whom many people found it impossible to say “no.” Dr. Butler concluded by saying that “We would not have NIA, or much of NIH without her.”

Dr. Hodes echoed Dr. Butler's sentiments about Ms. Mahoney and talked fondly of his visits with her and their discussions about the annual Florence Mahoney lecture. He noted that the last Mahoney lecture stimulated just the kind of exchange she would have savored. Dr. Hodes then held up the plaque that will be placed at the entrance to the NIA conference room and thanked Ms. Mahoney for all that she has done. Although Ms. Mahoney could not be in attendance, a videotape of the ceremony will be presented to her at Dr. Hodes' upcoming visit.

Future Meeting Dates

• February 4-5, 2003(Tuesday-Wednesday)
• May 20-21, 2003 (Tuesday-Wednesday)
• September 23-24, 2003 (Tuesday-Wednesday)
• February 3-4, 2004 (Tuesday-Wednesday)
• May 24-25, 2004 (Monday-Tuesday)
• September 23-23 2004 (Wednesday-Thursday)
  

Consideration of Minutes of Last Meeting

The Minutes of the May 2002 meeting were considered. A motion was made, seconded, and passed to approve the Minutes.

4. Report: Task Force on Minority Aging Research

Dr. David Espino gave a brief report on behalf of the Task Force on Minority Aging Research. He updated council members on the status of the Request for Applications (RFA) on aging, race, and ethnicity in prostate cancer, noting that 25 applications were received and six were selected for funding. A second RFA, Research Centers for Minority Aging Research, received many applications and was highly competitive. Six institutions were selected for funding, and a coordinating center will be identified soon.

Dr. Espino then requested input from the Council members on training grants. In the past, there have been supplements to training grants that have been set aside for minorities. Should there be supplemental funds for those interested in minority aging but not limited to minority applicants? The group was encouraged to provide feedback on this proposal and also to attend the next Task Force meeting.

5. Report: Working Group on Program and Clinical Investigators Working Group

1. Report on Geriatrics and Clinical Gerontology Program Review

Members of the Working Group on Program reported on the Council review (chaired by Dr. Weisfeldt) of the Geriatrics and Clinical Gerontology (GCG) program. Among recommendations from that review that were mentioned in the working group discussion were: (1) The new requirement in the Older American Independence Center RFA that applications focus on a single theme. Reviewers had asked that the program reconsider this requirement to allow individual directors to best shape their applications to match the conditions at their local institutions; (2) Reviewers and working group members encouraged research on rate of aging in different species and including humans in the comparison; (3) Reviewers had sought a broader investigation on processes that occur in the first half of life that are relevant to the diseases and conditions of late life. They considered the current focus on menopause as important but limited in this regard; (4) Concerning exceptional longevity, reviewers encouraged focus on precursors to longevity in 40 to 70 years old populations, recognizing that such a focus will require sophisticated modeling techniques. Dr. Hadley, the Associate Director of GCG, indicated that the full report contained a broader set of recommendations and urged Council members to read it in full.

2. Clinical Investigators Working Group

Members of the Clinical Investigators Working Group reported that they are making progress in their deliberations, noted the difficulty of the task and that another meeting organized by Dr. Salerno will occur in November and will develop recommendations. The group agreed that the training of clinical investigators has to start in medical school and progress through the postdoctoral years, but they concluded that a review of training programs is necessary to provide information on how to structure and strengthen the mentor/mentee component. After the November meeting, the group will develop a report, with the goal of presenting a plan of action by the February 2003 Council meeting. Dr. Hodes commended Dr. Judy Salerno for organizing the November meeting.

Dr. Salerno added that the upcoming meeting will focus on early training in aging research, beginning in medical school and extending through career development as independent investigators and faculty members. She emphasized the importance of providing sustained support for those interested in aging research. Dr. Salerno invited Council members to attend and to help synthesize the meeting proceedings. Dr. Hodes reiterated the invitation for Council members to attend and said he would be happy to organize another meeting. As an alternative, it was also suggested that conference calls may be helpful to generate ideas for initiatives.

NIH Extramural Loan Repayment Program

The NIH Extramural Loan Repayment Program for clinically trained individuals was re-introduced NIH-wide in FY2002. The NIA received 38 applications and paid 35 of these. A working group has developed eligibility criteria for the program. In FY 2003, eligibility will be broader. Applicants will no longer need to be supported by an NIH grant. Instead, any individual who can document support for at least two additional years of research is eligible. Also, people who were not funded in FY2002 may re-apply. In addition, applications will be peer reviewed, and a tracking system for applicants will begin in FY2003. The timetable for the program was highlighted; it is expected that the next announcement will be published by the end of September, applications will be due by the end of November, and peer review will occur between March and May. Members may contact Dr. Kelty for more information or go to the NIA Web site.

3. Report on Geriatrics and Clinical Gerontology Program Review

NIA Neuroimaging Initiative

Dr. Neil Buckholtz reported on the results of a workshop considering an Alzheimer's Disease Neuroimaging Initiative to provide a resource for neuroimaging, biological samples, and clinical data to be made available to the public. The initiative is being planned as a partnership among the NIA/NIH, academic investigators, the pharmaceutical industry, and the imaging equipment industry, with participation from the Alzheimer's Association and the Institute for the Study of Aging. The June 17-18, 2002, meeting featured scientific presentations followed by an advisory meeting to develop recommendations on how best to proceed. The plan is to develop a 2 to 3 year study using serial neuroimaging, positron emission tomography (PET), and collection of fluid and DNA to identify biomarkers. Thus far, working groups have met to set up protocols on magnetic resonance imaging (MRI), PET, biological measures, and study design/subject characterization. Recommendations from these groups, along with an NIA budget estimate, are expected by October 15, 2002. Program staff will contact industry representatives for potential cosponsorship by the end of October. An announcement is planned by January 2003.

Dr. Hodes remarked that this initiative follows and is modeled on the osteoarthritis initiative that set an important precedent. Requiring all participants to agree that the resource not be encumbered by intellectual property claims is critical but does not preclude the development of intellectual property rights. Dr. Hodes said that, in developing the osteoarthritis initiative, NIH staff were initially unsure if pharmaceutical companies would contribute funds to the initiative with this restriction. It took an education process with pharmaceutical companies and academia to make this work. Dr. Hodes emphasized that public/private partnerships should maximize, not constrain the development of intellectual property. A Council member commended NIA for taking this action.

Immunobiology and Aging Conference

The Immunobiology and Aging Conference focused on changes that occur in the immune environment during the natural aging process. Topics discussed included lymphopoesis and hematopoeitic stem cells, thymopoesis and attenuated thymic function, vaccine responsiveness in the elderly, T-cell signaling and the immnunological synapse, homeostatis and regulatory T cells, and how B cells change with age. The conference participants identified areas of research that are under-represented and of critical importance, including studies of changes in the innate immune system with increasing age. Participants also underscored the importance of recruiting additional immunologists into the field. The development of vaccines specifically designed for an aging immune system was identified as another priority area. Dr. Hodes and several Council members praised the NIA staff on the success of this meeting.

Statin Drugs and Alzheimer's Disease

Dr. Susan Molchan from the Neuroscience and Neuorospsychology of Aging Program discussed the conference on Statin Drugs and Alzheimer's Disease. This meeting was convened in response to investigator interest and recent data on the effect of statins in lowering cholesterol. The meeting participants considered studies on cholesterol metabolism as well as research on the basic science, epidemiology, and treatment of Alzheimer's Disease. The group recommended that NIA wait before issuing an announcement for a prevention study, because results from an ongoing European study of pravastatin (U.K. PROSPER) will be available in November. The group also suggested that NIA consider an RFA on the basic science of cholesterol and lipoproteins in the brain and central nervous system.

Workshop on Genetics of Late Onset Alzheimer's Disease

Dr. Tony Phelps presented results from the conference on the Genetics of Late Onset Alzhemer's Disease, which was held March 18–19 in Bethesda, Maryland. The goal of the conference was to develop strategies for identifying remaining late onset Alzheimer's Disease genes, the associated environmental factors, and the interactions of gene and environment. The main recommendations from the conference were to (1) share existing data, (2) to collect cell lines from multiplex families and case control lines from the general population, (3) to follow up on existing NIA and NIMH samples to clarify phenotypic profiles and piggyback on samples from other longitudinal studies such as the Framingham and Honolulu Heart studies, (4) to standardize sample criteria, and (5) to increase the sample size of minority populations. Many of the recommendations have already been implemented. The Indiana cell repository has been identified as the site for data storage and is being expanded to handle additional data collection. A coordinating center has also been identified. However, issues such as data sharing, re-consenting existing families, and procedures for handling data still must be resolved by the cell repository's advisory committee.

Dr. Phelps was complimented on the success of this meeting, and a lively discussion ensued. Dr. Hodes said that maximizing accessibility to the repository is important. One Council member asked about the interest of private industry in gene markers, and how centers will interface with industry. Dr. Phelps responded that samples sent to Indiana are available for use. Anyone deriving information from those samples is asked to send the information back so that the data can be pooled. He added that companies may be less willing to send back information and that this policy needs to be worked out. NIH as a whole is wrestling with the best ways to collaborate with industry while maintaining academic integrity.

There was discussion about how informed consent will be handled. Dr. Hodes observed that Council members identified the complexity and challenges of informed consent and working with Institution Review Boards (IRBs) at multiple institutions, adding that the NIA is trying to provide a template for use in the consent process.

A Council member asked how the repository will handle data from studies in which people have signed varying levels of consent. Dr. Hodes replied that those individual consents must be honored, but dealing with the data analysis issues will be challenging. Seeking consent for future use of data from participants currently being recruited was seen by several Council members as satisfying IRB review requirements. But informed consent issues remain for materials that have been banked in the past. It was noted that the increased focus on training IRBs and IRB administrators may lead to improvements in this situation. Another member, noting the recent legislation on human subjects protections, observed the importance of becoming involved in the political environment to address barriers to research.

Proteomics and Aging Conference

Dr. Bradley Wise gave a brief overview of the planned meeting on proteomics and aging that will bring together experts in high throughput technologies in proteomics and people working in the field of aging research. The purpose of the meeting is to discuss how existing and developing proteomic technology can be used to understand how changes in proteomic function affect the aging process. The conference is tentatively scheduled for December and will be cosponsored by the Biology of Aging and the Neuroscience and Neuropsychology of Aging Programs.

Other Discussion: Program Highlights and NNA Program Review

The Working Group on Program discussed the Council format, particularly whether Council is satisfied with a single Program Highlight being presented by each program. After considering an alternate format such as a panel discussion of a single topic, Council expressed satisfaction with the current format. The Working Group reported on an initial discussion of the program review of the Neuroscience and Neuropsychology of Aging Program, that will take place in May 2003. Topics under discussion include the scope of the review and the potential Council members to be included.

6. Comments from the Floor

Guests and other NIA colleagues were asked to introduce themselves and share any comments.

Ms. Jane Shure, NIA's Public Affairs Officer, reported that recent McArthur Awards were given to a linguist who developed the talking Web and a choreographer for an intergenerational dance group. This same group, the Liz Lehrman Dance Exchange, has participated in a Public Service Announcement (PSA) for NIA's Exercise in Aging initiative. Ms. Shure presented video samples of the PSA in both English and Spanish, and circulated the press package that has been disseminated to 1,400 broadcast stations. Early feedback shows that Florida, Arizona, and other states with heavy senior populations are playing the PSA. In addition, half a million copies of NIA's Exercise and Aging book have been distributed, including 45,000 copies of a Spanish language version. Ms. Shure acknowledged Council member Dr. David Espino, who has been a critical part of this effort and has taken numerous press calls. Overall, there has been a steady stream of requests for the book. Dr. Hodes added that this public health campaign was based on years of evidence-based research findings. NIA hopes to use this as a model for other outreach efforts. A Council member suggested that it would be worthwhile to ensure there is no overlap between this effort and the CDC network of prevention centers, which has an initiative on exercise in the elderly. Ms. Shure said that she has collaborated with representatives from the CDC's Center for Chronic Diseases, and that Dr. David Buchner at CDC was an advisor on the book. The CDC is promoting physical activity while the NIA effort particularly emphasizes strength training. She also discussed a joint project involving the NIA, CDC, and the Older Women's League to evaluate whether the Exercise and Aging book actually changes individual habits.

7. Comments from Retiring Members

Four Council members completed their terms at this meeting.

Dr. Hodes thanked Dr. Judith Campisi, commending her as the epitome of the type of investigator NIA hopes to support. He said she has been generous with her time, critical input, and judgment, and noted that it was a pleasure to work with her as a friend and colleague.
Dr. Campisi said that it was a pleasure and privilege to work on the Council, especially under the leadership of Dr. Hodes, and that she would welcome the opportunity to return.

Dr. Hodes also commended Dr. Rose Dobrof for her commitment to service and for sharing her unique perspective as a social worker and social scientist. He added that she brought a humane perspective to the Council proceedings. Dr. Dobrof thanked the group for their kindness and said that it was a privilege to serve.

The contributions of Dr. David Wise and Dr. Myron Weisfeldt, who were not able to attend this Council meeting, were acknowledged.

8. Program Highlights

   
   

1. Biology of Aging: Tissue Engineering

Dr. Herman Vandenburgh, Brown Medical School, discussed a technology he and collaborators have been developing for 15 years that involves combining tissue engineering with gene therapy for long term delivery of recombinant proteins. Although the research team is interested in delivering many proteins of interest, such as growth factor, Epogen (EPO), and insulin, the first clinical trial using this technology will likely target hemophilia.

Dr. Vandenburgh explained that recombinant proteins are a major health-related industry. However, most researchers are currently using a gene therapy delivery method that is far from ideal. He also noted limitations of recombinant proteins, including their expense, and their short half life once they are injected. This means the researcher has to deliver very large doses, and/or large doses are required, which influences patient compliance and increases the likelihood of side effects. As an alternative, slow release hormones are now available that need to be re-injected only every 2 to 3 weeks, but ideally researchers would prefer to use cells and tissues to deliver recombinant proteins in a way that nature delivers them in the body and ultimately help the body make its own proteins.

Dr. Vandenburgh discussed the limitations of gene therapy using plasmid DNA or viral vectors for delivering recombinant proteins. These limitations include poor efficacy with delivery vehicles, limited stability, and short-term expression of the protein. In addition, there is no way to deliver the protein locally once the viral vector is injected inside the body as the recombinant DNA goes to many organs in the body. This leads to a restricted immune response and makes re-treatment difficult. The process is also irreversible.

Dr. Vandenburgh and his colleagues have overcome many of these limitations by isolating stem cells from adult skeletal muscle and genetically engineering them into post-mitotic differentiated muscle fibers. When injected subcutaneously into the patient, these bioartificial muscle fibers (BAMs) are expected to secrete therapeutic protein for up to 6 to 10 months. While the findings have not been verified in humans, the technology has potential applications for treating patients with a variety of diseases. Because this technology involves autologous tissue delivery of therapeutic proteins, immune response is minimized. In addition, the technology uses long-lived, nondividing and nonmigratory muscle fibers capable of producing more protein than other cells. The technology also allows for both local and systemic delivery, pre-implantation monitoring, and is reversible.

Based on preclinical studies using small animals, researchers have used this technique to achieve continuous secretion of protein for up to 6 months. For example, researchers have demonstrated sustained delivery of EPO in vivo by enhancing what animals drink in their water.
Dr. Vandenburgh noted that this technology has potential targets in the cardiovascular field, including vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF2), and is of potential benefit to a large patient population. Researchers may also be able to deliver insulin-like growth factor (IGF) locally to pericardial space to treat congestive heart failure. In sheep studies, researchers found a three-fold increase in heart vascularization using VEGF protein. However, the technology produces side effects when delivered systemically.

Dr. Vandenburgh emphasized that vascular function is complex and that more than one protein is needed to stimulate both vasculogenesis and angiogenesis. Researchers will be more likely to successfully treat severe hemophilia first because there is a well-defined protein and a well-defined therapeutic endpoint (clotting time). There is also less concern about regulating the protein's expression because it is expressed the way nature delivers it. Dr. Vandenburgh noted that there is a “large safety window”—Factor VIII for severe hemophilia is a cofactor in clotting reaction, so there is less need to be concerned about overdosing the patient. Finally, delivery of very low levels of the protein (1 to 3 percent of normal levels) is sufficient to provide benefits to the patient.

The research team plans to file an investigative new drug (IND) application with the FDA in 8 to 12 months. Dr. Vandenburgh acknowledged his multidisciplinary research team for their contributions to this effort.

Council members expressed excitement about the new technology. There was discussion about the technical aspects of the technology. In response to a question about the effectiveness of systemic delivery compared to local delivery, Dr. Vandenburgh responded that systemic delivery has been shown in small and large animal models, but not in humans. The site of implant is very important, however, and will be determined by the protein targeted for delivery and the associated pharmokinetics. There was discussion about the regulatory promoter process.
Dr. Vandenburgh explained that his research team is using a long terminal repeat (LTR) viral promoter that has already been successfully used in thousands of patients.

Another Council member asked if there was evidence for less immunogenecity using this delivery method. Dr. Vandenburgh responded that when retroviruses are used in an ex vivo system, researchers are not exposing the patient to the same immune problems that are encountered with an in vivo system. Presumably, this means less inflammation, possibly because of the continuous delivery process.

Another Council member inquired about problems with multiple spliced forms of some hormones and problems with delivering one spliced form or another. Could researchers use technology that turns on an endogenous gene instead, and then make the full spectrum of those spliced variants? Dr. Vandenburgh said that this is a good approach for stimulating vasculogenesis, where four to six molecules are needed to yield new vessels in endogenous tissue.

2. Geriatrics and Clinical Gerontology: Old Age and New Options for Cervical Cancer Screening

Dr. Jeanne Mandelblatt, Director of Cancer and Aging at the Lombardi Cancer Center, Georgetown University and an NIA grantee, presented results from her research on the cost-effectiveness of cervical cancer screening in old age. (Mandelblatt, et al., JAMA 287 [18]: 2372-81, 2002). This study was originally conducted on behalf of the Office of Technology Assessment to determine if Medicare should cover Pap smears, particularly in light of conflicting guidelines from the American Cancer Society, the American College of Obstetricians and Gynecologists, the National Cancer Institute (NCI), and other organizations. This is a difficult question to address because cervical cancer is a slow-growing disease and there are competing causes of mortality.

Dr. Mandelblatt presented an overview of cost-effectiveness research methodology, noting that the methodology is evolving. Cost-effectiveness researchers attempt to examine all of the possible intended and unintended effects that follow from a given action, calculate a probability of occurrence, and then assign costs. Cost-effectiveness models allow the use of a standard methodology that can be useful for policymakers. Outcomes are typically expressed in terms of costs from years of life saved or quality-adjusted life year (QALY) saved, and results can be compared to evaluate the impact of different strategies.

The purpose of her study was to resolve the controversy over current guidelines for cervical cancer by determining if there should be an upper age limit for screening and to identify optimal screening technologies. The study compared combinations of screening strategies, which varied by types of tests administered (Pap smears and/or human papilloma virus [HPV]), age of testing, and timing of testing.

A Markov Model was developed to show possible trajectories of HPV, beginning with a healthy individual and progressing to various endpoints, including death, resolution of the HPV disease, and various stages of neoplasia. Next, the research team assigned probabilities by conducting an exhaustive, online search that yielded nearly 3,000 articles. Data on prevalence, disease progression, and test characteristics came from the published literature, survival data (stage, age, race-specific) came from the NCI-supported Surveillance, Epidemiology, and End Results (SEER) cancer registry, and cost data were obtained from SEER-Medicare. The research assessed the specificity of different tests and calculated costs of screening in terms of treatment costs and patient time.

Application of the model found that the prevalence of HPV decreased with age, either due to immunity or decrease in sexual partners. However, declines in immunity may account for higher prevalence in later years because younger women are more likely to clear the infection early, whereas older women may harbor a latent infection.

The results of this study showed that the majority of life savings from screening occurs prior to age 65. Adding HPV testing to Pap smears is a reasonable expenditure and will save the maximum number of lives. Testing for HPV alone every 2 years is a cost-effective alternative only if there is high HPV sensitivity, low test cost ($5/test), and the testing targets a high-risk population. By age 75, the number of additional lives saved is miniscule. More false positives will be generated. These may cause psychological harm and will increase the cost of screening.

Dr. Mandelblatt noted that this model informs clinical practice and screening recommendations, evaluates upper age limits for screening, informs Medicare coverage, and informs patient decisionmaking. The American Cancer Society is planning to incorporate this work in its recommendations. She concluded by thanking the NIA for supporting her work and her career development.

In discussion, Dr. Mandeblatt clarified that the data are simulated. She emphasized that the research team is confident of the data's validity and that the results model reality. Council members discussed cohort effects in cervical cancer due to the growing population of older women who had never been screened or who had given birth to their children before widespread screening was available. It was noted that a woman's screening history should inform future screening decisions, but added that this cohort effect should be disappearing with cervical cancer becoming less prevalent in older women over time. Dr. Mandelblatt noted, however, that cohort effects are also reflected in a different trend—middle-aged and divorced women who acquire new sexual partners, and thus, may be at new risk for HPV. Another issue to consider is the tendency for low–risk populations to screen more often than high-risk populations.

In response to a question from Dr. Hodes, Dr. Mandelblatt described how NIA support on a career development award nurtured her career development. She emphasized the critical importance of programmatic initiatives and support for protected time. She attributed part of her success to a career development award which gave her time to finish her Master of Public Health, work toward her Ph.D., and allowed her time for research activity to garner NIA and NCI grant support. Dr. Mandelblatt is now mentoring others for career development awards.

3. Behavioral and Social Research: Wealth and Health Outcomes

Dr. James Smith, an NIA grantee and economist at the RAND Corporation, presented findings from a paper coauthored with Dr. Dana Goldman entitled, “Can Patient Self-Management Help Explain the SES Health Gradient?” (Proc. Natl. Acad. Sci. USA, 99 [16]: 10929-10934, 2002). Dr. Smith noted that while people with higher socioeconomic status (SES) tend to be healthier, traditional public health explanations are incomplete; limited access to quality care and deleterious personal behavior cannot fully explain the disparity. Recent research has suggested the importance of early childhood factors and income inequality. Another factor being considered, and the focus of Dr. Smith's presentation, is patient self-management and adherence to treatment regimens.

Although the correlation between education and health is near universal, less well-known is that the health benefit of a college degree is more valuable among the chronically ill. Can adherence explain the gradient in health among the chronically ill? Adherence is a plausible explanation given that efficacious treatments are available, and these treatments are demanding on patients, requiring self–management and full compliance over time. The patient must understand the medical necessity to fully comply with the treatment. For example, treatment for HIV, highly active antiretroviral therapy (HAART), is complicated, requiring dozens of tablets and synchronized dosing times. The RAND HIV Cost and Services Utilization Study (HCSUS) of more than 2,800 HIV patients found that the better educated are more likely to adhere to treatment.

Goldman and Smith's study examines differences by education in treatment adherence among patients with two illnesses, diabetes and HIV, and then assesses the subsequent impact of differential adherence on health status. For both illnesses, the study finds significant effects of education on patterns of adherence.

Among HIV patients, the effect was as large as the race effect when comparing college graduates to non-high school graduates. In addition, income had no impact on adherence. When the impact of adherence on health status change was analyzed, partial adherence was found to provide no benefit. Only strict adherence to HAART therapy changes outcomes in health. Dr. Smith noted that this was a robust evaluation because self-reported health status was validated by results from 2-year mortality data. These studies also controlled for insurance status.

In diabetes, tight glycemic control is key to better outcomes for both Type 1 and Type 2 diabetes. In the Health and Retirement Study (HRS), men and women in their early 50s were asked to report on the kind of treatment medications they were taking, and to classify treatment patterns as good or bad. Those who were less educated switched oral medications more and were more likely to go off treatment altogether, both actions that led to worsening general health. However, marital status among men also influenced adherence. For instance, divorced men had worse health behaviors if they began the study married. However, men appeared to have no effect on their wives' behavior.

Recognizing that subjects in an observational study such as the HRS choose their treatment, the authors also examined data from the Diabetes Control and Complications Trial (DCCT), a randomized, prospective diabetes clinical trial that randomly assigned treatments. In this case, persons who were better educated adhered better at baseline, no matter what measure was used. When treatment regimens were analyzed separately (standard versus intensive) researchers found that intensive monitoring had a greater benefit for those who were less educated. This underscores the costs of poor self-management for people who are less educated.

Collectively, these studies illustrate the following: (1) adherence is a key part of the SES gradient for the chronically ill, (2) education is not a proxy for income or memory, (3) education explains adherence to treatment regimens for HIV and diabetes patients, and (4) better adherence means better health.

Future studies are needed to determine whether findings can be generalized to other chronic conditions (e.g., heart disease, asthma), and to elderly populations. In addition, researchers need to examine the role of patient-physician interactions in promoting positive behaviors. Perhaps most importantly, it still remains unclear why education, and not income, is so critical. In his conclusion, Smith emphasized that the SES health gradient is not immutable.

Council members discussed reasons for the importance of education. More educated persons may be much more aware of the consequences of certain risk behaviors and this affects how they interact with their physician. Those with less education may be reluctant to challenge doctors. However, others noted that personality factors, such as conscientiousness, are thought to be unrelated to SES and education.

It was noted that hypertension studies showed that health educators play a critical role in adherence. Because doctors do not have sufficient time to educate, it is important to engage laypersons in efforts to educate as a way to eliminate the education effect. In response to questions about the role of memory in adherence and self-management, Dr. Smith reported that many measures of memory had no effect on adherence.

4. Neuroscience and Neuropsychology of Aging: Neurodegenerative Diseases — More Similar Than Different

Dr. Marcelle Morrison-Bogorad, Associate Director of the NNA Program, discussed the role of abnormal protein folding in neurodegenerative diseases, such as Huntington's Disease, Ataxia, Parkinson's Disease, and Alzheimer's Disease. She explained that abnormal folded proteins, or partially folded polypeptide chains, can form aggregates. Dr. Morrison-Bogorad then discussed ways to reduce toxicity from abnormal protein folding. The researcher can either stop aggregrates from forming or reduce their toxicity once formed, through chaperones and other molecules, or degrade aggregates with a ubiquitin/proteosome system.

She then demonstrated how chaperones such as heat shock proteins (hsps) can help reduce cell toxicity. One heat shock protein, hsp70, has been shown to protect against a-synuclein induced dopaminergic neuronal degeneration in Drosophila (Auluck et al. Science, 295 [5556]: 865-8, 2002). In a series of experiments, the number of control dopamine neurons was much greater than the number in flies where human synuclein was expressed. When a chaperone, hsp70, was co-expressed, neurons were protected against the toxicity of the a-synuclein gene. They all survived. In another experiment, (Warrick et al. Nature Genetics, 23: 425-8, 1999) the same molecular chaperone, hsp70, also suppressed polyglutamine mediated neurodegeneration in Drosophila, leading to recovery of eyes and visual function.

Dr. Morrison-Bogorad also discussed other strategies for preventing aggregation-induced degeneration. Some compounds may be able to intervene in this process. As examples,
Dr. Morrison-Bogoard discussed the use of ataxin—polyglutamine to recover eye structure in flies, and the use of polyglutamine in worm models to block aggregation and restore movement. Dr. Morrison-Bogorad also mentioned the use of heat shock/ubiquitin modifiers, as well as other candidate modifiers such as proteins with RNA binding domains, proteins in the machinery that makes RNA, and Glutathione –s–Transferase.

As an example, Dr. Morrison-Bogorad discussed a study published in 2002, “The Threshold for Polyglutamine-Expansion Protein Aggregation and Cellular Toxicity is Dynamic and Influenced by Aging in Caenorhabditis Elegans” (Morley et al.. Proc Natl Acad Sci USA, 99 [16]: 10417-22, 2002), which demonstrated that motility decreases as polyglutamine aggregation in muscles of the C. elegans cell wall increases. In these worms, aggregation can be easily visualized, as can C. elegans movement. Researchers found that aggregation also increases with aging, but an extended lifespan mutation delays aggregate accumulation as well as the time it takes to become immobile. Dr. Morrison-Bogorad described this as a thrilling experiment that may shed light on the links between aging and neurodegenerative diseases. She also noted that the Biology of Aging program is looking at a number of candidate genes that extend aging.

Council members praised Dr. Morrison-Bogorad on her excellent presentation on how to modify changes in protein composition. Although research on aging genes is exciting, it is unclear if it will be a key to interventions in humans. However, this novel research does have implications for humans by opening the way for therapeutic approaches and standard ways of thinking about how to proceed.

In response to a question about how this model relates to other amyloid diseases outside of the brain and to systemic inflammation, Dr. Morrison-Bogorad explained that a cell is essentially a cell and that these molecules affect a number of different kinds of aggregates. A discussion ensued concerning whether neurodegenerative diseases are caused by viruses or bacteria, and if aggregates of amyloid protein are truly the culprit in these diseases. As one Council member observed, getting rid of amyloid processes by going after inflammatory processes does not eliminate the amyloid. Dr. Morrison-Bogorad responded that no matter what causes aggregates or inflammation, researchers still need to find ways to diminish them.

9. Adjournment

The 87th meeting of the National Advisory Council on Aging was adjourned at 12:25 p.m. on September 25, 2002. Dr. Hodes closed the Council session by thanking all speakers and the Council members for living up to and exceeding its high standards. The next meeting is scheduled for February 4 to 5, 2003.

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 Analytical Sciences, Inc.

Attachment A

MEMBERSHIP ROSTER
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING

(All terms end December 31 with the exception of those names marked with an * which were extended until June 30, 2002)

Chairperson

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

Dennis A. Ausiello, M.D. (2003)
Chief, Medical Services GRB-740
Massachusetts General Hospital
Boston, MA 02114

John C. Cambier, Ph.D. (2003)
Ida and Cecil Green Professor and
Chairman, Integrated Dept. of Immunology
National Jewish Medical & Research Center
and Univ. of Colorado Health Sciences Center
Denver, CO 80206

*Judith Campisi, Ph.D. (2002)
Senior Scientist
Division of Cell and Molecular Biology
Lawrence Berkeley Laboratory
University of California
Berkeley, CA 94720

Rose W. Dobrof, DSW (2002)
Brookdale Professor of Gerontology
Brookdale Center on Aging
Hunter College of the City of New York
New York, NY 10036

David V. Espino, M.D. (2004)
Professor
Dept. of Family & Community Medicine
Division of Community Geriatrics
University of Texas Health Science Center
San Antonio, Texas 78229-3900

Lewis H. Kuller, M.D., DrPH, MPH (2004)
Professor and Chairman
Department of Epidemiology
Graduate School of Public Health
University of Pittsburgh
Pittsburgh, PA 15261

Stanley B. Prusiner, M.D. (2004)
Director and Professor
Institute for Neurodegenerative Diseases
School of Medicine
University of California
San Francisco, CA 94143-0518

Judith A. Riggs, M.A. (2004)
5230 Watson Street, N.W.
Washington, DC 20016

Ilene C. Siegler, Ph.D. (2003)
Professor of Medical Psychology
Dept of Psychiatry & Behavioral Sciences
Duke University
Durham, NC 27705

*Myron L. Weisfeldt, M.D. (2002)
William Osler Professor of Medicine
Director, Department of Medicine
Johns Hopkins University School of Medicine
Baltimore, MD 21287

David A. Wise, Ph.D. (2002)
Professor
National Bureau of Economic Research
Cambridge, MA 02138

*Phyllis M. Wise, Ph.D. (2003)
Dean, Division of Biological Sciences
University of California Davis
Davis, CA 95616-8536

*WGoP Member

Ex Officio Members

Tommy G. Thompson
Secretary
Department of Health and Human Services
Hubert H. Humphrey Building
Washington, D.C. 20202

Elias Zerhouni, M.D.
Director, National Institutes of Health
Public Health Service Bethesda, Maryland 20892-0148

James F. Burris, M.D.
Deputy Chief Research and Development Officer
Office of Research and Development
Department of Veterans Affairs
Washington, D.C. 20420

Colonel George F. Fuller, M.D.
USUHS
Department of Family Medicine (FAP)
Bethesda, MD 20814-4799

John Wren
Director, Office of Program Development
Administration on Aging, DHHS
Washington, D.C. 20201

[ 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 4-5, 2003, and corrections or notations will be stated in the minutes of that meeting.