Council Minutes - May 2001

National Advisory Council on Aging

Summary Minutes: The Eighty-Third Meeting

May 22-23, 2001

CONTENTS

Introduction

1. Review of Applications
2. Call to Order
3. Biology of Aging Program Review Report
4. Consideration of Minutes of Last Meeting
5. Future Meeting Dates
6. Working Group on Program Report
7. Program Highlights
8. Working Lunch: Overview of NRC Report on Research Priorities in Behavioral and Social Sciences for NIH
9. Director's Status Report
10. Adjournment
11. Certification

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

The 83rd meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, May 22, 2001, at 3:00 p.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 closed to the public on Tuesday, May 22, from 3:00 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. The meeting was open to the public on Wednesday, May 23, from 8:00 a.m. to 2:30 p.m.

Council Participants:

Dr. Dennis Ausiello
Dr. John Cambier
Dr. Rose Dobrof
Dr. David Espino Dr.
Dr. Fred Gage
Dr. Mary Harper
Dr. Lewis Kuller
Dr. Stanley Prusiner
Ms. Judith Riggs
Dr. Dennis Selkoe
Ilene Siegler
Dr. James Vaupel
Dr. Jeanne Wei
Dr. Myron Weisfeldt
Dr. Phyllis Wise

Ex-Officio Participants:

Dr. Saadia Greenberg, AoA
Dr. Susan Cooley, VA

Absent:

Dr. Judith Campisi
Senator Mark Hatfield
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:

Tom Getchell, University of Kentucky
Linda Harootyan, Gerontological Society of America
Sherry Marts, Society for Women's Health Research
Tim Perrin, American Association of Gerontological Psychiatry

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

Syed Amir, CSR/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).

A total of 853 applications requesting $877,011,460 for all years was reviewed. Council recommended 461 for a total of $539,639,161 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. Morrison-Bogorad, Acting Deputy Director, called the meeting to order at 8:00 a.m. on Wednesday, May 23, 2001, and welcomed members.

3. Biology of Aging Program Review

Dr. Phyllis Wise, a Council member, chaired the Biology of Aging Program (BAP) Review Committee and presented the committee's report. Other members of the committee were: Drs. Dennis Ausiello, John Cambier, Judy Campisi, Joshua Lederberg, Richard Miller, and Jeanne Wei. The review was conducted on May 21, 2001.

The committee voiced strong support for the balance achieved by the Program to support research that (1) enhances and deepens understanding of fundamental concepts of the aging process and (2) focuses on age-related diseases which are likely to lead to identification and development of interventions to promote healthy aging.

They were enthusiastic about the reorganization of the Program to reflect the changing nature of our understanding of aging processes and to address new areas of science. The committee supported the mechanisms used by staff to bring new and well-established investigators into aging research. The Committee received responses to 11 out of 15 letters sent to investigators soliciting responses that reflected how their projects had been handled by BAP staff. Those letters were very supportive of the Program.

Recommendations for future directions of the Program and mechanisms to enhance the Program (which the Committee feels is already strong) are as follows:

• NIA as a whole needs to develop mechanisms to ensure that the best aging research does get funded--by instituting reform of study sections, establishing special study sections, increasing the role of Council.
  
• Support should be endorsed for scientific initiatives on stem cell research relevant to aging, functional senescence, comparative biology, new intervention testing, and complex systems, i.e., integrative physiology.

The Review Committee suggested that the Program consider developing an initiative to examine the role of protein structure and post-translational modifications and their impact on functional aging. Answers to questions in this area may not be revealed through study of the genome alone. While the Biomarkers Program funded ten years ago was not considered successful because it did not find a panel of biomarkers of aging, the Committee considered it worthwhile and endorsed a revision and reinstatement of the program in another form. They commended Dr. Warner for his leadership of these changes but recommended that some areas continue to need orchestration and leadership, i.e., insulin-signaling and Type II Diabetes. Finally, the Committee expressed the view that certain key initiatives need support other than through investigator-initiated research. Those areas include the Biomarkers Program, surrogate markers, and development of a core resource of transgenic animals, primarily but not exclusively, mice.

In discussion, one Council member asked for more information on the comparative biology initiative. Dr. Wise said the purpose of this initiative is to learn what we can from the diverse genetic and physiological aspects of aging among species. For example, birds live long despite high blood glucose. Another question concerned the influence of fetal exposure on aging. Dr. Wise clarified that the focus on fetal exposure is not a specific initiative but the interest is identifying whether early influences (including fetal exposure) contribute to longevity.

The remaining exchange focused largely on biomarkers. Discussion was lively. Dr. Wise indicated that the Biomarkers Program initiative was an attempt to identify biochemical, physiological, and genetic markers of aging that would allow us to know the age of an organism independent of its chronological age. Dr. Warner defined biomarkers: biomarkers should predict the outcome of a wide range of age-sensitive tests, predict remaining longevity, and be non-invasive. Council members questioned whether or not many such markers were not already identified-such as presymptomatic markers, Alzheimer's disease (AD) markers, early identification markers. One member said there is a need to avoid getting trapped in semantics, and a need to find what predicts senescence; comparative biology offers many opportunities in this regard. Another Council member noted that while inflammatory markers have been studied in relation to several diseases, their real nature may be as markers of longevity. One member, considering the additional resources now available to NIA, saw the opportunity to move from advances in understanding the biology of aging to clinical trials that take advantage of advances such as knowledge of the effects of caloric restriction. Finally, a member concluded by observing that Council members may benefit from having time set aside to present and discuss their own ideas.

4. Consideration of Minutes of Last Meeting

The minutes of the February 6-7, 2000, meeting were approved as submitted.

5. Future Meeting Dates

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

6. Working Group on Program Report

Dr. Gage reported on the meeting of the Working Group on Program (WGoP) that took place immediately prior to the Council meeting. The Working Group heard the plan for the Review of the Biology of Aging Program and considered it appropriate.

Dr. Phyllis Wise summarized activity relating to a Council Review of Initial Review that was discussed at the Feburary Council meeting. Council members Drs. Judy Campisi, Rose Dobrof, Dennis Selkoe, Ilene Siegler, Jim Vaupel, and Mike Weisfeldt volunteered to serve on a Review of Review committee with Phyllis Wise as chair. All except Rose Dobrof were present on a teleconference call on April 5, 2001. NIA staff members Drs. Miriam Kelty and Mary Nekola joined the call.

The Committee's task was: To explore ways to improve the quality of review of NIA applications that (a) are reviewed by NIA through study sections (Special Emphasis Panels) that were formed by NIA staff or (b) are reviewed by the Center for Scientific Review (CSR).

The members of the committee held widely varying views as to whether there was sufficient evidence to establish that applications are not already reviewed well. At least one member believed that some reviewers suffered from lack of knowledge and/or interest in the goals of the research applications. Others believed that there was no objective evidence of lack of quality in the reviewers chosen or in the review process.

After considerable discussion, the committee decided that it would be difficult if not impossible to gather data to assess and document the level of reviewer competence and interest. Moreover, how one could use these data to predict the quality of future reviewers was also not clear.

The committee decided that this is the wrong time to assess the quality of CSR study section reviews since the organization of study sections is undergoing change.

One member suggested that a "virtual" committee be maintained to respond to new issues about quality of the review process as they arise. Another member suggested that a simple and concise set of guidelines for the basic standards of achieving good peer review be put together. (The committee was later informed that such a set of guidelines already exists.)

In conclusion, committee members believed that there was insufficient evidence of lack of quality of the review process and were uncertain how to obtain data on quality of review or whether the data could be obtained. Therefore, they believed that an extensive continuing effort on the part of NIA staff or the committee to pursue this issue further at the present time is unwarranted.

Dr. Kuller shared his experience as a Study Section Member in the 1980s, and as a Council member and a study section member about ten years later. He thought that compared to many years ago, although overall review is qualitatively good, some changes have occurred that challenge quality of review. For example, applications now are reviewed by two or three people, there are fewer ad hoc reviewers, review focuses on broader aspects of the science, there are fewer site visits and reverse site visits, and there are more multidisciplinary and interdisciplinary applications that are reviewed unevenly because committee members have more expertise in some areas than others. Moreover, he noted that reviewers are more junior than in the past and lack breadth of experience. He suggested that adjunct expertise would be beneficial but believed that outside opinions are not solicited as often as in the past. He encouraged Institute staff to attend review meetings to provide better feedback to applicants and to monitor the adequacy of the review process.

In further discussion, several Council members observed that is common for senior scientists to judge reviewers junior and limited in various ways, and for changes to occur in science that influence the shape and nature of review groups. NIA review staff commented that NIA review includes mail reviews, conference calls with outside experts, and temporary reviewers who add expertise.
Dr. Nekola, the NIA Chief of Review, pointed out that in three years NIA sought assistance from more than 2000 reviewers. The shift in design to a broader review (focused more on larger issues and less on smaller details) means that less specific expertise may be present on review groups. A council member commended NIA staff for placing value on maintaining confidentiality in review and for their success in keeping review proceedings and outcome confidential.

Discussion shifted to CSR reorganization and to their response to the letter Council sent to CSR Director Dr. Ellie Ehrenfeld requesting that the Biology of Development and Aging Integrated Review Group (IRG) span both basic and clinical aging research. Staff described their input to the boundary teams working group (steering committee) to help set up the new integrated review groups and expressed satisfaction with NIA's participation in the process and with the inclusion of some experts in aging. The IRG Boundaries Team will meet in July to design the new IRGs and study sections, including their scope, number, and breadth.

NIA WebSite: The Working Group discussed the issue of ease of use of the NIA website by diverse users. The WGoP heard two presentations about the website: One focused on the history of the NIA website and plans for future development; and the other on efforts to incorporate outcomes of research on perception and cognition into design of a user-friendly website. Users range from scientists seeking grant-related information to the general public who may want to find health information or resources. Ms. Dailey, an NIA staff member, described a project involving NIA, the Library of Medicine, and selected investigators who have identified principles to accommodate older users. Council members stated that the same principles can and should be applied to the parts of the website directed at scientists who currently find the website difficult to navigate and marginally useful. Useful information should be quickly and easily obtained. Ms. Shure, Chief, Office of Communications and Public Liaison (OCPL), assured Council members that after usability testing, outcomes and design principles would be shared with the NIA Information Systems Office as well as with other NIH Institutes that also have older users who search for disease-related information and health resources.
Council members asked that staff send them ten questions and they will report at the next meeting on how long it took them and/or their associates to find the information on the website.

The Working Group next reported on advisory meetings and workshops that have taken place since the last Council meeting and that are planned. Dr. Hadley described an advisory workshop on Exceptional Longevity organized by NIA to invite advice on research to identify genetic and other factors that contribute to exceptional longevity. The Workshop followed-up recommendations made at an ealier workshop on genetic epidemiology. The Report of the Workshop on Exceptional Longevity can be seen at the website: http://nacanet.nia.nih.gov/longevityreport.htm .

A council member requested that the crossover phenomena of longevity among particular racial and ethnic groups be investigated. It was suggested that a Professional Service Contract be let to prepare a literature review. Others expressed doubt that this could be done well because of poor age ascertainment on death certificates.

The second conference discussed was one on Animal Models of Menopause. Participants noted that Rhesus monkeys and baboons appear to be good models of female reproductive aging and also of connections between that process and cardiovascular disease, bone loss, hot flashes, and changes in cognitive function. The Report of the Workshop on Non-Human Primate Models of Menopause can be accessed at http://nacanet.nia.nih.gov/meetings.htm . A council member noted that African women are only recently living long enough to experience menopause. (In some groups, postmenopausal women are considered to be unproductive and are isolated and sent away from the community and rejected.)

The final meeting discussed is one planned on Cognitive and Emotional Health: The Healthy Brain. The meeting is part of a larger initiative involving NIA, the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS) that will mine epidemiological and longitudinal studies for risk factors or predictors of cognitive and emotional health in adults. The workshop will have plenary speakers and include discussion to identify existing knowledge and research needs.

Council accepted recommendations from workshops held and approved the upcoming advisory workshop on The Healthy Brain.

At Council's request, the Working Group on Program considered issues surrounding the limited supply of well trained MD clinical investigators. The question was raised about whether the number of MD applicants for research grants has declined and/or whether their success rate is low compared to other applicants. The issue has been studied several times, most recently by an NIH Director's Panel on Clincal Research in 1997. That group made recommendations to enhance patient-oriented research as well as the number of physican investigators. The topic is salient now because of new legislation permitting NIH to allocate money for loan repayment for clinical investigators up to $35,000 per year. If loans could be paid back directly and not be considered taxable income to the physician, the program would have a major impact and be very attractive.

Data indicate that the MD investigators' success rate has declined about 10 percent over 10 years to about 30 percent currently. The most marked decline is in new RO1 awards to new MD investigators. MD-PhD investigators enjoy a higher success rate than MDs and their success rate has remained stable. Programs in several institutions have focused on providing high quality training to clinical investigators. However, there is a substantial discrepancy in long-term compensation between clinician investigators and clinical practitioners. This is exacerbated by the substantial loans accrued by most physicians during training that come due following fellowship. Therefore, the idea was expressed that the loan repayment program for clinician investigators might be best timed to coincide with appointment as junior faculty or during the term of a Career Development award when the individual is conducting independent research and planning RO1 applications.

A model that NIA might consider is a loan repayment program in which investigators come to the NIH campus to conduct research into HIV. It was suggested that NIA's Intramural Research Program (IRP) might benefit from a similar arrangement: investigators would get outstanding research experience and mentoring and the NIA would benefit from committed physician investigators who would spend about five years at the IRP.

In discussion it was noted that what constitutes appropriate training for physician-investigators has changed. In the past, science involved disciplinary rather than multidisciplinary activities, was individually driven rather than team-driven, and scientists did not have to deal with the information glut that has led to the specialization that now favors the PhD approach to scientific inquiry.

One Council member offered the view that the next generation of physician scientists will need different training from the last, specifically, they will need to address research problems using a multidisciplinary approach. Further, the experimental organism will most likely be human and the physician-investigator will go from bedside to bench or from phenotype to genotype. This will require an understanding of complex clinical problems and the ability to integrate them into key scientific questions. This approach requires teams of well-trained investigators. Training resources should be developed to meet future needs, including early and continuing training in medical school programs in patient-oriented research as it relates to basic science. There is a need for MD-PhD students to start well-rounded training early so that more than two percent can be recruited as physician researchers.

The members continued by observing that there is a need to focus on the importance of stimulating curiosity about etiology and pathogenesis of disease. Too few physicians have the tools to do good etiological or epidemiological research or can compete with PhDs who are better trained in basic science. Those who succeed in an initial RO1 award often fail when they recompete, largely because they do research part-time after they finish clinical duties. What they can do with their current training and time is limited. They need to be trained to conduct hypothesis-driven research on important questions. Reducing the financial burden is important but it alone will not solve the problem.

After other members observed that MDs in their labs approach scientific questions differently from PhDs, there was discussion of the program funded by the Doris Duke Foundation to integrate research training and experience with the clinical and basic science curriculum in medical school. Students work with mentors and have flexibility to pursue experiences that allow them to follow up on their interests. There was a brief discussion of the need for MD investigators to contribute to behavioral and social sciences research questions as well.

The Council recommended that a subcommittee should consider next steps that might be appropriate for NIA. After discussion, it was agreed that neither another study nor a meta-analysis of existing studies seems warranted. There was discussion of a successful program that the Centers for Disease Control (CDC) ran to train epidemiologists. A question was asked about implementation of the loan repayment program legislation. A subcommittee will be appointed to explore how NIA can address the issues and participate in the loan repayment program. Several members volunteered to work on the issues.

The Working Group was updated on the development of the new National Institute of Biomedical Imaging and Bioengineering (NIBIB) that Congress established and that was signed into law in December 2000. The mission of NIBIB is to improve health by promoting fundamental discoveries in engineering and imaging research related to health and to promote the transfer of such technologies to medical applications. It will coordinate with other agencies and with the NIH Institutes to develop medical applications and to facilitate the transfer of those kinds of technologies to practical use.
Dr. Donna Dean is acting Director of the new Institute. Referral guidelines have been developed to assign applications to the new organization.

7. Program Highlights

A. Dr. John Breitner, of the Johns Hopkins University, was introduced by Dr. Marcelle Morrison-Bogorad, Acting Deputy Director, NIA, and Associate Director, Neuroscience and Neuropsychology of Aging (NNA) Program. Dr. Breitner discussed the rationale for a primary prevention, randomized, placebo-controlled clinical trial for Alzheimer's disease using non-steroidal anti-inflammatory drugs that has recently been initiated through NIA support.

Alzheimer's disease probably has its origins in middle life or maybe even earlier, with a very long latent stage, a relatively brief prodrome of mild cognitive symptoms, and later, the expression of Alzheimer's disease itself. Each of these stages offers an opportunity for preventive intervention, but the latent stage probably provides the best opportunity for interventions which will prevent disease completely. However, it is a very difficult, lengthy, and expensive process to demonstrate efficacy of any kind of intervention during that stage. Therefore, we need to rely on important and critically evaluated preliminary data from observational studies to suggest those interventions which may be the most effective, although the observational studies cannot provide definitive data. A number of candidate protective factors have been proposed as potential interventions. Dr. Breitner discussed a number of these, which were derived from a grant, supported by NIA for eight years and for which he was the principal investigator.

The study has analyzed a large population study in Cache County, Utah, in what is probably the longest lived county in the United States. The study is a classical longitudinal epidemiological design with a prevalence wave followed up a number of years later by an incidence wave. Exposures to various agents are established at the prevalence wave, and investigators look at the prevalence data to see what types of exposures are associated with change in risk of disease. The definitive test, however, is then to see what predicts incidence of disease using prospective methods.

One result from the study suggested that there was a very substantial risk of excess burden of Alzheimer's Disease in women after the age of 85. After fractionating the women according to a detailed lifetime history of use of hormone replacement therapy, it appeared that all of the excess risk was mitigated with sustained exposure to hormone replacement therapy, but all of that effect appeared to reside with exposures reported more than 10 years prior to the onset of dementia. Another analysis involved vitamins E and C. When the prevalence data analysis partitioned reported use of E with no C, C with no E, or the combination, all of the effect was in the combination of C and E. In those cross-sectional prevalence data, it appeared there was a two-thirds reduction in the burden of Alzheimer's disease among sustained users of these two vitamins.

Another factor involved the relationship of anti-inflammatory drug use and risk of Alzheimer's disease. Analysis of 17 published epidemiological studies and one meta-analysis suggested a reduced occurrence of the disease in individuals who had sustained treatment with non-steroidal anti-inflammatory drugs (NSAIDs) (McGeer PL, et al. Neurology 47: 425-432, 1996). For example, in the prevalence wave of the Cache County study, there was approximately half the risk in the group reporting sustained exposure to NSAIDs (Anthony JC, et al. Neurology 54: 2066-2071, 2000). More recent data from the study indicated that current exposure to NSAIDs, i.e., current at the prevalence wave, or exposure in the interval between the prevalence wave and the incidence wave, had no effect. However, people with three or more years of exposure to NSAIDs prior to or up to and including the prevalence wave, again had a reduced risk of disease, and individuals who had any sustained prior use of NSAIDs, regardless of duration, had a similar effect. So, the suggestion from these data is that these kinds of exposures may be effective in preventing the disease, but the time of exposure must be some years before onset of the illness

The potential preventative factors suggested by these kinds of observational studies need to be tested in clinical trials in order to determine if they really are effective in preventing disease. Therefore,
Dr. Breitner and his colleagues initiated a randomized, placebo controlled primary prevention trial in which they will enroll 2,625 individuals who are healthy, over the age of 70, and randomly allocated to Naproxen, a conventional non-steroidal drug, celecoxib, a selective COX-2 inhibitor, or placebo. These individuals must all have a first degree relative who had dementia. This increases their probability of developing Alzheimer's disease by approximately threefold, and the study is powered to detect a 30 percent decline in the incidence of Alzheimer's disease with seven years of observation. The study is breaking new ground in recruiting normal elderly subjects, and early results indicate that they will be able to achieve this kind of recruitment.

Council members discussed the effects of aspirin and appropriate dosages. Dr. Breitner said the researchers expect aspirin therapy to have a separate effect on prevention as opposed to treatment. He was asked to address the potential mechanisms for the ten-year HRT (hormone replacement therapy) effect and said the argument is that if estrogens were to be helpful in protecting against excito toxic effects at menopause, they would be most helpful in the perimenopausal and early postmenopausal period. However, he said he knew of no data to support that.

B. Dr. Rebecca Fuldner, Program Administrator in the Biology of Aging Program, introduced Dr. Susan L. Swain, Director of the Trudeau Institute. Dr. Swain presented data on the impact of aging on the immune system and the role of T cell responses in immunosenescence.

Senescence of the immune system in the elderly has been shown to affect both B and T lymphocytes resulting in a declining proportion of naive relative to memory T cells and in marked alterations in the production of effector T lymphocytes and protective antibodies. Dr. Swain and her research team are trying to understand the basic features of T cell responses that are susceptible to senescence. Over the past several years, Dr. Swain has published a number of observations about the CD4 T cells from aged animals, and has found that aged T cells respond poorly in an immune response, producing reduced levels of cytokines and expanding less than young CD4 T cells. Dr. Swain's team has developed a T cell receptor transgenic mouse model in order to provide a system to study the defects of the cells further and to test methods of overcoming the defects with the uses of different adjuvants or with augmentation with specific cytokines, for example. Several of these approaches have been shown to shift the Th1 and Th2 helper T cell phenotypes and improve the response to vaccination in animal models. Dr. Swain reported results showing that aged animals up to two years old still have a large population of naive T cells that express the T cell receptor and are responsive. They examined the in vivo response of naive CD4 T cells from young versus aged mice, transferred to young hosts, to evaluate the extent of the CD4 T cell aging defect and to see if it could be overcome by the use of different adjuvants.

Dr. Swain reviewed research demonstrating that naive CD4 T cells from aged as compared to young mice divide more slowly and make smaller effector populations when peptide is introduced in alum. As was expected from their recent in vitro studies (Haynes, L., et al. (1999) J Exp Med 190: 1013-23. 1999; Haynes, L., et al. Vaccine 18: 1649-1653. 2000), the responding aged donor Tg cells had a markedly reduced capacity to make IL-2 as assessed by intracellular cytokine production. However, when a complete Freund's adjuvant with heat killed mycobacteria (CFA) was used, the young and aged naive cells divided equally, could both produce IL-2, and made a comparable level of effectors. They found that only adjuvants that induced inflammatory cytokines such as TNFa, IL-1, and IL-6 could augment the function of aged CD4 cells so that the cells could expand and produce IL-2 similar to cells from younger mice. They also found poor responses of young CD4 T cells in TNFa KO hosts. Of interest is the fact that the same three cytokines (TNFa, IL-1, and IL-6) also restore the expansion and IL-2 production of aged cells in vitro, as well as CD28 KO cells which also make little IL-2. In the in vitro studies, the target of the proinflamatory cytokines was the naive CD4 T cell. This was thought to occur through some kind of as yet ill-defined costimulatory mechanism. Dr. Swain's research team is currently screening adjuvants for inflammatory cytokine production to find those that show the most promise. In the longer term, the approach may lead to ways to induce improved vaccination in the elderly.

The investigators have been looking at the results of this CD4 T cell defect on the generation of memory cells as well. In a second study, they examined the generation of memory cells from naive CD4 cells from aged mice. In vitro, naive CD4 cells from aged mice could differentiate into polarized Th1 and Th2 effectors in the presence of exogenous IL-2. These effectors, even though derived from aged naive cells, produced levels of cytokines similar to effectors generated from young mice (Haynes, L., et al. J Exp Med 190: 1013-23. 1999; Haynes, L., et al. Vaccine 18: 1649-1653. 2000). The team postulates that this mimics the good effector generation seen when CFA is used in vivo. They transferred young and aged Th1 and Th2 effectors into T cell deficient hosts to generate polarized memory populations. After several weeks, the memory cells were recovered and examined for expansion and cytokine production. They found that even though the young and aged effector populations were similar at the time of transfer, the memory cells generated from the aged effectors expanded very little upon restimulation ex vivo and produced very low levels of cytokines, compared to those derived from young naive CD4 cells. They used CFSE and BrDU to monitor cell division and DNA replication in restimulated memory populations and found that the aged memory cells did not undergo even one round of division in the four-day culture period even when exogenous IL-2 was added. Therefore, when these aged effectors become memory cells, they re-exhibit aging defects. They show decreased CD25 expression, decreased cytokine production, except for interferon, and decreased in vitro or in vivo expansion. These experiments are highly significant because even if a vigorous primary response can be induced with a particular adjuvant, it will not provide improved vaccine effectiveness in the elderly unless a potent memory response is also induced. Therefore, the research team plans to explore further what leads to the aged defect and to then investigate strategies to circumvent the development of the defect.

Dr. Swain reviewed findings from other studies with implications for the current finding. If stem cells are taken from aged mice, these cells respond appropriately so the age-related defect that the research team observed does not exist prior to specialization, and therefore the team is focusing on what the defect in the aged naive immune cells is. One possibility they are considering is that the naive cells in aged animals have existed longer than those in young animals because there is no more thymic export of naive T cells to flush them out, and, so, it may be a result of the actual chronological age of the naive cells.

Dr. Swain acknowledged that all these experiments were conducted by Laura Haines and Sherry Eden, and they were supported by a grant from the NIA.

Council members asked if cytokines would be administered with the vaccine to help boost the immune response. Dr. Swain said tests and experiments are being planned to look into that question. However, she leans more toward the use of adjuvants to induce the immune system to make the pro-inflammatory cytokines.

Council members also asked whether the receptor-expressing cells studied could be autoreactive
(Dr. Swain reported evidence against there being normal autoreactivity) and on the relation between the defect in the pro-inflammatory cytokine response and the defect in IL2 production. (Dr. Swain reported that the two defects appear to operate by different pathways.)

C. Dr. David Cutler, a professor at Harvard University and a member of the National Bureau of Economic Research, was introduced by Dr. Richard Suzman, Associate Director of the Behavioral and Social Research Program (BSR). He presented findings and some of the implications from the Manton and Gu paper on the disability decline (Manton KG, and XiLiang G. PNAS 98: 6354-6359, 2001).

In a brief background statement, Dr. Cutler explained that although survey evidence through the early 1990s suggests a reduction in the prevalence of chronic disability in the older United States population, there is inconsistent evidence across surveys as to the magnitude of the decline and whether the decline is expected to continue. Manton and Gu (2001) conducted analyses from the 1982, 1989, 1994, and 1999 waves of the National Long Term Care Survey (NLTCS) in order to assess the magnitude of the reduction of disability among the elderly in the United States from 1982 through 1999, and to investigate whether an acceleration in the rate of decline occurred in the most recent period.

Dr. Cutler reported that the 1999 NLTCS documented a dramatic decline in the overall prevalence of disability among older Americans over the past two decades. While 26.2 percent of the elderly were assessed as disabled in 1982, this figure dropped to 19.7 percent in 1999 (age-standardized to 1999), a relative decline of 25 percent over 17 years. The relative rate of disability decline has been accelerating, increasing from 1.0 percent from 1982 to 1989, to 1.6 percent from 1989 to 1994, to 2.6 percent from 1994 to 1999. The improvements in recent years are also noteworthy for a newly observed decrease of at least 400,000 in the number of people estimated to live in nursing homes. After age standardization, there was a 26.3 percent relative and 22.0 percent absolute decrease in nursing home use from 1994 to 1999. An important dimension of the chronic disability patterns is the sharp reduction in disability rates among black Americans during the 1990s. The drop in prevalence of 4.7 percent between 1989 and 1994 reversed prior trends of disability prevalence increases for this population between 1982 and 1989. From 1994 to 1999 the estimated decline (5.9 percent) in disability prevalence was even larger for black Americans than for 1982 to 1989. This means over the entire time period, disability rates for blacks have been falling as rapidly as for whites, thus, disability decline seems to be not concentrated in particular groups in the population but is observed throughout the elderly population.

In order to forecast future disability trends, Dr. Cutler observed that the causes of the current decline must be understood and their relative influences on decline in disability must be determined. He indicated there is good evidence that multiple factors contribute to the observed decline. These factors include improved medical technology and treatment, changing patterns of health-related behavior, changing knowledge and attitudes toward treatment of older adults, and increased education in more recent cohorts. Yet we poorly understand the relative contribution of these factors to the disability decline.

Dr. Cutler commented that the findings to date, together with research to understand the relative contributions of the listed factors, have broad implications regarding the well-being of the elderly population along several dimensions. A continued reduction in the prevalence of disability may help control costs for many health-related expenditures such as Medicare, Medicaid, and other aspects of long-term care. An additional economic benefit will be the amount of human capital that is retained in the labor force as a result of persons being able to work longer due to less disability. However, he cautioned that the relationship between disability decline and health-care costs across the later years of life is complex.

Council discussion focused on reporting issues. Might the disability decline be partly or completely a change in how disabilities are reported as a function of increased education? Dr. Cutler agreed that the possibility existed. Other questions included how useful international data may be (very useful but poorer quality and, as yet, incomplete data); Are there better metrics for expressing the benefits of disability decline than lifetime health care costs? (Yes. Dr. Cutler is working on models that place an economic value on a healthy year of life.); disability increases in the younger population (differently measured, hard to compare); and on changing care practice in nursing homes (yes, part of the broader factor of changing attitudes toward treatment and intervention).

D. Dr. Dalane W. Kitzman of Wake Forest University School of Medicine presented the Geriatrics Program's research highlight. Dr. Kitzman spoke on recent insights on diastolic heart failure (DHF) in the elderly. He presented data from his two recent publications that were, in part, NIA-supported.

Heart failure (HF) is the most expensive health care problem facing our nation (consuming at least 10 billion health care dollars per year). Three-fourths of HF patients are aged 65 years or older. Among older persons, HF is the most frequent hospital discharge diagnosis and is a major cause of morbid and mortal events.

Until recently, most HF cases were assumed to result from impaired systolic function. Studies by Dr. Kitzman suggest that a second form of HF exists that may be caused by a stiffening of the heart muscle contributing to an inability of the heart to fill adequately with blood ("diastolic dysfunction"). His research also suggests that this syndrome of diastolic heart failure (DHF) is much more common in the elderly and is much less common in younger and middle-aged persons. Though previous studies suggested that DHF might account for as much as 33 percent of HF cases, the number was considered an overestimate because prior studies were primarily derived from tertiary care centers and referral based laboratories.

Lacking until recently were population-based studies of HF. Dr. Kitzman recently published an analysis of the prevalence of HF from the Cardiovascular Health Study (CHS), an NIH-supported (including NIA) project (Kitzman, DW, et al. Am J Cardiol 87 (4):413-419, 2001). Complete data from persons > 65 years were available in over 4,000 subjects. The age range was 65 to 100 years, with a mean age of 78 years. Dr. Kitzman found that the overall prevalence of HF was 9.5 percent, significantly higher than essentially all prior population-based studies. He also found that even within this older cohort, there was a significant age-related increase in HF. By age 85 and older, over 18 percent of men and over 14 percent of women had prevalent HF. Importantly, in 55 percent of persons with confirmed HF, left ventricular systolic function was normal, as determined by an ejection fraction of 50 percent or greater - i.e., a diagnosis of DHF. When confounding disorders were taken into account, 42 percent of HF cases met the criteria for isolated DHF. Compared with older men, older women with HF were more likely to have preserved left ventricular systolic function. Among women, with confirmed HF, 67 percent had normal systolic function versus only 42 percent in men. The reasons why older women are more affected by DHF remains to be determined. Risk factors for DHF other than increasing age and female gender were history of hypertension, chronic obstructive pulmonary disease (COPD), obesity, and, in men only, ischemic heart disease. He observed that currently available studies on the pathophysiology and therapy of HF are almost solely focused on systolic HF and therefore, are not readily applicable to the majority of elderly HF patients since they are afflicted with diastolic, and not systolic, HF.

In the second part of his talk, Dr. Kitzman presented new data supporting the contention that diastolic dysfunction may be an important contributing cause of the fluid buildup in the lung associated with hypertension (Gandhi, SK, et al. N Engl J Med 344:17-22, 2001). Patients presenting with acute pulmonary edema (fluid buildup in the lung) often have hypertension. Treatment of hypertension, including fluid buildup, leads to resolution of a life-threatening heart failure symptom, shortness of breath. It has been suggested that this condition is due to a transient problem in the heart's ability to empty blood into the circulation (systolic dysfunction--defined as an ejection fraction of less than 50 percent) that resolves when treated successfully. The notion that a problem in the heart's ability to fill properly with blood (diastolic dysfunction) may be an important contributor to the symptoms of heart failure has not been addressed.

Dr. Kitzman studied 38 patients (14 men and 24 women, mean age of 67 years) who presented with shortness of breath, acute pulmonary edema, and severe hypertension. To determine which type of HF the patients had, he used ultrasound technology (two-dimensional Doppler echocardiography) to measure, both before and after treatment, the percentage of blood the heart emptied (ejection fraction) with each beat - a normal heart can pump 50 percent or more of its volume with each beat. The mean systolic blood pressure was 200 mm Hg initially and was reduced to 139 mm Hg, following drug treatment. Despite the marked drop in blood pressure, the ejection fraction was similar during the acute episode of pulmonary edema and after drug treatment (ejection fraction = 50 percent) in about half of the patients treated. No patient had severe mitral valve regurgitation (back flow of blood in the heart). Since half of the patients had a normal emptying of the heart during the acute episode of HF and also after drug treatment, left ventricular systolic dysfunction was unlikely to account for their HF. Rather, diastolic dysfunction, a problem with the filling of the heart, was the most likely cause of their HF.

There is little information available about how best to treat DHF in the elderly. Currently, DHF is treated with the same drugs used to treat traditional, i.e., classic (systolic) HF. Expanded research is needed on the causes, progression, and treatment of DHF in the elderly.

Questions of Dr. Kitzman included whether the greater prevalence of ischemic disease in men might account for the observed gender difference in prevalence of DHF (Though the issue is not completely resolved, the difference in ischemic heart disease does not appear to be the sole driving factor.); and whether treatments appropriate for systolic HF are also appropriate for diastolic HF (There may be a final common pathway though small-scale studies to date imply therapies for systolic HF may be harmful to diastolic HF patients.) Discussion also ensued on the role of hypertension (especially increases in systolic blood pressure) as a precipitating factor on the lack of good clinical trial data on diastolic HF, and on the excessive mortality associated with HF.

8. Working Lunch: Overview of NRC Report on Research Priorities in Behavioral and Social Sciences for NIH

Dr. Raynard Kington, Director of the Office of Behavioral and Social Sciences Research (OBSSR), in the Office of the Director, NIH, presented an overview of the National Research Council (NRC) report on research priorities in behavioral and social sciences for NIH. This report, entitled "New Horizons in Health: An Integrative Approach," identifies broad questions at the interface of social, behavioral, and biomedical sciences whose resolution could lead to major improvements in the health of the U.S. population.

Dr. Kington pointed out that NIA has been a leader among the NIH Institutes in integrating behavioral and social science perspectives. He explained that the mission of his office, OBSSR, is to enhance behavioral and social sciences research and training across the NIH; to expand the biobehavioral interdisciplinary perspective across the NIH; and to improve communication among health scientists and with the public at large about important advances in behavioral and social sciences. OBSSR does this by working collaboratively with Institutes and Centers (ICs) in developing research agendas, supporting relevant requests for applications (RFAs) and Program Announcements (PAs), and providing consultation to ICs as they develop programs in behavioral and social sciences. OBSSR does not have grant-making authority.

The NRC report addressed ten priority areas:

1. Predisease pathways--Identify early and long-term biological, behavioral, psychological, and social precursors to disease;
2. Positive health-Identify biological, behavioral, and psychosocial factors that contribute to resilience, disease resistance, and wellness;
3. Gene expression-Understand environmentally induced gene expression and its connection to positive and negative health outcomes;
4. Personal ties-Explicate the mechanisms by which proximal social interactions influence health and disease outcomes;
5. Health communities-Identify the collective properties of social and physical environments that influence health and disease outcomes;
6. Inequality-Clarify the mechanisms through which socioeconomic hierarchies, racism, discrimination, and stigmatization influence health and disease outcomes;
7. Population health-Understand macro-level trends in health status and evaluate the performance of the health care system;
8. Interventions-Expand the scope and effectiveness of strategies for social and behavioral interventions to improve health;
9. Methodology-Develop new measurement techniques and study designs to link information across levels of analysis (molecular, cellular, behavioral, psychosocial, community) and across time;
10. Infrastructure-Establish ways to maintain long-term study populations and to train scientists to integrate health-related knowledge across multiple disciplines.

Council discussion focused on critical stages of education; the impact of behavioral and social research on public policy; uses of alternative medicine among the rural and southern elderly; the role of OBSSR in facilitating cooperation among Institutes; and on new methods of measuring health and wealth.

9. Director's Status Report

Dr. Hodes indicated that the President's budget for FY 2002 represents a 12 percent increase over the FY 2001 budget and continues a trend in recent years of successive substantial increases. He cautioned that the President's budget request is the first stage of an extended budget process. The successive increases have allowed NIA to increase support for research project grants, maintaining this funding at about 65 percent of the budget. Small business allocations are set by legislation as a constant proportion of our budget. Training and fellowships are at about 2.4 percent of budget, a level determined by NIH policy. Contracts are 5.5 percent of the budget. The Intramural program at 9.3 percent, though growing, remains below the average for an Intramural program at an NIH institute. Research, management and support costs have been declining as a share of the budget and are now 3.3 percent of the total.

Though funds available for research have increased substantially in the past few years success rates have not increased. Dr. Hodes pointed out that the new funds have attracted increased numbers of applications. At the same time the average costs of research grants have increased. Both factors have depressed success rates.

NIH staff are modeling budget trends on the assumption that double digit increases in budget will cease and the NIH and NIA will return to the smaller increases of prior years. There is concern about the effect of the substantial commitment base that the Institutes, including NIA, have built up during the years of substantial growth. In a budget year with a smaller increase, the ability to fund new awards may decrease significantly because most of the funds for that year would be required to meet commitments from prior years' awards. Dr. Hodes anticipated that at the September meeting budget models and options would be available to allow an informed discussion of the issue.

On staff changes, the recruitment for the Deputy Director is awaiting the outcome of review at the Office of the Secretary, DHHS. Incoming Secretary Thompson has expressed substantial support for NIH.

NIA and NIH have also received substantial support at a legislative level. Though the House Appropriations and Senate Appropriations meetings were brief and focused on NIH as a whole, both were well-attended, elicited supportive questions, and have occasioned remarks from Senator Specter that NIH is "the crown jewel" in the Federal government. The House has also held "theme" hearings, including one on Lifespan issues in which NIA, Child Health, Nursing, and Environmental Health participated. A Senate hearing on Alzheimer's disease elicited a large audience with both lay and professional witnesses. The level of support for our research remained high at all these hearings.

Questions from Council members included the status of human embryonic stem cell guidelines and the concern that those making policy may not be familiar with the status of embryonic cells in storage or of the scientific potential of the research. Dr. Hodes indicated that there is substantial and informed legislative interest on the scientific and ethical issues but indicated that there is a continuing need to educate decision-makers on these issues. Members also asked whether NIA has experienced a sharper decline in success rates than other NIH Institutes. Dr. Hodes indicated that NIA's decline is sharper than other NIH ICs and that the reasons for that decline have been modeled and understood. He cautioned that there are limited means available to maintain a reasonable success rate. Strategies being considered include using years of large increases to fund resources or equipment that then reduce the costs of doing research in years when funds are more scarce. Council members also discussed limiting years of support, cutting grant costs and use of small grants. Dr. Hodes indicated that such strategies need to be carefully considered in light of the results of modeling of the effects of average costs on success rates and pay lines in future years. Members said that any restriction in funds may hurt both new investigators and aging research in particular as the field is one that is still relatively new and growing.

Dr. Harper, a Council member, expressed appreciation for the NIA staff who visited Tuscaloosa and participated in the dedication of the Mary Starke Harper Geriatric Psychiatry Center. Dr. Hodes extended his thanks to Dr. Harper for her contributions and indicated that the event was both spectacular and an appropriate celebration of Dr. Harper's achievements.

Dr. Hodes finished by addressing two issues brought up in earlier discussions at Council and Council-related meetings. He indicated that the Institute will appoint a subgroup of Council members to explore options for incorporating research-relevant background into medical-school curricula. He also indicated that program staff will work with Dr. Cambier on appropriate new directions in aging and immunobiology.

10. Adjournment

The 83rd meeting of the National Advisory Council on Aging was adjourned at 2:30 p.m. on May 23, 2001. The next meeting is scheduled for September 24-25, 2001.

Attachments:

1. Roster of Council Members
2. Director's Status Report to the NACA

11. Certification

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

______________________________________
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
NATIONAL INSTITUTE ON AGING
(All terms end December 31)

Chairperson
Richard J. Hodes, M.D.
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

Cambier, John C., Ph.D. (2003)
Ida and Cecil Green Professor and
Chairman, Integrated Dept. 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 W., DSW (2002)
Brookdale Professor of Gerontology
Brookdale Center on Aging
Hunter College of the City of New York
New York, New York

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

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

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

Kuller, Lewis H., M.D., DrPH, MPH (2004)
Professor and Chairman
Department of Epidemiology
Graduate Sc<lhool of Public Health
University of Pittsburgh
Pittsburgh, Pennsylvania

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

Riggs, Judith A., M.A. (2004)
Director of Public Policy
Alzheimer's Association
Washington, D.C.

Selkoe, Dennis J., M.D. (2001)
Professor of Neurology and Neuroscience
Center for Neurologic Diseases
Brigham and Women's Hospital
Boston, Massachusetts

Siegler, Ilene C., Ph.D., MPH (2003)
Professor of Medical Psychology
Dept of Psychiatry & Behavioral Sciences
Duke University Medical School
Durham, North Carolina

Weisfeldt, Myron L., M.D. (2002)
Chairman Department and Professor
Department of Medicine
Columbia University
New York, New York

Vaupel, James W., Ph.D. (2001)
Director and Professor
Max Planck Institute for Demographic Research
Rostock, Germany

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

Wei, Jeanne Y., M.D., Ph.D. (2001)
Senior Physician
Division of Gerontology
Beth Israel Deaconess Medical Center
Boston, Massachusetts

Wise, Phyllis M., Ph.D. (2003)
Professor and Chair
Department of Physiology
College of Medicine
University of Kentucky
Lexington, Kentucky

Ex Officio Members

Tommy G. Thompson
Secretary
Department of Health and Human Services
Washington, D.C.

Judith A. Salerno, M.D., M.S.
Chief Consultant, Geriatrics and ExtendedCare Strategic Healthcare Group (114)
Department of Veterans Affairs
Washington, D.C.

Ruth L. Kirschstein, M.D.
Acting Director
National Institutes of Health Acting
Public Health Service
Bethesda, Maryland

Norman Thompson
Principal Deputy Assistant Secretary
Administration on Aging, DHHS
Washington, D.C.

LTC George F. Fuller, M.D.
White House Physician
Washington, D.C.

NOTE: Former Senator Hatfield resigned from the Council on May 2, 2001.