National Advisory Council on Aging

Summary Minutes: The Ninetieth Meeting

September 23-24, 2003

CONTENTS

1. Review of Applications
2. Call to Order
3. Update on Biology of Development and Aging IRG
4. Report: Task Force on Minority Aging Research
5. Reports: Working Group on Program
6. Comments From Retiring Members
7. Presentation: Shared Interests Between NIA and NIMH
8. Program Highlights
9. Adjournment
10. Certification

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

The 90th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, September 23, 2003, 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 23, from 3 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 24, from 8:00 a.m. to 2:00 p.m.

Council Participants:

Ex-officio Participants:

Col. George F. Fuller (USUHS, DOD)

Absent:

Dr. Elizabeth H. Blackburn
Dr. James Burris (VA)
Dr. Spero M. Manson
Mr. John Wren (AoA)

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

Members of the Public Present:

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

Mr. Joe Ellis, OER, OD
Dr. Alan Holt, FIC
Dr. Thomas R. Insel, NIMH
Dr. Don Schneider, CSR

1. Review of Applications

This portion of the meeting was closed to the public, in accordance with the determination that it concerned 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 742 applications requesting $681,280,929 for all years underwent initial review. Council recommended 471 for a total of $464,582,891 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.

2. Call to Order

Dr. Hodes called the meeting to order at 8:10 a.m. on Wednesday, September 24, 2003, and welcomed members.

Director's Status Report

Dr. Hodes began with a review of the process, activities, and timeline related to the scientific Roadmap for the NIH. Development of the Roadmap has benefited from diverse and thoughtful input from hundreds of individuals representing multiple areas of research and public constituencies. Roadmap participants were asked to identify the most important scientific challenges that ought to be addressed trans-NIH , and obstacles to their pursuit. Specific initiatives that emerged can be grouped into three general areas: New pathways to discovery, largely in the area of basic cellular and molecular science; research teams of the future, acknowledging the importance of interdisciplinarity; and finally, a reengineering of the clinical research enterprise.

Implementation of the Roadmap is the next step. Details about particular commitments were subsequently announced at a September 30 public press event (http://nihroadmap.nih.gov/). Decisions about areas selected for the highest priority and immediacy were based in part on the potential for transforming the conduct of research, synergy among the Institutes and Centers, the compelling need for the initiative, and the opportunity to capitalize on the unique position of the NIH to accomplish something that other entities cannot.

Dr. Hodes addressed the basic development of technologies on a scale that could be applied more broadly, for example, investment in technologies for high throughput screening of a generic sort, or molecular libraries and molecular imaging repositories as shared and public-use resources. He discussed the challenges associated with identifying high risk but innovative and potentially high reward research, and also emphasized the need for interdisciplinary teams as distinct from a collection of researchers from many disciplines. He reported that all NIH Institutes and Centers (ICs) have enthusiastically made the corporate decision to support a common pool of resources to fund current and future Roadmap activities and initiatives.

In response to a question from a Council member about how regular research grant recipients would participate in the research networks envisioned by the Roadmap, Dr. Hodes suggested a future discussion with Council about the advisability of making funds available specifically to supplement principal investigators (PI's) to take advantage of network resources.

Another Council member encouraged continued support for longitudinal cohort studies, many of which have matured and offer an opportunity to understand systems biology at a human organization level. The same member noted the importance of harmonizing minimum data sets and informatics structure to maximize information gained from these resources, as well as the need to examine unique populations. Dr. Hodes clarified that even at its most expansive, the Roadmap is only a modest fraction of NIH outlays. Specific research questions will still be addressed through the mechanisms with which researchers are most familiar.

In response to a question about priorities for public/private partnerships, Dr. Hodes described the establishment of a cross-NIH mechanism for best practices, and a possible policy issuance that outlines procedures for NIH interactions with the private sector. To illustrate that partnerships are possible with existing policies and mechanisms, he cited the Osteoarthritis Initiative led by NIA and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) to develop imaging and other biomarkers and surrogate markers germane to osteoarthritis research. The Osteoarthritis Initiative involves contributions from major pharmaceutical companies along with NIH funds to develop a database that will be freely accessible to the public and private sectors. This arrangement was developed with existing rules and authorities, and provides a model for other public-private initiatives, including NIA's neuroimaging initiative. As mechanisms currently exist for many types of appropriate arrangements, Dr. Hodes suggested that lack of communication about existing mechanisms or successful prototypes may be the limiting factor.

Dr. Hodes reported next on the Institute of Medicine's (IOM) study of NIH organization, an activity that was stimulated by Dr. Harold Varmus's concern that coordination across the complexity of 27 institutes might warrant a restructuring to realize more efficient operations. The IOM was charged with producing the report one year after the new NIH director was appointed. Although the IOM was originally charged with considering changes in the number of NIH institutes or centers, the IOM Committee did not make any recommendations about this because any consolidation of institutes was considered to be practically and politically difficult. However, the IOM Committee did suggest two areas to consider for possible consolidation: the National Institute of Alcohol Abuse and Alcoholism (NIAAA) and the National Institute of Drug Abuse (NIDA); and the National Institute of General Medical Sciences (NIGMS) and the Nation Human Genome Research Institute (NGHRI).

The IOM also recommended that NIH set terms for IC director appointments and improve the IC director review process. Currently, on an approximate five-year cycle, an expert panel is convened by the NIH director to review the performance of an institute director and make recommendations. The IOM recommended additionally that IC directors be limited to two 5-year terms, and that the NIH Director be limited to two 6-year terms.

Dr. Hodes highlighted some of the Report's other recommendations: assure that centralization of management functions (e.g., grants management support) will not undermine NIH's ability to function; strengthen the overall NIH clinical research effort, perhaps by creating an NIH deputy director for clinical research and consolidating some of the infrastructural aspects of clinical research; enhance and increase trans-NIH strategic planning and funding, and strengthen the ability of the Office of the NIH Director to set or recommend research direction; establish a process for creating new OD offices and programs; create a Director's Special Projects Program to support high risk, high potential payoff research in both the extramural and intramural programs; standardize level-of-investment data and information management systems; reconsider the special status of the National Cancer Institute (NCI) which currently has a director that is appointed by the President and is allowed to go directly to Congress for its appropriation, bypassing the NIH process; retain integrity in appointments to advisory councils and reform advisory council activity and membership criteria so that political considerations do not compromise the objectivity of the advisory input to NIH; and increase funding for Research Management and Support which covers NIH operating costs.

The NIH Roadmap initiative and the deliberations of the IOM Committee were concurrent, yet the NIH Roadmap is responsive to some of the IOM recommendations, for example, strengthening the Office of the NIH Director and in centralizing the clinical research infrastructure. The NIH has not made any comments or response to the IOM recommendations.

One Council member observed that the major implications from NIH-funded research to clinical practice and to prevention do not change clinical practice as quickly as is desirable. He mentioned a report from a large collaborative clinical trial suggesting that a treatment of hypertension for stroke victims reduces the risk of subsequent dementia by about 25 percent or 30 percent. He asked whether the IOM Report commented on the extent to which NIH should participate in ensuring that the results from potentially important clinical trials are translated and applied to practice. Although the IOM Report had not emphasized this topic, Dr. Hodes concurred that more effort needs to be made across agencies to ensure broader communication.

The discussion turned next to communicating scientific information. A Council member noted that control of reporting on scientific findings rests primarily with private publishers. Management of scientific literature might be improved to allow the public who pay for the science to have greater access to research results. Although this topic was not addressed by the IOM Committee, Dr. Hodes noted that the issue is of particular interest to Dr. Harold Varmus, who during his tenure as the NIH Director, advocated a federally coordinated or federally sponsored repository that would make information freely available. The Council member contended that there needs to be a mechanism for this discussion because lack of access to research results is a major impediment to practical applications.

Dr. Hodes addressed the NIA budget. The FY2002 actual appropriation was $891 million. The FY2003 appropriation was $994 million and the proposed appropriations for FY2004 are $994 million in the President's budget and House budget and $1.03 billion in the Senate appropriation. A government-wide recission brought NIA below the $1 billion level for FY2003. There is essentially no growth in the President's request for FY2004. The Senate called for a 3.8 percent increase. Since the House and Senate have not reconciled their budgets, NIA expects to function under a continuing resolution at FY2003 budget levels for several months.

In response to a question about one-time expenditures in FY2003, Dr. Hodes explained that in FY2003, in the context of biodefense, there was a line item in the budget of about $600 million for new buildings, an amount greater than the more usual $250 million for NIH buildings and facilities. This amount was reduced in FY2004 to a level below the steady state of about $250-$300 million, or essentially a level that is perhaps able to maintain safety and improvements on current buildings but allows no new construction. As a result, some buildings cannot be completed.

Future Meeting Dates

• February 3-4, 2004 (Tuesday-Wednesday)
• May 24-25, 2004 (Monday-Tuesday)
• September 22-23, 2004 (Wednesday-Thursday)

Consideration of Minutes of Last Meeting

The minutes of the May 2003 meeting were considered. A motion was made, seconded, and passed to approve the minutes.

3. Update On Biology Of Development And Aging IRG

Dr. Don Schneider, Center for Scientific Review (CSR), NIH, presenting on behalf of Dr. Sherry Dupere, Chief of the Biology of Development and Aging Integrated Review Group (IRG), provided an update of the new Biology of Development and Aging (BDA) IRG. He began by describing the process that led to the creation of the IRG, including the creation of the design team chaired by Dr. Art Lander, with Dr. Jeff Halter as vice chair. Four study sections were designed. Development -1 and Development-2 with the first emphasizing gametogenesis and organogenesis, and the second emphasizing pattern formation and early development. Aging Systems and Geriatrics is more translational or clinical, focusing on integrative studies of post-maturational changes. Cellular Mechanisms in Aging and Development combines the molecular and cellular mechanisms of development and aging with a focus on cell dynamics, cell cycle, and apoptosis.

Provisional rosters for this IRG were posted in May 2003. Applications submitted beginning in June 2003 were scheduled to be reviewed by the new study sections in fall 2003. In July 2003, two Scientific Review Administrators were hired, both former NIA staff. A critical mass of applications is needed as a regular workload of about 70 applications per panel is to be maintained.

Dr. Schneider then described the percentile system for scoring with respect to new study sections, and the treatment of applications caught in the transition. He also acknowledged the team effort of many contributors to the process, including NIA staff and Dr. Ellie Ehrenfeld, the director of CSR, who established an unprecedented blue ribbon panel on scientific boundaries for review that led to a formal report in January 2000. Although the IRG has received enthusiastic support from the scientific community, Dr. Schneider emphasized the need for more applications.

Applications now reviewed in behavioral and neuroscience IRGs will not be assigned to the BDA IRG. Nevertheless, an NIA staff member expressed concern that marginal applications would be directed to the new study sections to increase numbers. Dr. Schneider expressed CSR's intention not to pervert referral guidelines; any given applicant should have at least two study sections that can appropriately review his/her application. He also stated that applicants are encouraged to self-select where they think their applications should be reviewed. CSR posts study section rosters to help applicants identify their preferred study section.

4. Report: Task Force On Minority Aging Research

Dr. David Espino reported that the Task Force on Minority Aging Research dealt with three major issues at their meeting on September 23: (1) developing a process for NIA staff to discuss various initiatives that may or may not pertain to underrepresented minority groups; (2) discussing a report on minority supplements presented by Dr. Robin Barr; and (3) developing a minority mentored K01 type of award.

In his report on minority supplement awardees, Dr. Barr presented an analysis of indicators of productive research careers (publications and grant application success rates) between 1994 and 2001. Dr. Barr reported that about 50 percent of the candidates who had a minority supplement submitted subsequent applications to NIH. The average success rate for these individuals did not differ in general from the overall average success rate. It also appears that about 50 percent of those funded through a minority supplement are studying issues related to health disparities. Enhanced career success appears to be associated with sustained mentorship.

In describing the group's efforts with respect to development of a minority mentored K01 type of award, Dr. Espino pointed to the K01's unique benefit of providing partial salary support for mentors. Because of the recent legal proceedings involving the University of Michigan, the group is unclear whether it is possible to proceed with this initiative. In response to a question by a Council member, Dr. Barr clarified that the National Heart, Lung, and Blood Institute (NHLBI) has a minority mentored K award, as does NCI. Both are already published initiatives, and will be suspended if their date for renewal occurs before the policy on affirmative action programs is clarified. The minority K award was considered by Council members to be more effective than a minority supplement, and should be strongly supported. The minority K award was also considered to be a logical next step for a minority supplement awardee.

5. Reports: Working Group On Program

Dr. David Espino reported on the deliberations of the Working Group on Program (WGOP), that met on September 23. He briefly mentioned administrative developments such as NIH restructuring and Roadmap activities, and reported on the Clinical Investigators Working Group's (Task Force of the WGOP) discussion of the Paul B. Beeson Career Development Awards in Aging initiative. One recommendation from the Clinical Investigators' Working Group was that to help clinical investigators sustain research careers, NIH should allow investigators who are supported on career awards to gain additional salary from research grants if they are successful in gaining independent research grant support during the course of the career award. The Clinical Investigators' Working Group also discussed initiatives to support medical students.

The Working Group on Program considered the recent review of the Neuroscience and Neuropsychology of Aging (NNA) Program. Dr. Espino summarized five recommendations from the program review: (1) to recognize NIA staff for their support of NNA programs and the importance of maintaining the outstanding quality of the staff; (2) to set priorities using current strategies, relying more on Program Announcements (PA) instead of Request for Applications (RFA); (3) to maintain the number of R01s; (4) to endorse the R21 as a mechanism for promoting new research; and (5) to increase funding for Alzheimer's Disease Centers (ADCs)which are seen as underfunded by allowing for flexibility of centers to carry out more core functions (including contracting out of certain functions), or, in the absence of increased funding, reducing the number of centers to strengthen the funded centers.

Discussion ensued about the need to maintain adequate staff, recognizing that program budgets had doubled but staff had not. This was seen as part of the constant erosion of support throughout the federal government for management and administration because of an inherent bias that federal money ought to be invested in programs and not in bureaucracy. The problem is seen as particularly acute given how dramatically the venue of biomedical research has changed, from a focus on a single investigator to coordinated, discovery-driven, research networks that consume more staff time.

Council members discussed the outcome of a letter drafted by them to the Secretary of DHHS expressing concerns about staffing support at NIA and the uncertainties arising from efforts to contract out work currently performed by NIH staff. The reply from Secretary Thompson was circulated. It provided reassurance that program staff functions are considered inherently governmental and are not at risk of being contracted out. However, Council members expressed some dissatisfaction with the narrowness of the response from the Secretary, and asked that Secretary Thompson be invited to attend the next NIA Council meeting, noting that he is listed as an ex officio member of the Council. Council members felt that because the research environment has changed, the needs of science must be communicated clearly to the Department. They expressed strong concerns that program staff be provided adequate technical support to do their work. It was suggested that it might be opportune to write another letter after the release of the Roadmap Initiative, and at that time to communicate the need for more staff and job security to realize the goals of the Roadmap.

Dr. Hodes informed participants that staff requirements are part of the Roadmap exercise, and are being addressed across NIH. He noted that there are two independent constraints with respect to deployment of human resources – available dollars and available staffing allocations (FTEs). NIH and NIA are working hard to match those resources, especially since the Roadmap and the general tenor of science are both increasing the demands on scientific management expertise.

In further discussions, Council members asked whether workload analyses are undertaken to understand the tradeoff between resources and tasks. Dr. Hodes responded that this type of analysis has been conducted previously. The dilemma has been that dedicated NIA staff have shown a capability of sustaining increases in workload, making them vulnerable to continued imposition of increased workload. However, such efforts are not sustainable in the long term. NIA continues to seek constructive ways to accommodate staffing limitations by using external advisors under contract or who volunteer their time and has the added benefit of bringing in different perspectives. Staff resources are an important consideration in determining whether the Institute should participate in various initiatives. Dr. Hodes offered to present examples of staffing requirements, perhaps at the next Council meeting through the WGOP.

Dr. Espino reported on the Working Group's discussion about statistical data related to extramural programs. In reviewing the three most recent Council rounds, NIA appears to mirror closely the overall NIH average for percentile distribution of application reviews. The Working Group discussion also included a focus on the success of the loan repayment program. From FY2002 to FY2003, applications increased by 37 to a total of 60 applications for loan repayment. The funds available increased from approximately $1.6 million to $2.5 million.

Finally, Dr. Espino briefly summarized five presentations about past meetings and upcoming initiatives.

Genetics of Late-Onset Alzheimer's Disease (LOAD) Case-Control Workshop

The purpose of this meeting was to determine the goals and the study design for a national case-control study to be used as a standard sample set to confirm Alzheimer's Disease (AD) risk factor genes, and also to discuss inclusion/exclusion criteria for cases and controls. Dr. Espino summarized an informed WGOP discussion of how consenting procedures are done, Health Insurance Portability and Accountability Act (HIPAA) strategies, and ways to communicate them.

Congress on Sleep, Health and Aging

This meeting was cosponsored by NIA and a large group of other NIH ICs, the National Science Foundation (NSF), and outside organizations. It covered the entire spectrum of sleep in late life. The papers from this meeting will appear in a series of issues of the Journal of the American Geriatrics Society .

Stem Cells in Aging

Much discussion of the Working Group focused on cross-cutting issues related to stem cells and aging. Staff is recommending concept clearance for an RFA on valid and reliable assays on stem cells and functioning.

Longitudinal Data on Aging Working Group Meeting

Dr. Espino reported on a detailed discussion at the WGOP related to the implications of longitudinal data on aging. Staff are recommending concept clearance for an RFA focusing on secondary data analyses projects that will provide information, based on human longitudinal data, on the relationship of aging changes and risk factors in early-, mid-, and late-life, to health outcomes in old age.

Executive Function: Current Knowledge and Future Research Opportunities

NIA co-sponsored this workshop with the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Mental Health (NIMH), NIDA, and NIAAA. NIA joined planning for this workshop too late to notify Council prior to the workshop in June 2003. Recommendations from it are expected for the February 2004 Council meeting.

In the general discussion, one Council member underscored the issues associated with consent for use of biological samples, especially DNA. He described the intersection of three concerns: (1) confidentiality and privacy for the individual research subject; (2) what the institutional review boards (IRBs) will allow; and (3) scientific needs. Dr. Hodes suggested that a useful step might be to examine how such informed consent issues have been addressed in the genetics field.

Dr. Kelty asked members for their concurrence to proceed on these planning activities, as they are likely to lead to initiatives involving NIA resources. All proposed initiatives that were brought to the meeting from the WGOP passed by voice vote.

6. Comments From Retiring Members

Before inviting comments from retiring Council members, Dr. Hodes brought to the Council's attention the tragic death of former Council member Pat Goldman-Rakic of injuries incurred from an automobile accident. Dr. Hodes recognized her contribution to NIH and to the research community as an outstanding neuroscientist, a member of the National Academy of Sciences, and a wonderful human being.

Dr. Hodes then thanked Dr. John Cambier, noting his early contributions to NIA as a member of the Board of Scientific Counselors which provides oversight and peer review to the intramural program, and also his contributions in the areas of immunology, immunobiology, cell biology, and the broader perspective that he has shared on the wide range of scientific and other issues that the Institute has faced. He will continue to be involved in planning some aging immunobiology meetings as part of the national and international communities of aging and immunology investigators. Dr. Cambier attributed his growing interest in aging research to his interactions with NIA over almost a decade.

Dr. Ilene Siegler's interest has been in areas of behavioral science ongoing. Dr. Hodes recognized Dr. Siegler's strong input in review of NIA's programs, and in advising the Institute on the broader purview of behavioral sciences. Her openness and her consistent service to the Working Group on Program and the Minority Task Force have demonstrated a sustained effort above and beyond what is reasonably expected of Council members. Dr. Siegler thanked NIA for the magnificent opportunity to see the inner workings of the Institute, and to work with the extraordinarily talented group of staff.

Each retiring Council member was presented with a plaque and letter signed by Secretary Tommy Thompson.

The meeting was interrupted briefly by the arrival of the Malaysian Minister of Health and his staff to observe the Council process.

7. Presentation: Shared Interests Between NIA and NIMH

Dr. Hodes introduced Dr. Tom Insel, the Director of the National Institute of Mental Health, and described the relationship between NIMH and NIA as having reached a new intensity and level of productivity and reciprocity.

In describing NIMH and its mission, Dr. Insel began by illustrating the high prevalence of mental disorders as a cause of death or disability in mid-life. He indicated that current forecasts are that the highest prevalence of mental disorders is expected to shift from the midyears to late life over the next 20 years. To address this problem, NIMH supports over 4000 research and training grants and invests in comparisons, such as the “Men in Depression” campaign featured in Time and CNN. NIMH has a major focus on translational research, and has also invested heavily in research to promote improved services. He described NIMH as shifting in recent years from efficacy trials to large scale clinical networks that are focused on the effectiveness of treatments in a more real world setting.

Dr. Insel described NIMH's four basic research divisions, and illustrated research from their portfolios. He highlighted NIMH's recent work on the aging brain, in particular in the areas of neurogenesis and on how neurogenesis may be associated with depression and suicide among the elderly.

The rate of neurogenesis changes in aging, and yet the brain maintains some plasticity; activity or enrichment can increase the rate of neurogenesis. For example, a study of London taxicab drivers followed longitudinally finds an increase in hippocampal size that appears to be associated with the process of acquiring a spatial map of London. These observed relationships are supported by preclinical data showing increased rate of cell birth among rodents in enriched environments. Research from Dr. Fred Gage's lab suggests that the rate of neurogenesis in aged rats can increase significantly if they are placed in an active and enriched environment.

NIMH's interest in the concept of a link between neurogenesis and depression is associated with several reports of hippocampal atrophy. Every clinically useful antidepressant has been found to increase neurogenesis in the rat brain. Recent studies also have shown effects of antidepressants in mice emerging after three or four weeks of treatment, in how these animals respond to a novel situation and how quickly they go after food in a novel situation. When neurogenesis was selectively blocked in the hippocampus at the same time that the animals were treated with antidepressants, the animals lost the behavioral effects, suggesting that the behavioral effects and antidepressants are contingent on the increase in neurogenesis.

The program area of depression in the elderly is now moving into NIMH's Psychopathology Division. Depression is associated with vascular events in left frontal and left striatal regions but not in the right hemisphere to the same degree. Mood disturbances occur in about 40 percent of patients with stroke. These observations raised questions about whether the localization of stroke could inform the localization of emotion and/or depression in the brain. Vascular depressions, very small, white matter hyperintensities that show up on MRI, are of interest because they occur in the frontal circuits that seem to be associated with impaired executive function as well as the development of depression. Those suffering from depression may actually be experiencing vascular changes.

A particularly difficult area for diagnosis is depression in Alzheimer's patients. A recent paper proposed criteria for diagnosing depression in Alzheimer's disease patients. Depression in Alzheimer's may occur fairly early in its course and, most importantly, it may often be the onset of depression that triggers the transition to a nursing home or the loss of independence and autonomy. Yet the depression may be treatable.

A major challenge is that there are different potential avenues to the same phenotype. Alzheimer's itself confers a degenerative process that may produce changes in mood. A meeting with NIA on “Perspectives on Depression: Mild Cognitive Impairment and Cognitive Decline” is being planned to begin to address this very important public health issue by developing a strategy to tease apart these different aspects.

Dr. Insel also reported on recent research suggesting that GSK-3 alpha may be a target not only for depression but also for Alzheimer's disease. Glycogen synthase kinase was reported originally to cause changes in structural development in zebrafish and then in tadpoles (such as two-headed tadpoles). It has also been found to be involved in cross-correlating other systems including tau, raising the possibility of its importance for Alzheimer's and in APP processing. If the alpha form of this enzyme, GSK-3 alpha, is inhibited, it blocks the formation of beta amyloid. A GSK-3 alpha antagonist was a very powerful blocker of the progression of lesions in a mouse model. Lithium, the best GSK-3 antagonist known, has been available for 40 years as the treatment of choice for bipolar disorder, yet no one has asked whether that treatment protects against the onset or progression of Alzheimer's.

Dr. Insel commented on NIMH activities related to the study of suicide, supported through NIMH's Intervention and Services Division. He cited 2002 data from the World Health Organization in reporting that there are 30,000 deaths from suicide in this country every year, and 800,000 worldwide, or about 50 percent of all violent deaths globally. Suicide is a major public health problem that usually goes unrecognized. In the U.S., males commit suicides at a rate of four to one over females. The highest rate of suicide is among white males and Native American males. Suicide rates for African American males are considerably lower, and at the national average of 10.3 generally. Curiously, African American females have the lowest rate of suicide in the U.S., a rate that is about one-fourth of the national average, around 2.5. The rate among men over the age of 65 is the highest, at three times the national average, comprising 20 percent of the suicides in the country. The rate of depression among elderly suicide victims is about twice what it is in younger suicide victims; there is a much greater risk for suicide if one is depressed after age 65. Although the suicide rate for males outnumbers that for females in Western countries, the rate for women outnumbers that for men in other countries, particularly in China and other parts of Asia.

Elderly people are more competent at committing suicide; about 1 in 4 suicide attempts are successful among the elderly while for young women the rate is 1 in 200 attempts. Dr. Insel also noted an increasingly recognized phenomenon of “sub-intentional” suicide,” where elderly, particularly in nursing homes or living in assisted living situations, begin to stop taking their medication, put themselves in harms' way, and commit passive gestures towards ending their lives without being counted as suicides.

Seventy percent of the men who commit suicide in this age bracket have seen a physician in the month prior to their suicide. Yet none had been referred for mental health care or even for assessment for suicidal ideation or suicide risk. Suicide is most common in the rural parts of the U.S. The highest suicide rates are in Nevada and Alaska, in part because guns are most prevalent and mental health services are least available in these states. Ninety percent of mental health services are available in urban areas. Older men, even when they are referred, are least likely to seek care because of the cost and the stigma associated with receiving mental health care. At the time of the study Medicare did not cover medications and paid only 50 percent towards physician visits.

Dr. Insel reported that NIMH is the fifth largest institute in support of aging research, and is currently investing about $106 million in this area, or 8.5 percent of the budget. NIMH has a workgroup of program officers across the divisions who meet regularly to improve communications among basic neuroscientists, service researchers, and supporters of psychopathology research. NIMH is also participating with NIA in a workgroup on Alzheimer's disease. Dr. Insel stressed the importance of NIMH's services portfolio and his ambition to have a greater public health impact, and welcomed joint collaborations between NIMH and NIA to maximize public health impact, particularly in the areas of basic neurosciences, mental disorders, interventions and services.

In response to a question about translation of research findings to practice, Dr. Insel stated that he saw the NIMH as providing the evidence base, establishing a demonstration project and then handing it off, perhaps to their sister agency, SAMSHA. One Council member observed that a major challenge to translation is the abysmal state of reimbursement for clinical practice in the mental health arena. Dr. Insel acknowledged that it has been difficult to change behaviors and concurred that it is important to persevere both in terms of developing evidence-based practices, but also in understanding the effects of economic incentives.

Discussion turned next to the issue of collaboration among NIH IC's. For example, one Council member noted that the NINDS is interested in white matter studies because it is a risk factor for stroke. NIA is obviously interested because white matter changes are related to dementia, and NIMH is interested because of depression. Dr. Insel observed that collaborations among Institutes have increased dramatically over the years, and the emphasis has been on trying to focus on some of the big problems that can be addressed across Institutes. Although “piggybacking” on ongoing efforts is a step in the right direction, prospective planning and collaboration at the outset of a study is preferable. The NIH Roadmap activities and clinical infrastructure harmonization, and the “Healthy Brain Initiative” were mentioned as examples of trans-NIH efforts.

8. Program Highlights

A. Neuroscience and Neuropsychology of Aging: Prion Proteins

Dr. Stanley Prusiner, an NIA Council member and Director of the Institute for Neurodegenerative Diseases and Professor in the School of Medicine at the University of California, San Francisco, focused on prion diseases: the mechanism of prion formation and what is known about its structure; early diagnosis as the surest way to effective treatment; and therapeutics. He described age-dependent, human, neurodegenerative diseases (e.g., Alzheimer's, Parkinson's, frontotemporal dementia, Huntington's, amyotrophic lateral sclerosis [ALS], Progressive Supramuscular Palsy [PSP], spinocerebellar ataxias, Pick's, and prion diseases).

Studies of prion diseases have yielded new concepts. Prions are infectious proteins that are devoid of DNA and RNA. The prion diseases are age-dependent neurodegenerative diseases that may be manifest as sporadic, genetic, and infectious illnesses. The prion protein is generally encoded in a gene in all mammals and is comprised of about 250 amino acids. After the terminae are cut off and post-translational modifications are added, there is a protein of about 210 amino acids (PrP C ). PrP C undergoes a conformational change to form the disease-causing protein PrP SC , which is largely protease-resistant. The section of the protein that has the infectivity, PrP27-30, will polymerize into amyloid. PrP SC may adopt a variety of conformations, each of which specifies a specific disease phenotype and represents a distinct prion strain.

Dr. Prusiner described the use of electron crystallography, image reconstruction studies and crystalographic averaging to identify where deletions of amino acids occur. Through studies of chimeric PrP molecules expressed in transgenic mice that are susceptible to human prions, two regions have been mapped, one to what is termed Protein X binding site. Protein X is unknown. Another region is the PrP SC interaction site, where a molecule of PrP C is converted into a molecule of PrP SC .

Dr. Prusiner turned next to diagnosis, describing a new technique that his team had developed, the “conformation-dependent immunoassay.” This technique allows the measurement of PRP C without destroying large amounts of PrP SC . The conformation-dependent immunoassay data are important for developing diagnostic approaches and monitoring of newly-developed therapies such as rational drug design and gene therapy, using dominant negative inhibition of prion propagation.

Rather than considering PrP SC as a “misfolded” or “aberrantly-folded” protein, he proposed that prion disease may be disorders of PrP kinetics, with PrP SC an alternatively folded protein that is normally present at sufficiently low levels so as not to be detectable by prion bioassays. Perhaps PrP SC has an as yet undefined function that has been preserved throughout mammalian evolution and normally is present and functional at low levels. PrP SC may begin to accumulate when formation exceeds degradation; eventually, high levels of PrP SC accumulate and cause CNS disease. Whether the mechanism underlying the accumulation of PrP SC is similar to that responsible for other neurodegenerative diseases remains to be established.

Dr. Prusiner described clinical studies using quinacrine. Quinacrine has a 70-year history in the treatment of parasitic diseases with well documented low toxicities in humans, which has permitted clinical studies in Creutzfeldt-Jakob disease (CJD) patients. Clinical studies of quinacrine in mice and in patients with prion disease are in progress. The decline in neurologic function in some sporadic CJD patients seems to be slowed by quinacrine. In two CJD patients treated with quinacrine but who later died, the levels of PrP SC were reduced. Treatment of mice with quinacrine for 30 days beginning 60-70 days after inoculation produced about a 20 percent prolongation of the incubation period. Dr. Prusiner cautioned that these studies are neither randomized nor blind, and the sample size is small. There may be some selectivity in subjects since families must agree for the patient to participate, and those may be sicker than others. Key areas to investigate include proper dosage level and protocol, proper treatment duration, and quinacrine blood and brain levels.

Dr. Prusiner concluded that it is necessary to realize effective pharmacotherapeutics. Other major objectives in prion research include developing non-corrosive disinfectants; elucidating the function of PrP C , PrP SC and the Doppel (Dpl) paralog; determining the molecular changes that feature in the transmission and replication of prions; identifying PrP ligands that feature in PrP SC formation such as protein X; determining the structure of PrP SC and the molecular basis of prion strains; elucidating the events responsible for the pathogenesis of the prion diseases.

Discussion centered first on the rarity of the prion disease and economics of testing for the disease and subsequent treatment. The incubation period for the disease can be anywhere from 2 years to 50 years. Dr. Prusiner stated that everyone in Britain could be tested; when the cost of the test comes down, it might be possible to test all people who are age 55 and over when they present for a physical exam. Dr. Prusiner described the development of 2,000 new compounds a year that are quinacrine derivatives as particularly promising, as the little data in humans with quinacrine have been very encouraging.

B. Geriatrics and Clinical Gerontology: Role of RANK Ligand in Mediating Increased Bone Resorption in Early Postmenopausal Women

Dr. Sherry Sherman introduced Dr. Sanjeev Sundeep Khosla, Professor of Medicine, Mayo Clinic College of Medicine, and Research Chair in the Division of Endocrinology, Metabolism and Nutrition at the Mayo Clinic and Foundation.

Dr. Khosla began by describing the magnitude of the problem of osteoporosis. Osteoporosis or low-bone mass currently affect 44 million U.S. women and men aged 50 and older, and the number affected is estimated to increase to 52 million by the year 2010, and to 61 million by the year 2020. The estimated annual cost in 2001 dollars to the U.S. healthcare system was about $17 billion. The overall goal of Dr. Khosla's research program is to better understand the pathogenesis of osteoporosis, which he considers to be the key to prevention as well as to developing more physiologically relevant treatments.

Dr. Khosla reviewed the bone remodeling cycle for those unfamiliar with bone biology. Bone is not a static, but a highly dynamic tissue that is constantly undergoing “remodeling” to respond to changes in mechanical loading, repair of microcracks that occur with even normal activities, and, since bone serves as the major reservoir for calcium in the body, to help respond to changes in the need for calcium by the organism.

The focus of Mayo's research effort over the past 20 years has been on sex steroids and, in particular, estrogen regulation of bone and calcium metabolism. In 1988, the Mayo group was one of two groups that concurrently demonstrated the presence of estrogen receptors first in osteoblasts and later in osteoclasts. Based on multiple lines of investigation, the Mayo team has formulated a working model whereby estrogen deficiency is responsible both for the early and the late life phases of bone loss in postmenopausal women. In addition, it also appears that estrogen, in fact, plays a dominant role in regulating bone metabolism in men, and that estrogen deficiency may also contribute significantly to bone loss in aging men.

While estrogen, as well as a large number of other hormones and cytokines can regulate the processes of bone formation and resorption, work in a number of laboratories over the past five years has uncovered what is perhaps the final mediator of the regulation of bone resorption, the RANK ligand (RANKL)/RANK/osteoprotegerin (OPG) system. The bone forming, or osteoblast lineage cell, makes RANKL, which binds to its receptor, RANK, on the surface of the bone resorbing, or osteoclast precursor cell in the bone marrow. RANKL, along with another molecule made by the pre-osteoblast, Macrophage Colony Stimulating Factor (M-CSF), are both necessary and sufficient to develop osteoclasts. The pre-osteoblastic cells also make a soluble decoy receptor, OPG, that binds and neutralizes RANKL. Thus, changes in the RANKL to OPG ratio determine, in the end, how many osteoclasts are formed in the bone marrow and are available to resorb bone.

Dr. Khosla next described a study with two primary objectives: (1) To develop a method for assessing cytokine and growth factor production by the appropriate cells in the bone micro-environment in vivo in humans; and (2) to determine if RANKL expression by bone marrow cells plays a role in mediating the increase in bone resorption in early postmenopausal women. The findings from this study were published in the April issue of the Journal of Clinical Investigation (JCI) (Eghbali-Fatourechi, et al. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. JCI 111:1221-1230, 2003), along with an accompanying commentary (Bell NH, JCI 111:1120-1122, 2003). The researchers isolated pre-osteoblastic cells using two-color flow cytometry and performed a number of validation studies to establish that the isolated cells were, indeed, in the osteoblastic lineage. The main finding of the study was that postmenopausal women had significantly higher RANKL expression on bone marrow osteoblastic, T-, and B-cells as compared to premenopausal women or postmenopausal women who were on estrogen. In addition, the level of RANKL expression per cell correlated positively with bone resorption markers and inversely with serum estradiol levels, attesting to the biological validity of the findings.

The Mayo group plans to apply these methods to further clinical investigative studies examining the regulation of bone resorption and formation by sex steroids in aging women and men; the mechanisms by which intermittent parathyroid hormone increases bone formation in women; and possible age-related changes in gene expression of key growth factors in marrow pre-osteoblastic cells. Dr. Khosla closed by gratefully acknowledging the NIA and his project team for their support.

In the discussion, one Council member suggested that detecting OPG on the cell surface might be more relevant than measuring OPG mRNA levels in osteoblastic cells. In addition, there was a discussion about the evidence supporting a role for estrogen as the major determinant of bone metabolism in men.

C. Behavioral and Social Research: Causes and Consequences of Health Care Intensity

Dr. Richard Suzman introduced Dr. Jonathan Skinner's study of geographic differentials in health as an important part of BSR's initiatives on health disparities. Dr. Skinner holds joint appointments in the Economics Department at Dartmouth College and in the Dartmouth Medical School. The research he presented demonstrates large disparities in health spending across the U.S. with total spending roughly 60 percent higher in the highest quintile compared to the lowest quintile of spending. The key research question was about quality of care that overall expenditures buy.

Dr. Skinner discussed some new evidence on whether the health care technological revolution has provided benefits to Americans at least as dramatic as the rise in health care costs. He and his colleagues found, as in previous research, that there have been dramatic improvements in survival following heart attacks (DM Cutler and M McClellan. Is technological change in medicine worth it? Health Affairs ; 20[5]: 11-29, September/October 2001). These improvements have also been coupled with rising health care costs, and in the aggregate, it might appear that the improved survival has been worth the increased costs. However, Dr. Skinner's group find using more recent data that the improvements in terms of health benefits (as measured by one-year mortality rates) have flattened out since 1997, while costs have continued to rise. At least since 1997, then, rising health care costs have not been justified by improved outcomes. Furthermore, regions in the US where survival improved the most were not the regions where costs increased the most. Dr. Skinner contended that the dramatic benefits in treatment of heart attacks must be attributed to improved technology, but improved survival appears to be associated with effective care such as the use of beta blockers and aspirin, which are inexpensive, rather than more costly and intensive care with low marginal benefits and having the largest impact on health care costs.

Focusing on ethnic disparities, Dr. Skinner's group found in an analysis of total knee replacements by Hospital Referral Region, that for 430,726 knee replacements (using Medicare data), rates for African-American men were extremely low and were half the rate for white non-Hispanic men. There is considerably more overlap in rates between African-American and non-Hispanic white women. Importantly, there are regions where the rates are almost equal and regions where the rates are very different. Differences are attributable to the health care system and not to the race or ethnicity of the patient.

Discussion in Council noted that among women, African-Americans have higher rates of osteoarthritis than white, non-Hispanic women, and among men, African-Americans show higher rates of co-morbidity than white, non-Hispanic men. These differences complicate interpretation of ethnic differences in treatment as attributable to health care system differences, or to differential treatment by ethnicity.

Dr. Skinner addressed African-American/white differences in intensive care unit (ICU) admission in the last six months of life. In almost every area of the country, African-American males or females are far more likely to be admitted to an ICU in the last six months of life. He noted that black men and women have higher disease burden, and that Medicare expenditures are substantially higher among African-Americans compared to whites. These patterns may suggest that African-Americans are subject to efforts to remedy conditions that were not treated earlier.

Dr. Skinner identified a number of policy implications: (1) to monitor performance and disparities at the level of the hospital or provider group to encourage “accountable care providers”; (2) to develop guidelines where clinical evidence is poor, particularly in the treatment of chronically ill patients; and (3) to reward quality, not quantity of care. The data assembled by Dr. Skinner might be used to identify best practices and associated costs.

In response to a question about access, Dr. Skinner noted that regions that are more segregated, e.g., Detroit, have greater discrepancies in access to care.

One Council member found it striking that the supply-driven variations in intensity of care are not associated with better or worse outcomes. He asked whether the disorganization associated with supply was generated by patients faced with many options and leads to uncoordinated care. Dr. Skinner remarked that doctors treating patients in the highest quintile based on intensity of care comment about fragmented care and being unable to get their patients into hospitals. On the other hand, patients in Florida are dissatisfied if they are not seen by specialists because that is what they have come to expect.

D. Biology of Aging: Small Molecule Activators of Sirtuins Extend Saccharocmyces cerevisiae Lifespan

Dr. Anna McCormick introduced Dr. Konrad Howitz, Director of Molecular Biology at BIOMOL Research Laboratories, a biochemical research company. Dr. Howitz spoke about research that he has done in collaboration with Dr. David Sinclair, an Assistant Professor of pathology at Harvard Medical School ( Nature 425: 191-196, 2003). Much of the work at BIOMOL concerns the creation and commercialization of enzyme assay systems, particularly ones for targets of pharmaceutical interests.

It has become clear in recent years that acetylation of certain lysine residues in histones is important in regulating gene expression and the activity of non-histone proteins, such as p53. BIOMOL is developing histone deacetylase (HDAC) assays. HDAC inhibitors show promise as cancer therapeutics, but screening was hindered by available radioactive assays. BIOMOL created a high-throughput assay based on an acetylated lysine substrate. The assay worked well with HDACs 1, 2 and 3, class I HDACs that are abundant in HeLa nuclear extract, and with class II enzymes. The question that remained was whether it would work with sirtuins (class III HDACs).

The sirtuins are a widely distributed group of NAD + -dependent deacetylases named for the yeast gene-silencing factor, Sir2 (or silent information regulator 2). In yeast and the nematode C. elegans , extra copies of sirtuin genes have been shown to increase the organism's lifespan. BIOMOL used PCR to clone the human sirtuins (called SIRTs 1-7) and found that SIRT2 did work, although somewhat poorly, with the substrate. Dr. Howitz was contacted by Dr. Sinclair, whose lab had discovered that nicotinamide shortened yeast lifespan by inhibition of Sir2. He was trying to characterize the kinetics of nicotinamide sirtuin inhibition with both Sir2 and human SIRT1.

BIOMOL's discovery of sirtuin activators originated from further research and development on deacetylase assays. In the case of SIRT1 this led to the creation of a substrate based on p53 residues 379-382. SIRT1's efficient deacetylation of this substrate allows the user to obtain a good signal at low substrate concentrations. This has benefits in terms of identifying inhibitors that compete with substrates for enzyme binding sites. It was also critical in the identification of polyphenol sirtuin activators, since they act in a manner opposite to competitive inhibitors and actually decrease substrate K m 's.

BIOMOL produces a number of compound libraries grouped according to structure or activity. In a kinase inhibitor library, two compounds were discovered, piceatannol (a Syk inhibitor) and quercetin (PI-3 kinase inhibitor), that appeared to stimulate SIRT1 activity about eight-fold and five-fold respectively.

Genetic manipulations that increase sirtuin activity have been shown to increase longevity in “lower” eukaryotes. Dr. Sinclair and his lab looked at the effects of polyphenol SIRT1 activators on yeast replicative lifespan and at the in vivo acetylation levels of p53 lysine-382. Resveratrol (a compound found in red wine) extended yeast lifespan by more than 70 percent. In human cells it decreased p53 lysine-382 acetylation and increased cell survival under radiation stress. Particularly striking is the fact that resveratrol seems to increase yeast lifespan by the same pathway as calorie restriction. Calorie restriction has been demonstrated to increase lifespan in mammals while lowering the occurrence of age-related maladies such as cancer, neurodegeneration, and diabetes. If resveratrol or other SIRT1 activators can truly mimic calorie restriction in mammals, then the end result of this research could be the development of drugs that extend lifespan while ameliorating a variety of age-related disorders.

The production of plant polyphenols, including resveratrol and the other sirtuin activators, is induced by environmental stresses on plants, such as drought, nitrogen deprivation or UV radiation. These are stresses similar to those that can increase yeast lifespan via a sirtuin-mediated pathway. Hormesis is the idea that mild stresses, and this may include calorie restriction, can be beneficial to health. Drs. Sinclair and Howitz coined the term “xenohormesis” for the concept that molecules produced in response to stress in one organism, e.g., a plant, can have hormesis-like health benefits in another organism, e.g., a plant eater.

9. Adjournment

The 90th meeting of the National Advisory Council on Aging was adjourned at 1:56 p.m. on September 24, 2003. Dr. Hodes closed the Council session by thanking all speakers and the Council members for their participation. The next meeting is scheduled for February 3-4, 2004.

10. Certification

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

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

Prepared by Miriam F. Kelty, Ph.D. with the assistance of Rose Li and Associates, Inc.

Attachment A

MEMBERSHIP ROSTER
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING
(Terms end December 31)

Chairperson

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

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

Marie A. Bernard , M.D. (2005)
Donald W. Reynolds Chair
Department of Geriatric Medicine
University of Oklahoma College of Medicine
Oklahoma City , OK

Elizabeth H. Blackburn , Ph.D. (2006)
Professor
Dept of Biochemistry & Biophysics
University of California
San Francisco , CA

Melissa M. Brown , M.D. (2006)
Director
Center for Value-Based Medicine
Flourtown , PA

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

*David V. Espino , M.D. (2004)
Professor and Vice Chair
Dept. of Family & Community Medicine
Division of Community Geriatrics
University of Texas Health Science Center
San Antonio , TX

Linda P. Fried , M.D., MPH (2006)
Professor, Medicine, Epidemiology & Health Policy
Director, Division of Geriatric Medicine & Gerontology
Director, Center on Aging and Health
The Johns Hopkins Medical Institutions
Baltimore , MD

F. Michael Gloth , III , M.D., (2005)
President
Victory Springs Senior Health Care
Reisterstown , MD

Eugene M. Johnson, Jr. , Ph.D. (2005)
Norman J. Stupp Professor, Department of Neurology
Professor, Dept. of Molecular Biology & Pharmacology
Co-Director, Alzheimer's Disease Research Center
Washington University School of Medicine
St. Louis , MO

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

Ronald D. Lee , Ph.D. (2005)
Professor, Department of Demography
College of Letters and Science
University of California
Berkeley , CA

Spero M. Manson , Ph.D. (2006)
Professor of Psychiatry and Head
American Indian & Alaska Native Programs
University of Colorado Health Sciences Ctr
Aurora , CO

Peter W. Nauert, J.D. (2005)
Principal
Insurance Capital Management
Chicago , IL

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

*Judith A. Riggs , M.A. (2004)
Washington , DC

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

Leon J. Thal , M.D. (2005)
Professor and Chair
Department of Neurosciences
University of California San Diego
School of Medicine
(and Staff Physician, Neurology Service,
San Diego Veterans Medical)
La Jolla , CA

* Phyllis M. Wise , Ph.D. (2003)
Dean, Division of Biological Sciences
University of California Davis
Davis , CA
Durham , NC
*WGoP Member

EX OFFICIO MEMBERS

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

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

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

Colonel George F. Fuller , M.D.
USUHS
Department of Family Medicine
Bethesda , MD

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

[ 1 ], [ 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 3-4, 2004, and corrections or notations will be stated in the minutes of that meeting.