Council Minutes - February 1998

NATIONAL ADVISORY COUNCIL ON AGING

The Seventy-Third Meeting

Summary Minutes:
February 5-6, 1998

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

CONTENTS

1. Call to Order
2. Behavioral and Social Research (BSR) Program Review
3. Intramural Research Program Review
4. Working Group on Program
5. Minority Task Force Report
6. Highlights of Recent Research Findings
7. Review of Applications
8. Adjournment
9. Certification
   

Department of Health and Human Services
Public Health Service
National Institutes of Health
National Institute on Aging

National Advisory Council on Aging
Summary Minutes
February 5-6, 1998

The 73rd meeting of the National Advisory Council on Aging (NACA) was convened on Thursday, February 5, at 1:00 p.m. in the Natcher Building, Conference Rooms E1&2, National Institutes of Health (NIH), Bethesda, Maryland. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA), presided.

In accordance with the provisions of Public Law 92-463, the meeting was open to the public on Thursday, February 5, from 1:00 p.m. to 4:30 p.m. and on Friday, February 6, from 8:00 to 10:00 a.m. The meeting was closed to the public on Thursday, February 5, from 4:30 p.m. to recess and on Friday, February 6, from 10:00 a.m. to adjournment 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.

Council Participants:

Dr. Elizabeth L. Barrett-Conner
Dr. Helen M. Blau
Dr. Fred H. Gage
Dr. Patricia S. Goldman-Rakic
Dr. Richard A. Goldsby
Dr. Mary S. Harper
Dr. William Hazzard
Dr. James S. Jackson
Dr. Gerald E. McClearn
Dr. John W. Rowe
Dr. Dennis Selkoe
Dr. John Q. Trojanowski
Dr. James W. Vaupel
Dr. Robert B. Wallace
Dr. Eugeneia Wang
Dr. Jeanne Y. Wei
Dr. David A. Wise

Ex Officio Participant:

Dr. George F. Fuller, USUHS
Dr. Judith A. Salerno, DVA

Absent:

Dr. Jeffrey Bluestone
Mr. Hugh Downs

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

Members of the Public Present:

Shirley Brown, Gerontology News
Penelope Cafferall, Alliance for Aging Research
Pat Kobor, American Psychological Association
Sharon Moss, American Speech, Language, Hearing Association
Al Nugent, Midwest Research Institute

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

Dr. Stephen Daniel, Office of the Director, NIH
Dr. Margaret Huyck, Office of Behavioral and Social Sciences Research, OD, NIH
Dr. Michael Micklin, Center for Scientific Review

1. Call To Order

Dr. Hodes welcomed Council members and guests and asked new members to introduce themselves.

Future Meeting Dates

• May 21-22, 1998 (Thursday-Friday)
• September 24-25, 1998 (Thursday-Friday)
• February 3-4, 1999 (Wednesday-Thursday)
• May 27-28, 1999 (Thursday-Friday)
• September 23-24, 1999 (Thursday-Friday)

Consideration of Minutes of Last Meeting

The minutes of the September 25-26, 1997, meeting were approved as submitted.

Director's Status Report

Dr. Hodes informed Council that NIH received a 7.2% budget increase for FY 1998. He reviewed budget information showing that the NIA budget is allocated as follows: 62.5% for Research Project Grants; 8.8% for the Intramural Research Program; 3.7% for Research Management and Support, 2.9% for Training, 12.3% for Research Centers, and 3.0% for Other Research Support. Budget tables are appended to these Minutes.

Dr. Shalala met with NIH Institute and Center Directors to assert her support for a FY 1999 substantial budget increase for NIH. Dr. Hodes indicated that such an increase is likely, and he invited Council members to suggest areas in which additional resources might be used effectively. Input from Council, along with scientific opportunities identified through NIA planning activities, helps the NIA define its priorities and special initiatives.

Dr. Hodes commented that part of the NIH budget structure is the special emphasis areas identified by Dr. Varmus. They include: biology of brain disorders; new approaches to pathogenesis; advanced instrumentation and computers; new strategies for prevention; new avenues for development of drugs and other therapeutics; and, genetic medicine.

Council members viewed video clips selected from 1997 television coverage of research on aging.

Each year, Council is required to review and approve the Statement of Understanding between NIA staff and the National Advisory Council on Aging (NACA). Council approved an amendment that raises to $100,000 amounts deleted by initial review groups that can be restored by staff without advice from Council. The Institute recommended and Council approved that the advice of Council be sought for restoration of amounts over $100,000.

2. Behavioral And Social Research (Bsr) Program Review

The BSR Program was reviewed by an ad hoc committee of Council members and area experts prior to the Council meeting. A report of that review was presented. In outlining the scope of the program, Dr. Abeles, Associate Director, BSR, noted that NIA's BSR Program is probably the most broad behavioral science program at NIH in that it supports research that interfaces with neuroscience and biology of aging and ranges from research on individual differences to research on social structures. BSR Program staff chair both the Behavioral and Social Science Research Coordinating Committee at NIH and the Federal Forum on Aging-Related Statistics. Through these groups, BSR staff provide leadership in data collection, analyses and reports, and setting research agendas across Federal agencies. The BSR Program priorities are described in the BSR Sourcebook available on the NIA Home Page at http://www.nih.gov/bsr/bsrar.htm. From its inception, the program has been a major contributor to knowledge in areas such as: malleability of cognitive function; lifestyle risk factors in health and functioning; demography; and, research resources that include longitudinal and other large databases.

Dr. James Jackson reviewed the charge to the review group that he chaired: to assess program balance and to evaluate the effectiveness of the BSR Program overall. The review took place during a 6-month period. He said that overall the program was seen as excellent in terms of its research portfolio, scientists supported, and research staff.

Reviewers acknowledged the importance of behavioral and social science research for NIA and NIH. The program's application of research findings is notable, as are its contributions to practice, interventions, and public policy.

Reviewers found the demography and population epidemiology area to be well-developed. Projects supported, investigators, and impact of supported research have been spectacular. The development of biodemography and its identification as a field is attributable to the BSR Program. The area of adult psychological development was also considered to be well-developed. Social science research was assessed as less focused than the other two broad areas. BSR's role in training was found to be substantial but it was deemed to merit even further emphasis.

Scientific and personnel resources were judged similar to those in other NIA programs. The review team felt, however, that staff are responsible for such broad scientific areas that they are limited in their abilities to develop new areas which may be promising or present a special opportunity. The BSR research budget was judged to have increased less than for other NIA programs.

To evaluate the effectiveness of the program, reviewers believed that: 1) outcome measures need to be developed; 2) policy contributions made by the research supported need to be identified; 3) what is innovative about the research should be assessed; and, 4) adoption of research results into practice needs to be reviewed.

The group recommended that there be more cross-branch initiatives within BSR, training support be developed further, and collaborations among BSR and other programs be increased. For example, there should be greater collaboration between the interdependent fields of neuroscience and cognitive science. Some gaps were identified by reviewers. In the adult psychological development area, more activity was recommended in: behavior genetics; cognitive functioning; higher cognitive processes; personality; cognitive and social psychological functioning of the oldest old; characteristics of older workers and their interactions within the work place; and, human factors. In the social science program area, issues deserving greater emphasis include: behavioral and lifestyle predictors of medical care; the doctor-patient relationship; changing social structures; prevention; and, health-related outcomes of a changing health care system. A greater focus on biodemography was recommended for the demography and population epidemiology program. Secondary analyses of large data sets were encouraged. Reviewers recommended that there be an examination of the dynamic interplay among chronic disease, age, disability and mortality, and efforts to ensure that new cohorts and measures are added to surveys.

In the written report reviewers plan to submit, they will focus on ways to increase senior staffing of BSR, recommend changes in organizational structure that may facilitate more collaboration with other programs, and recommend outcome measures to assess effectiveness.

In discussion, a Council member asked how NIA compares to other institutes with respect to program breadth, emphases, and funding, and changes in funding patterns over time. Reviewers did not address those issues. Dr. Abeles responded that the NIA BSR Program places a strong emphasis on basic behavioral and social research, while other institutes tend to focus on health promotion or particular disease-related research. Other issues discussed included the need to bring disciplinary interests together in thinking about cognitive science, and the fact that most assessment measures currently used have not been normed on minority and/or elderly samples. It was noted that the Health and Retirement Survey, and the Asset and Health Dynamics Among the Oldest Old Survey, are making progress on assessment constructs within older populations.

3. Intramural Research Program Review

Dr. Hodes introduced Dr. Dan Longo, Scientific Director, NIA. Dr. Hodes reminded Council that the intramural research program reflects the extramural programs in breadth. The Board of Scientific Counselors (BSC) has the responsibility for primary review of the intramural program. The BSC meets twice yearly and each laboratory is reviewed about once every 4 years. The Board sends a report to the Scientific Director and to the Director, NIA. A decision is made to implement the Board's recommendations or not, and the Scientific Director reports back to the BSC a year subsequent to the review. Council members participate as ad hoc reviewers as appropriate, and thereby are familiar with the intramural program and BSC reviews. Council members can participate in reports on the reviews to Council. Two laboratories discussed at the Council meeting were the Longitudinal Studies Branch and the Epidemiology, Demography and Biometry Program.

Dr. Longo indicated that prior BSC reviews and the current BSC review are consistent in recommending changes to the Baltimore Longitudinal Study on Aging (BLSA) and to the Longitudinal Studies Branch. One result has been an organizational change: the Longitudinal Studies Section is now housed within the new Laboratory of Clinical Investigation. Aside from the organizational change, the time is opportune to make changes in the conduct of the longitudinal study. Dr. Longo introduced Dr. Michelle Evans, Deputy Scientific Director, NIA, who reported.

BSC reviewers made recommendations relating to scientific direction of the BLSA, data management, and biologic resource management as well as to other areas. It was recommended that an advisory group for the BLSA be established. This recommendation has been implemented. The advisory group is a subcommittee of the BSC, supplemented with ad hoc consultants, to provide overall direction and guidance, and to develop a long-range plan for the Study's future directions. A second recommendation was to create a central database in a modern computer language so that data from all participants could be accessed, along with an index. The database has been converted to SAS and is now more accessible to researchers. Comprehensive documents are on-line that list protocols, variables, serial measurements on individuals, and patient contacts. A policy regarding data ownership and availability of data resources to researchers is under development, as is a topical on-line BLSA bibliography. Data on core measures and selected other data sets are available. Other recommendations being implemented concern sample collection files for biologic resources.

Additional issues are being addressed that impact on the long-range conduct of the study, e.g., the rationale underlying inclusion of subjects ranging in age from 20-100; the scientific rationale for minority recruitment and retention; options of varying duration and frequency of subject visits; adding home visits; and, telephone follow-up interviews. The issue of hypothesis-driven research has been discussed with the BLSA advisory group. Also being considered are: development of a program to investigate genetic/ environmental interactions that underlie different trajectories of aging using modern technologies; ways to investigate theories of aging; ways to elucidate behavioral, social, and economic influences on health and longevity by increasing the diversity of the BLSA population; and, ways to use molecular markers to allow early diagnosis of age-related disease and disability.

A new direction being considered is the establishment of disease-specific sample populations that could be involved in intervention studies. It is envisioned that the core longitudinal population would continue and that, in addition, an effort would be made to define and accrue smaller cohorts for studies of cancer, cardiovascular disease, immune function, etc. Other modifications recommended by the advisory group include design of a streamlined core battery of biological and psychosocial measures that would be analyzed centrally. The biomaterials bank should be enhanced. Less frequent visits for persons at younger ages also was suggested. It is anticipated that working groups will recommend directions and/or specific studies in neuroscience and in behavioral science areas. Short-and longer-term priorities are being posited by the advisory group and the internal working group charged with reviewing the BLSA.

In discussion, it was recommended that NIA make clear whether BLSA data are a national resource accessible to all investigators, and the extent to which data are withheld, either entirely or for a predetermined time, for use by intramural staff. It was noted that many of the planned activities are prerequisite to use of BLSA data by external researchers. Also, the data are sufficiently rich that expertise beyond that currently in the intramural program should take advantage of the resource. It was clear that current activities and plans would enable better use of the data now and in the future.

Further discussion raised the issue of the extent to which planning for use of BLSA data is integrated with planning for other longitudinal studies of aging. Knowledge about other studies worldwide will minimize duplication of effort or facilitate intentional replication. It was pointed out that other NIH institutes have expressed interest in BLSA data as a resource for their missions. The possibility of interacting with scientists in other countries and involved in other studies was discussed briefly. NIA will continue its efforts to seek external advice and to collaborate with other scientists.

Several members of Council welcomed the approach being taken toward reviewing and modifying BLSA files and reexamining its goals and protocols. Nonetheless, some concern was expressed about adding studies of patients with disease to the population in which normal aging has been studied, especially because there already exist established populations with diseases. Study of changes in disease conditions may become time-consuming and act to shift the focus of the study away from normal aging. The extramural community can do intervention studies. Discussion continued about the role of intramural investigations in geriatrics and gerontology to develop and test clinical interventions, a discussion that will be continued as assessment of the BLSA proceeds.

Council thanked Dr. Longo and Dr. Evans for their presentations and the range of issues generated, and for taking a fresh look at difficult problems. The relationship between intramural research and extramural scientists is complex, and at times different strategies are used to approach problems. The balance among observation, longitudinal epidemiology, and intervention studies remains an important issue in geriatrics and deserves attention, as do other issues raised about the BLSA. Dr. Hodes suggested that the advisory group, BSC, and other appropriate consultants, including interested Council members, continue deliberations and report back to Council within the next year.

Moving to a presentation of scientific progress, Dr. Longo introduced Dr. Jeffrey Metter. Dr. Metter reported on his work in collaboration with Johns Hopkins University scientists on the use of prostate specific antigen (PSA) that uses BLSA data to address new scientific questions.

The work accomplished by the BLSA in prostate diseases represents an example of how this long-term study can contribute to discoveries in medicine. The work on prostate diseases demonstrates one option for future directions for the BLSA: the ability to redefine disease, i.e., to allow for earlier disease diagnosis. The BLSA has contributed to redefinition of a number of important disease processes that affect the elderly, including cardiovascular disease, diabetes mellitus, Alzheimer's disease (AD), and dementia, sarcopenia, and prostate diseases.

Prostate diseases are an important health problem in elderly men, with at least 25% of men requiring treatment for benign prostatic hyperplasia (BPH) and 10% developing prostate cancer. In recent years, PSA has altered the ability to diagnose prostate diseases. PSA is a serine protease produced by prostate epithelial tissue that is released into the blood stream. Levels in blood reflect the size and growth of the gland. The ability to identify prostate cancer has increased to a greater extent than the understanding of how to use this information.

The BLSA has contributed to an understanding of prostate disease. Data are available on men since 1958. Over the past 6 years, a major effort has been made to characterize the prostate glands in all male participants. It has been possible to identify a well-studied group of men with normal appearing prostate glands as a control. Few studies have this capability. Because of the longitudinal nature of the study, it has been possible to look at how PSA changes over time in healthy men, as well as in men who develop BPH and prostate cancer.

A number of accomplishments have been made by the BLSA in improving diagnosis of prostate cancer. Using PSA, it has been shown that total PSA allows for the diagnosis of prostate cancer at least 4 years earlier than without its use. One difficulty with PSA is a high false positive rate, because the more common BPH also increases PSA. The rate of change of PSA over time can improve the specificity of the test, i.e., improve the accurate separation between prostate cancer and BPH. More recently, it has been found that, by looking at the ratio of free to total PSA, prostate cancer can be diagnosed 8 years earlier than without its availability. Furthermore, by looking at the ratio, it may be possible to separate aggressive from nonaggressive cancers at the same time.

At present, work is continuing to define the parameters that optimize the value of screening. This includes identifying frequency of screening, age groups and PSA levels that justify continued screening, and exploring risk factors that may refine the process. A current project is examining genetic markers that may differ in prostate cancer. If specific patterns are identified, they may provide further markers that can improve early cancer screening.

BLSA research has contributed to characterizing the natural history of the development of BPH. The association between gland size, symptomatology, and diagnosis is not unitary. Thus, better means are needed to identify men who will require treatment, the nature of their treatment, and, potentially, prevention. Currently, the pathophysiology of BPH is not well understood. All men do not develop BPH with increasing age, so this process is not part of normal aging. At present, the research group is examining a clinical staging approach to determine whether men can be subdivided into groups that reflect different patterns of gland change which could contribute to improved treatment and prevention. Two projects to explore the genetic contributions to BPH are planned. The first would examine established genes involved with prostate cancer and explore their contribution to BPH. The second would be to search for genes associated with early prostate growth.

The work described is an example of how intramural and extramural scientists can collaborate to analyze existing BLSA data using new approaches to redefine a disease. In discussion, the issue was raised of clinical follow-up of questionable observations. In such situations, study participants are contacted; after talking with them, information is sent to their physicians. An evaluation and biopsy are offered, if indicated, at study expense. The nature of PSA and continuing efforts to differentiate aggressive from non-aggressive disease were considered. Council noted that the prostate work is an example of how a study of normal aging can lead to identification of disease markers that lead to studies of diseases of aging, and how such studies may raise difficult ethical issues. Similar issues pertain to identification of genetic risk factors for breast cancer and for AD. The policy issue of whether normal aging and disease can be separated was again noted. Council expressed an interest in reconsidering the broad issue.

Dr. Longo introduced Dr. Richard Havlik, Associate Director, Epidemiology, Demography and Biometry Program (EDBP), NIA. This is an intramural program that reports to the Director, NIA. The program conceives of research ideas and then proposes to implement them, often by letting contracts to the extramural community and working collaboratively with extramural colleagues in conducting and reporting research.

The EDBP last reported to NACA almost 3 years ago and was reviewed more recently by the NIA BSC. The mission of the program is to initiate, carry out, analyze, and report research on physical disability and functioning, cognitive functioning and disability, and age-associated diseases and conditions. The previous presentation dealt with results from the long-term study of four communities, Established Populations for the Epidemiological Study of the Elderly (EPESE). The program continues to analyze data from these studies, especially from the biracial population in North Carolina. Currently, the program is concentrating on other major studies. In the area of physical disability, there is a study of 1,000 disabled older women in Baltimore who are being followed to determine the course and causes of their disability. Recently, EDBP initiated recruitment of a projected 3,000 white and African-American men and women in Pittsburgh and Memphis. These men and women have initially been determined to be free of physical disability and will be followed for the onset of disability, as well as to understand the factors such as diseases and impediments that contribute to the process. In the area of cognitive functioning, the Veterans Study of Memory in Aging follows about 2,000 WWII veterans who suffered head trauma with concussion, pneumonia, or other problems, and developed late-life dementia.

The ongoing Honolulu-Asia Aging Study has as a theme the identification of early risk factors for AD. It uses a longitudinal design in a community of Japanese-American men in Hawaii studied in midlife by the National Heart, Lung and Blood Institute. The EDBP first added dementia studies in 1991-3 and has continued to accumulate cases through reexaminations. Also, it has been possible to make comparisons with data collected in Japan and Seattle, Washington. The availability of blood pressure data from midlife in this population, which is now approximately 78 years of age, has allowed a consideration of the effect of elevated and untreated blood pressure on subsequent outcomes, including cognitive functioning, clinical dementia and the indicators of AD on autopsies collected from study participants. When the blood pressure pattern from 25 years earlier was used, there was a linear increase in risk of poor cognitive performance for the subgroup that had on two or more visits systolic BP greater than 160 mm Hg. Also, there was a significant relationship with subsequent vascular disease. Both elevated and low midlife systolic blood pressure predicted plaques and tangles on autopsy, the hallmarks of AD. These findings may have ramifications for the understanding and treatment of AD, and may illustrate the rationale for the continuing EDBP commitment to longitudinal studies.

In discussion, several questions about specific methodology were raised and addressed. A question about program structure also was raised – specifically, whether other NIH institutes have similar programs that do not report to the Scientific Director and that conduct intramural research through extramural mechanisms. Dr. Havlik responded that several institutes have such programs and use extramural contract mechanisms to support the research they conduct.

4. Working Group On Program

Dr. Gerald McClearn, Chairperson, Working Group on Program (WGoP), reviewed topics discussed by the Working Group on Program, including: program reviews; the NIA grants portfolio; the agenda for the Winter Retreat; the reinvention roundtable; a recommendation on the threshold for requiring special actions for staff modifications to IRG recommended budgets; and, presentation of the training subcommittee report. As the BSR and intramural program reviews were discussed earlier in Council, Dr. McClearn summarized only the discussion of the review of translational research. The full report and the Institute response are appended to these minutes. Dr. Kelty explained the change to the Statement of Understanding. Item 5 will now read "Funds deleted by initial review groups may be reinstated without the prior advice of the NACA when the funds do not exceed $100,000 per year in direct costs and are for resources necessary to carry out the project within the original scope as approved. Council recommendations, program policy, relevance, and resources will serve as a guide in making such adjustments."

Council members expanded discussion of the Winter and Summer Retreats, in which new initiatives are proposed and developed, to include concern over lack of research training opportunities for newly trained clinicians and the need for new initiatives and mechanisms to provide that training. NIA staff indicated that NIH is addressing that problem via a forthcoming initiative to provide 2 years of training in research for junior clinicians. Discussion continued on the poorer success rates of clinicians who propose to do patient-oriented research than clinicians who propose to do basic research. Members expressed interest in returning to the topic and in allowing time for more open-ended discussion at a future meeting of Council.

Dr. Helen Blau summarized the work of the Task Force on Training. She indicated that initial activity had focused on showing the need for a substantial stipend increase for predoctoral and postdoctoral trainees. She cited effects of the current low stipend rates on NIH training and fellowship grants. She revealed figures showing that these rates are significantly lower than those from other government agencies, those for international fellows, and for intramural fellows supported by NIH itself. On behalf of the committee, she had written to Dr. Varmus and Dr. Baldwin to seek their support in proposing large increases in stipends. Other concerns of the committee include the length of time individuals remain in training, what happens to the trainees once they have completed training, how training funds are distributed by areas of science, and how these numbers relate to potential jobs. A special concern is the lack of well-funded research training opportunities for M.D. researchers.

In discussion by Council members, a number of additional points were made, including: there is an acute need for more resources for geriatric research training; that both NIH and the research community itself undervalue training relative to research funding; that it is easier to agree on a stipend increase for trainees than to agree on whether we need more or fewer trainees in particular areas; and, that a significant amount of training is supported through research grants – outside formal training mechanisms.

Dr. McClearn briefly reviewed the Working Group discussion on reinvention activities currently being considered by NIH. There are a number of different changes to procedures that are meant to simplify and speed the receipt, review, and funding of awards. The Working Group recommended that an NIH representative be asked to speak to Council on the status of these reinvention activities.

Dr. Hodes introduced the topic of accommodating the need for extended discussion of items of interest to Council members. One suggestion was to leave 1 hour of time free and to use it to return to topics raised at earlier points in the meeting. Dr. Gage noted that translational research was one topic that had raised considerable discussion at the Working Group but had not been discussed at Council. Other members agreed that the discussion had raised important issues that needed to be resolved. Dr. McClearn indicated that translational research would again be on the agenda at the next Working Group meeting and indicated that other topics raised in discussion at Council could also be placed on future Working Group agendas.

5. Minority Task Force Report

Dr. Jackson, Chairman, Minority Task Force, prefaced his remarks with a discussion of the reasons for a particular emphasis on minority aging research. He cited a moral priority: the recognition that some groups have been left out of the normal routes to wealth or health, and the moral obligation to address the needs of these groups. He cited the major differences in health status by ethnicity in the United States and pointed out the public health obligation to address these differences. He noted the need to ensure the richest possible pool of talent for biomedical and behavioral research and how that translates into ensuring that individuals from different and diverse backgrounds are part of the mix of talent. He linked the need for research to reduce differences in late-life health among ethnic groups to the need to train more minority researchers whose interests are likely to be in these health differences.

In his report, he described the Task Force's twin concerns as building up the research workforce of minority researchers and increasing research on minority populations. The Task Force reviewed efforts to obtain data to understand the amount and kind of research on minority aging that is being funded by the Institute and recommended changes to the data collection. The aim is to make issues of minority health more visible to the research community as a whole. The Task Force also discussed recent legal challenges to programs that recruit minority students to research and ways to refine eligibility for these programs.

6. Highlights Of Recent Research Findings

Dr. Hodes introduced this session by explaining that, at each Council meeting, Institute staff describe recent research highlights from research supported by their programs.

Dr. Huber Warner of the Biology of Aging Program (BAP) described work by Drs. Harley, Shay, and Wright on slowing telomere shortening during cell replication. Research has long established that cells replicate only a limited number of times. A likely candidate in setting that limit is the length of the telomere, a unit at the ends of chromosomes that has been shown to shorten with each replication of the cell. Drs. Harley, Shay, and Wright introduced the transgene for the catalytic unit of telomerase, a gene which was cloned recently by other NIA grantees, into cultured human cells. They noted first that introducing the transgene did slow the shortening of telomeres. More importantly, they found that cells which had not been transgenically altered, senesced after 50 to 60 doublings, whereas the genetically altered cells continued to divide through at least 20 additional population doublings. This is the first experimental evidence that the length of the telomere is a limiting factor in cell replicative potential. Discussion by Council members included noting that press accounts of the result generalize too easily from a single result in vitro to speculation about the ability to reverse aging; that although work with transgenic mice that over-express telomerase would appear to be a logical step towards in vivo testing, prior results with mice suggest caution as to whether this is an appropriate model; and, that further work in vitro needs to be done to explore whether the cells retain their normal function with the additional doublings.

Dr. Ronald Abeles, Associate Director, Behavioral and Social Research Program (BSR), NIA, introduced Dr. McClearn, a Council member and grantee. Dr. McClearn described his work on genetic and environmental influences on cognitive functioning in late life. Dr. McClearn explored whether the commonly expressed hypothesis that, with increasing age, environmental differences contribute more and genetic differences less, to functioning, is supported for cognitive functioning. He explained that the quantitative trait loci method partitions variance in the observed measures into genetic shared environmental and nonshared environmental sources. He showed that this procedure derives from a well-accepted theoretical model that assumes multiple interactive effects of genetic and environmental components on functioning. His population is a unique group of monozygotic and dizygotic twins in Sweden. By comparing similarities in cognitive functioning within monozygotic and dizygotic twin pairs, it is possible to estimate the relative contribution of genetic factors to performance on the measures of interest. Dr. McClearn and his colleagues reported that genetic influences remain stable on cognitive functioning in late life, contrary to the hypothesis of increasing environmental influence. Though the percentage genetic contribution varied somewhat depending on the particular cognitive measure, a principal component analysis, which identifies the principal underlying cognitive factor or factors behind performance on the particular tests, revealed an estimate of around 50% genetic influence on the first and most central component. Council members amplified on Dr. McClearn's remark that this result is for a particular population. He acknowledged that it is important to generalize the findings and identified work that is already examining different populations. Other questions concerned the value of this Swedish population in exploring the effect of estrogen supplements on cognitive functioning, the statistical issue of ways to avoid the grouping of non-shared environmental influences in the error term when analyzing the data, and possibly increased shared-environmental influences among African-Americans.

Dr. Evan Hadley, Associate Director, Geriatrics Program (GP), NIA, reported on a recently published study from Tufts University showing positive effects of an intervention to reduce osteoporosis in men and women. The study was one of a set funded by NIA to explore ways to reduce the debilitating effects of osteoporosis in late life. The investigators compared placebo and intervention groups of men and women over age 65 at the start of the study and who, at that time, showed moderate bone density (i.e., they were not severely osteoporotic). The intervention group received calcium supplements along with vitamin D. The treatment group showed significant prevention of bone loss relative to the control group and continued to increase total body bone density while the control group showed decreased density. Although not designed to measure decreases in fracture rates, the study was able to show that the intervention reduced the incidence of non-vertebral fractures by about half relative to the control group across the 3 years of the study. The study was the first to show a decrease in osteoporosis among men. Evidence from the study is consistent with the hypothesis that the treatment acts by reducing secretion of parathyroid hormone which pulls calcium out of the bone to maintain serum calcium when serum levels are low. Council members discussed the surprising finding of differences in fracture rates in such a short-term study among individuals who were not severely osteoporotic at the start of the study.

Dr. Marcelle Morrison-Bogorad, Associate Director, Neuroscience and Neuropsychology of Aging Program (NNA), NIA, described the phenomenon of malfolding proteins that is now thought to be common to several neurodegenerative diseases, including the prion diseases - Huntington's, Parkinson's, and Alzheimer's. Neurodegeneration in each of these diseases is accompanied by a sequence of normally folded proteins unfolding into less folded intermediates, which are then more likely to malfold into proteins that, under some conditions, agglomerate into the insoluble aggregates typical of these diseases. The destructive sequence can have any of several causes. Mutations in the original protein might cause abnormally folded proteins to degenerate further rather than revert to normal folding. Lower levels of chaperone proteins might also be a cause, as could altered levels of cutting enzymes. There could be any of several aggravating factors that operate on the malfolded proteins to make them more likely to aggregate. These different stages in the aggregation pathway, in turn, offer scientists different chances to intervene to stop the progression of the disease. Because, in AD, scientists have already identified the location of the precursor protein to amyloid plaques, they are now trying to identify cutting enzymes that cut the precursor protein into an intermediate that cannot form amyloid or that reduces the rate of amyloid formation. Council members echoed Dr. Morrison-Bogorad's statement that the protein malfolding problem is central in neurodegenerative disease. In addition, one member stressed the need within neurobiology to generate accurate relevant cellular models that reflect the in vivo condition. The absence of these models is slowing progress relative to other areas of biological research.

7. 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 621 applications requesting $366,088,994 for all years was reviewed. Council recommended 442 for a total of $222,050,837 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.

8. Adjournment

The 73rd meeting of the National Advisory Council on Aging was adjourned at 12:00 noon on February 6, 1998. The next meeting is scheduled for May 20-21, 1998.

Attachments:

9. Roster of Council Members (Not available)
10. Director's Report to the NACA (Not available)
    

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.