Council Minutes - January 2002

National Advisory Council on Aging

Summary Minutes: The Eighty-Fifth Meeting

January 29-30, 2002

CONTENTS

1. Review of Applications
2. Call to Order
3. Report: Task Force on Minority Aging Research
4. Reports: Working Group on Program and Clinical Investigators Working Group
5. Report: Intramural Research Program
6. Program Highlights
7. Review of Intramural Research Program
8. Adjournment
9. Certification

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

The 85th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, January 29, 2002, at 3:00 p.m., in Building 31, Conference Room 6, National Institutes of Health (NIH), Bethesda, Maryland. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA), presided.

In accordance with the provisions of Public Law 92-463, the meeting was closed to the public on Tuesday, January 29, from 3:00 to 5:00 p.m. for the review, discussion, and evaluation of grant applications in accordance with the provisions set forth in Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code, and Section 10(d) of Public Law 92-463. 1 The meeting was open to the public on Tuesday, January 30, from 8:00 a.m. to 2:00 p.m.

Council Participants:

Dr. Dennis Ausiello
Dr. John Cambier
Dr. Judith Campisi
Dr. Rose Dobrof
Dr. David Espino
Dr. Fred Gage
Dr. Mary Harper
Dr. Lewis Kuller
Ms. Judith Riggs
Dr. Ilene Siegler
Dr. Jeanne Wei
Dr. David Wise
Dr. Phyllis Wise

Ex-Officio Participants:

Dr. James Burris, VA
Dr. George Fuller
Dr. John Wren (AoA)

Absent:

Dr. Stanley Prusiner
Dr. Dennis Selkoe
Dr. James Vaupel
Dr. Myron Weisfeldt

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

Members of the Public Present:

Dr. Philip Ades, University of Vermont
Ms. Nancy Aldrich, Aging Research & Training News
Dr. Karlene Ball, University of Alabama
Mr. Ed Davis, NRH/SUburban Regional Rehab
Ms. Anne Harrison Clark, PAA/APC
Ms. Linda Harootyan, GSA
Ms. Cindy Joseph, GSA
Ms. Pat Kobor, APA
Ms. Susan Jessee, McKesson Clinical Services
Dr. Jennifer Manly, Columbia University
Ms. Amanda Mason
Amber McCracken, Alliance for Aging Research
Ms. Stephanie Reed, American Association for Geriatric Psychiatry
Dr. Carol Schutz, GSA

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

Dr. Robert Nussbaum, NHGRI/NIH
Ms. Georgeanne Patmios, OD/OBSSR/NIH

1. Review of Applications

This portion of the meeting was closed to the public in accordance with the determination that it was concerned with matters exempt from mandatory disclosure under Sections 552b(c)(4) and 552b(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix). 1

A total of 701 applications requesting $562,857,903 for all years underwent initial review. Council recommended 318 for a total of $279,041,945 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 8:00 a.m. on Wednesday, January 30, 2002, and welcomed members.

Director's Status Report

Dr. Hodes, in his Director's Status Report, announced that the President has signed the FY 2002 budget at a level that continues the planned doubling of the NIH budget over five years. In the fourth successive year of budget increases, NIA received a 13.7 percent increase that will support continued growth of the Institute. NIA has begun to plan beyond next year when there may be a change in the upward trend. If the rate of increase in the NIA budget decreases substantially, ways to provide continuity in funding and to maintain success rates will need to be developed.

The NIA allocates about 65 percent of its budget to Research Project Grants. Training is at 2.4 percent but will increase to allow for stipend increases. Centers are at 8.9 percent, contracts at 5.5 percent, other mechanisms including Career Development Awards are at 2.3 percent, and the intramural research program is at 9.8 percent of the NIA budget. For FY 2002, the distribution across mechanisms is similar to the distribution in recent years Dr. Hodes pointed out that although the budget has increased 3 to 7 percent from 1994-1998 and by 13 to 15 percent from 1999–2002, there has been only a modest change in success rate, which has ranged between 23-31 percent.

Council inquired specifically about whether there has been a real increase in the Research Centers budget. Dr. Hodes responded that the absolute dollars but not the percentages have increased.

A member raised the issue of whether the Institute has a plan to evaluate its Research Centers programs. Dr. Hodes indicated that each Center program is evaluated in terms of its own goals. This is done through recompetition that involves changes in the solicitation request to reflect program changes and development. Program performance and the suitability of the structure and profile of the program are examined by staff as part of the preparation for a new solicitation. Critical issues are identified, at times outside consultation is sought, and a new solicitation is designed that reflects deliberations that take place over an 18 month period.

A Council member asked about the budget planning process, specifically about whether the Institute models increases and decreases and the implications of them for the various programs. The response was that NIA and all other NIH institutes model different budget scenarios and amend them as new data become available. Currently, there is substantial discussion about whether the outlay of funds can be distributed so that certain identified costs, e.g., infrastructure costs, equipment, or support for epidemiological studies and genomic studies can be paid up front consistent with research needs to prepare for lower costs in future years when increases may level off. Such options, however, have modest impact because of the budget process and spending requirements.

The issue of budget earmarks was raised and a question asked about whether recent increases are associated with more earmarks. Dr. Hodes indicated that though there had been few earmarks in recent years, future budgets will include an earmark for bioterrorism-related research.

Dr. Hodes next announced that two long-time NIA staff members are retiring: Karyn Ross, NIA Chief of Financial Management and Information Systems Branch, and Judy Crockett, Administrative Officer. Both were with NIA for more than 20 years and worked very closely with several Directors. New staff members were introduced: Dr. Laura Shrestha, Deputy Associate Director, Behavioral and Social Research has come to NIA from the World Bank, and before that from the University of Pennsylvania. Dr. Kathy Mann is a Program Analyist with the Behavioral and Social Research Program. Ms. Georgeanne Patmios has rejoined the same program after spending a year with the NIH Office for Behavioral and Social Science Research.

Dr. Kelty reminded Council that the next meeting will be May 21-22 and that on May 20 the Geriatrics Program Review will take place. All Council members are welcome to attend the review.

Future Meeting Dates

• May 21-22, 2002 (Tuesday-Wednesday)
• September 24-25, 2002 (Tuesday-Wednesday)
• February 4-5, 2003(Tuesday-Wednesday)
• May 20-21, 2003 (Tuesday-Wednesday)
• September 24-25, 2003 (Wednesday-Thursday)

Consideration of Minutes of Last Meeting

The Minutes of the September 2001 meeting were considered. A motion was made, seconded, and passed to approve the Minutes.

3. Report: Task Force on Minority Aging Research

Dr. Espino, Chair of the Council Task Force on Minority Aging Research, summarized ongoing research activities and planned initiatives in minority aging. These included: (1) Describing the role of the intramural mobile research vehicle in reaching out to minority neighborhoods in an effort to increase minority participation in, and awareness of, the intramural research program activities; (2) an effort to harness the resources of major centers in the biology of aging both to help to develop faculty at minority-serving universities and colleges and to interest them in the biology of aging; (3) a planned initiative on the federal workforce in Washington to explore effects of socioeconomic status (SES) on health in a U.S. population modeled on the English Whitehall study that established effects of varying levels of SES on health and longevity; and, (4) the Religious Orders study that works with a cooperating order of nuns to reach older nuns who are members of minority groups.

Dr. Harden also summarized the task force's discussion of the President's plan for management reform of federally supported applied research activities. A specific plan with associated outcome markers for health disparities has developed into an intent to apply similar markers to all research and development activities. The Office of Management and Budget is evolving criteria to evaluate research including: merit-based competition, high importance, public benefit, and outcomes-oriented nature of the work. The plan is to develop standards that allow decisions on whether further investment is warranted or whether funding should be terminated in research areas. The philosophy is that applying management standards of efficiency, accountability, and effectiveness to federally-funded research activities will enable better targeting of research dollars with consequent gains in applicable research findings.

Dr. Hodes indicated that the NIH practices of peer review, established criteria for funding including public importance, coupled with program reviews at Council and internal NIA assessments of particular program activities, such as Centers, are broadly consistent with the goals of the President's plan.

Council members expressed concern over current reporting and process requirements and sought clarification over their own role and the roles of other elected and appointed officials in priority-setting. Others considered ways to better explain the importance of discovery research to public officials and the community at large. Dr. Hodes confirmed that some segments of the plan for management reform are to be implemented in FY 2003.

Dr. Harden presented data on enrollment in ongoing clinical research at NIA of both genders and of members of different ethnic and racial groups. The three years of data presented were for studies conducted in FY 1998, FY 1999, and FY 2000. She also thanked Dr. Espino who has committed substantial time and effort to helping NIA develop an appropriate Spanish-language version of NIA's popular exercise manual and to publicizing it in the Hispanic community through multiple media events.

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

The Geriatrics Program will be reviewed by the NACA in conjunction with the May 2002 meeting. The purpose of the review is to offer advice to the program and Institute about current and future research directions. The entire program will be reviewed, including a recently proposed reorganization. Planning for the review will be by conference calls.

Staff prepared data requested by the Clincial Investigator's Working Group that examined the status of physician-investigators relative to PhD investigators, with an emphasis on new investigators. New PhD investigators outnumber new MD investigators. Proportionally, more MDs are Principal Investigators on K mechanism awards than are new investigators on traditional research grants. Fewer MD than PhD investigators apply for RO1 grants and therefore fewer are awarded to them. The fact that the number of MD applicants who applied for grants did not increase as fast as the PhD applicant pool implies that in the future there will be fewer MD investigators as well as a scarcity of mentors to train new investigators. It was observed that the major difference is in the size of the applicant pool and not in the success rate. Discussion ensued about possible reasons. Options mentioned included lack of uninterrupted time for research, press of clinical duties, preference for clinical work, and inadequate research training for a satisfying and productive research career. Recommendations made include: Efforts need to be made to retain MD K awardees in research; develop adequate training programs to encourage MDs to continue in research; site visit trainees to encourage them and to monitor progress; increase training opportunities in intramural programs, and support mentors for the time and effort they devote to training physician investigators. It was suggested that in developing detailed recommendations, NIA consider whether research symposia involving career development awardees and their mentors would encourage MD K awardees to remain in research careers. It also was suggested that the bibliographies of this group be reviewed.

Council recommendations were for NIA to develop programs earlier in the pipeline of training—to engage the interest of medical students. The Institute is interested in the pipeline starting with undergraduate study through clinical aging research specialization training. A meeting of people and organizations that share NIA's interest in these issues is being planned to explore synergy across programs and better ways to present opportunities to recruit and retain clinically-trained investigators. Council suggested that those involved with creative programs in medical schools and representatives of some specific organizations be invited. The meeting is planned for late spring or summer.

Dr. Hodes commented that Council's consideration of research by physician investigators addresses an important problem in a unique way, and that Council's work and recommendations might have broad application. Discussion of recommendations will continue at the May Council meeting. He assured members that a specific proposal they develop would be incorporated into NIA's planning process.

The Working Group continued its discussion of reorganization of integrated review groups (IRG) and study sections. Council members reviewed the proposed structure of the Development of Biology and Aging (BDA) IRG and of the Musculoskeletal, Orthopedics, and Skin Sciences IRG. Recommendations for the structure of both IRGs were posted on the NIH website. About 150 sets of comments were received. Generally, the community of researchers in aging areas commented positively about the BDA and MOSS IRGs. Staff of the Center for Scientific Review will prepare options for how to handle scientific areas that cross IRG boundaries and will discuss them with their advisory council. NIA will continue to monitor the IRG reorganization process. The Endocrinology, Metabolism and Reproductive Sciences IRG will be developed next.

The Working Group approved (accepted) recommendations made at three recently held advisory meetings: One on Cognitive and Emotional Health, one on Racial and Cultural Effects on Measurement of Cognition, and a third on Hutchinson-Guilford Progeria Syndrome.

The meeting on Racial and Cultural Effects on Measurement of Cognition generated discussion about correlation of psychological measures and imaging. Council members recommended that staff contact an expert in testing through the American Psychological Association to discuss assessment measures. Another member suggested a recommendation on culturally appropriate language be added and that a culturally appropriate brief cognitive battery be developed for clinicians' use. Because immigration results in fairly rapid changes in the nature of the population, it was requested that the recommendations include a stipulation that the measures be revised periodically.

The advisory meeting on Hutchinson-Guilford Progeria Syndrome was held in response to Congressional language and in conjunction with the Progreria Research Foundation. The syndrome is rare and dramatically shortens life. A repository for biological materials is in place. A program announcement is planned to stimulate research on this disease.

Proposed advisory workshops and conferences were presented for concept clearance and discussion. They included workshops on: Genetics of Alzheimer's Disease, Dietary Supplements in the Elderly, Neurocognitive Changes after Cardiac Surgery, Extracellular Matrix, Aging Muscle and Skin, and Restless Leg Syndrome. The Working Group on Program recommended to Council that concepts for the workshops planned and for initiatives that stem from them be approved. Council voted accordingly.

The Working Group recommended and Council approved acceptance of the Statement of Understanding between the Institute and Council. The Statement specifies actions that staff may take without specific Council action to enable the orderly conduct of business. It also specifies types of information about grant programs that is provided to Council at each meeting.

The Working Group received statistical data for applications considered at the current Council meeting, an annual data report showing extramural trends in number and nature of awards, distribution of applications and awards across programs, and distribution of the NIA portfolio by budget mechanisms and average costs. Council was reminded that the data may be useful in their communications with the public.

5. Report: Intramural Research Program

A. Dr. Richard Havlik reported on the Laboratory of Epidemiology, Demography, and Biometry: Past and Future.

The research targets of the Laboratory of Epidemiology, Demography, and Biometry (LEDB) are: cognitive functioning and dementia, physical functioning and disability, and diseases and conditions associated with aging. LEDB is using new opportunities in genetics and its strengths in describing environment to address etiological questions. For example, do midlife cardiovascular risk factors contribute to late-life dementia, possibly through subclinical inflammation as an underlying mechanism? The Honolulu-Asia Aging Study took advantage of a previous study of midlife cardiovascular risk factors to show that elevated systolic blood pressure (SBP) (greater than 160 mm Hg) is associated with poor function (less than 74 on a 100 point cognitive function test). When APOE4 status was taken into account, the relative risk increased almost threefold. However, when the population was limited to those with untreated hypertension, the relationship with poor functioning was dramatically higher for those with both high SBP and APOE4 (Peila et al. Stroke 32: 2882-2889, 2001).

In a separate study, the variability of SBP during the midlife period was hypothesized to be related to brain pathology. At higher levels of SBP variability compared to lower levels, there were twice as many frequent white matter lesions (highest 20 percent), suggesting that possible variations of blood flow in the arteries penetrating deep in the brain have an adverse effect (Havlik R, et al. Stroke 33: 26-30, 2002).

The Women's Health and Aging Study included women screened at baseline who were found to be somewhat disabled. The hypothesis was that factors affecting the trajectory of decline could be identified and that interventions might be possible, even at later stages of the process. Analysis indicated the beneficial effect of a class of anti-hypertensive drugs, the angiotensin converting enzyme (ACE) inhibitors on walking. Over three years, those with continued drug use maintained their speed while the others declined. To address a possible mechanism, leg strength was assessed. There was less decline in muscle strength in the continuous drug takers, suggesting this as an explanantion (Onder et al. Lancet . In press). There are two other LEDB studies actively collecting data on factors related to the onset of physical disability. These are: the Health Aging and Body Composition Study and the InChianti Follow-up Study.

For the future, LEDB will move its research to a new level. In order to understand the development of age-associated conditions, better descriptions of phenotypes earlier in the disease process are necessary. A new study in Reykjavik, Iceland, is re-characterizing 8000 previously studied individuals. It will enable LEDB to explore a number of hypotheses dealing with cardiovascular disease, brain disease, bone, and muscle and fat with a broad based set of objectives. However, state of the art imaging studies and molecular techniques are necessary. Because of the unique genetics and environment in Iceland, it will be possible to look for complex relationships, such as early life factors related to both brain and heart disease. The second program direction is translational research and clinical trials. An assessment of cognitive function and brain structure with MRI will be added to a study being done to optimally control glucose, lipids and BP control in Type 2 diabetics. With accumulating data suggesting that cardiovascular risk affects cognitive function, this clinical trial will be quite informative. The LEDB plans are to exploit breakthroughs in biological understandings, to emphasize the dual roles of genetics and environment, and to look for opportunities in translational research, including a possible mobility trial.

A Council member commented on the enormous advantage of having detailed phenotypic information available on this population that was collected over many years was recognized. At issue, however, was whether the Icelandic population, which is relatively homogeneous, is useful for testing candidate genes that have been identified in other more heterogeneous populations. The member wondered whether the main advantage of the population would be as a source of candidate genes that then could be tested in other populations.

B. Dr. Vilhelm A. Bohr, Chief, Laboratory of Molecular Gerontology (LMG), presented his report on progress in the LMG.

Dr. Bohr commented that the Laboratory was pleased with the very positive evaluation by the Board of Scientific Counselors (BSC) in November, 2000. The BSC recommendations were to strengthen the work on DNA repair with focus on base excision repair of oxidative DNA damage and to recruit two new tenure track investigators. The Board also supported the laboratory's request that Dr. Michael Seidman be proposed for conversion to tenure. Dr. Seidman has now been promoted to tenure and has received an increase in resources. The Laboratory has recruited two new tenure track investigators, Dr. Patricia Gearhart and Dr. David Wilson. A staff scientist has been recruited to work in the area of base excision repair.

The LMG is studying processes (including mutations, DNA damage, genomic rearrangements, and other deficiencies) that lead to instability of the genome and those that keep the genome stable. These changes are known to accumulate with aging, can cause many of the phenotypic changes seen with aging and may be the cause of the exponential increase in cancer susceptibility with aging. Thus, the work in LMG is directed towards understanding the processes of DNA repair, hypermutation, and recognition and repair of genomic alterations. The molecular defects that cause premature aging disorders are investigated as model systems of normal aging and of age associated diseases. Molecular studies in human populations, mainly of the BLSA cohort are examining genetic polymorphisms in relation to aging and to premature aging.

The laboratory consists of sections and units that each have their own research programs. At the same time there is a lot of collaboration between the groups and there are projects of general interest to the whole lab.

Dr. Patricia Gearhart is interested in the molecular pathways of somatic hypermutation, and has recently found that these involve some of the newly discovered human DNA polymerases. A mutation defect in the disorder xeroderma pigmentosum is also associated with a DNA replication defect (Zeng X, et al. Nat Immunol 2: 537-541, 2001). Dr. Robert Brosh is interested in DNA helicase mechanisms. These enzymes are involved in DNA repair, transcription, replication and other processes and they work by unwinding stretches of DNA. In studies of the biochemical properties and protein interactions of these enzymes, Dr. Brosh has recently found that some types of DNA constructions that are seen in genomic instability are also substrates for human helicases. Dr. David Wilson will join the lab soon. He is interested in enzymes that work on repairing oxidative DNA lesions. These studies involve structural aspects of protein chemistry and functional interactions with other proteins. Dr. Michael Seidman has a long-standing interest in mechanisms of mutation and DNA repair. He has been interested in the formation of triple helices in DNA, special structures that are seen in promoter regions and other places in the genome. Studies are focused on their biological importance, relation to aging, and on their repair. He is also using these triple helix structures to site specifically target individual genes for inactivation. This approach has significant therapeutic potential (Puri, N, et al. J Biol Chem 276: 28991-28998, 2001). Dr. Vilhelm Bohr is investigating DNA repair processes at the biochemical and cellular levels and in relation to aging and cancer. He is particularly focused on the DNA repair process in mitochondria where DNA lesions are known to accumulate with aging. Another major area of his research is on the mechanisms that are defective in the premature aging disorders, particularly Werner and Cockayne syndromes. This is studied on the biochemical and cellular levels, and there is a focus on pathways in which the Werner and Cockayne proteins may participate in cellular metabolism. In recent years, some new protein interactions have been observed in the laboratory that directly suggest a role for the Werner protein in DNA repair and recombination (Brosh RM Jr, et al. , EMBO J 20: 5791-5801, 2001). The work has also led to the notion that Werner protein can locate to the telomeric ends and can function in the restoration of dysfunctional telomeres.

Questions of Dr. Bohr invited his comment on a recent article connecting the p53 “anti-cancer” gene with premature aging (Tyner, S D et al. Nature 415: 45-53, 2002); whether he had considered using binding proteins to stabilize telomeric ends; and whether he saw similar reactions in normal and cancer cells to the WRN and TRF2 proteins. Dr. Bohr saw the p53 result as preliminary but plausible. He indicated that binding proteins themselves trigger helicase reactions. With the laboratory goal of studying how WRN and TRF2 affect function at telomeric ends, these reactions may complicate the study. He agreed that the reactions of normal cells to these proteins will contribute to understanding their role in pathology.

C. Dr. Paul T. Costa, Jr., Chief, Laboratory of Personality and Cognition (LPC), presented the report on his laboratory to Council.

The LPC is comprised of two sections, the Cognition Section (CS) and the Personality, Stress and Coping Section (PSCS), and a Unit on Emotions and Quantitative Psychophysiology (EQP).

The EQP Unit is headed by Dr. Julian F. Thayer who set up a research unit to develop a program on emotion and psychophysiology that is designed to identify and link physiological processes, emotional reactions, and personality traits to adaptational processes and outcomes. Dr. Costa and Dr. Thayer have ongoing research projects to study the perception of affect and cardiovascular response among Healthy Aging Nationally Diverse Longitudinal Samples (HANDLS) and Baltimore Longitudinal Studies on Aging (BLSA) samples, the genetics of autonomic variability among older African-Americans, and several involving collaborations with other U.S. and international investigators (Thayer JF, Lane RD. J Affective Disorders 61: 201-216, 2000).

The CS, led by Dr. Alan Zonderman, has two tenure-track investigators, Drs. Susan M. Resnick and Pauline M. Maki. Dr. Resnick's research involves brain change predictors of cognitive decline. Dr. Resnick's main accomplishments have been to implement the Neuroimaging contract, and to develop analytic methodologies to analyze the data. With over 1,000 assessments, this represents a unique resource to answer longitudinal questions about the degree of structural and functional brain changes occurring among non-demented individuals, and the brain changes that might be predictive of mild cognitive impairment and Alzheimer's disease. Dr. Resnick has shown that the corpus callosum size is related to cognitive performance in women and not men. Dr. Resnick and colleagues also reported that four-year changes indicate brain volume decline for the total group. Not only structure but also function shows age differences. Comparisons of regional cerebral blood flow in 70-year-old men and women with and without the APOE e4 genotype show selected decreases in the insular, cingulate and inferior temporal regions. The cingulate blood flow decreases might have implications for longitudinal declines in emotional reactivity as well as attentional and memory functions implicated by the insular and temporal areas. An even more important blood flow reduction is found in the hippocampus, which has great ramifications for short-term memory and information processing in the elderly. CS investigators are also interested in factors that lead to increased risk and protection in brain-behavior relations and aging. In a recent study, APOE e4 genotype was associated with a greater rate of hippocampal volume loss.

For years, the CS has conducted naturalistic observational studies in the BLSA. Now, with Drs. Maki, Resnick, and others the CS is doing clinical intervention studies. CS investigators are examining the effects of exogenous compounds, like estrogen and selective estrogen receptor modulators (SERMs), on cognition and brain functioning. Dr. Pauline Maki's research focuses on fluctuations in endogenous hormones and changes after exogenous hormone intervention. A recent paper indicated that fluctuations in endogenous hormones across the menstrual cycle are associated with changes in cognitive abilities (Maki PM, Zonderman AB, Resnick SM. Amer J Psychiatr 158: 227-233, 2001). Comparisons of HRT users with never users suggest better learning and memory on standardized assessments among HRT users. Dr. Maki and colleagues have ongoing clinical intervention studies, one of which is the collaboration with the Women's Health Initiative (WHI) Study of Cognitive Aging or WHISCA.

For the past 25 years, PSCS investigators Robert McCrae and Paul Costa have been studying personality traits using the Revised NEO Personality Inventory (NEO-PI-R). Dr. Costa illustrated some of their major findings including that (a) traits are organized into five groups or factors (Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness), (b) traits change substantially from adolescence to age 30 and only quite modestly, if at all, thereafter, and (c) traits have pervasive effects on health perceptions, well-being, vocational interests, leadership, coping strategies, creativity, and more. For the past decade, a major focus has been on generalizing these findings beyond the U.S. This line of research, led by Dr. McCrae, has sought to determine whether personality traits are universal. The NEO-PI-R has been translated into over 30 languages and research using these translations support universality. One recent study indicated that gender differences are also universal. Women everywhere tend to score high in anxiety, vulnerability, straightforwardness, and openness to aesthetics; men tend to score high on competence, assertiveness, excitement-seeking and openness to ideas. (Costa PT Jr, Terracciano A, McCrae RR. J Personality & Social Psychol 81: 322-331, 2001.)

There is a paucity of personality data on adequate instruments for men and women in their 70s, 80s, and 90s. Dr. Costa displayed new data on an abbreviated form of the instrument, the NEO-FFI on a large community-dwelling sample from over 1600 men and women whose ages ranged from 65 to 100.

Other new data were presented on changes in personality consequent to onset of a major depressive disorder (MDD) and its successful treatment and remission. Among responders to psychopharmacological treatment, there are significant declines in Neuroticism and increases in Extraversion, Openness, and Conscientiousness. Non-responders do not demonstrate personality changes.

Lastly, Dr. Costa described preliminary results from an ongoing collaborative study on the role of Conscientiousness in the progression of HIV. HIV+ patients who are low in Conscientiousness show more accelerated disease progression over a one-year follow-up in terms of increases in viral load and decreases in CD4 cell counts. Future plans are to examine the relationship between Conscientiousness and HIV disease progression over two and three years, with endpoints including the development of serious AIDS symptoms and mortality; and to examine the impact of other personality factors on disease progression and health behaviors relevant to managing HIV.

Members' questions included: (1) Are age differences that have been observed evidence of secular trends or of longitudinal change? (There is no evidence to distinguish these causes in the present study, though there has been evidence of secular trends found in other studies.) (2) Was the personality change observed in responders in the drug-treatment study on depression drug-dependent? (There was an association between blood-levels of the drug and size of the personality change observed, though the effect is moderated by degree of conscientiousness.) (3) Would the drugs have the same effect on normals? (It is not known.)

6. Program Highlights

A. Dr. Jennifer Manly of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians & Surgeons, presented data from her recent NNA-supported study on ethnic disparities in cognitive function with age.

On many tests of cognitive function in elders, ethnic minorities obtain lower scores than Whites. Discrepancies persist even after matching ethnic minorities and Whites on demographic variables, including years of education. In a study of cognitively-normal adults by Taylor and Heaton (Taylor MJ, Heaton RK. J Int Neuropsychol Soc 7: 867-874, 2001), cultural effects on performance on the WAIS-III Full Scale IQ test were evident. When scores were corrected for age, 10-12 percent of Whites were misclassified as impaired, while over 40 percent of African-Americans and 30 percent of Hispanics were misclassified. When scores were corrected for age, gender and years of education, the percentage of misclassified Hispanics dropped to about 18 percent but the percentage of misclassified African-Americans remained about the same. Questions remain as to how to best remove what appears to be cultural bias from these tests. Possible solutions include creating new tests that are specific to each ethnic group, developing culturally neutral or “culture-free” tests, or using existing tests and collecting separate normative values for each ethnic group. Culture-free or neutral tests may be difficult, if not impossible to achieve. Dr. Manly cited an example of a test of figure matching used in their battery that was considered culture-free but proved to be the test most susceptible to ethnic differences in their sample. Additional obstacles include the diversity within each ethnic group--educational, geographical, and economic. When separate norms are developed for each ethnic group, race becomes a proxy for educational, economic and behavioral differences. If the focus was changed to the factors that vary, such as educational quality, these factors could be adjusted before interpreting cognitive test scores, regardless of race.

For Dr. Manly's study, subjects enrolled were neurologically normal, free of stroke, psychiatric disease, and substance abuse and had been independently diagnosed as non-demented by a physician. About 200 African Americans and 200 Whites were matched on years of education, age, and gender mix. The average length of years of education was 11.5 and average age in years was 75. Significant differences were found between African Americans and Whites on measures of verbal memory, non-verbal memory, abstract reasoning, fluency, comprehension, and visual spatial skills such as a drawing task and a figure matching task.

Subjects also were assessed for reading ability. For some subjects, reported years of education is an overestimate of their actual reading ability. A disproportionate number of African Americans were in the group where grade level was an overestimate of actual reading ability. Dr. Manly noted that the majority of the elderly African Americans who live in northern Manhattan were educated in rural, segregated settings in the South. Many of them attended one-room schools and learned how to read in church, not in formal settings. Per pupil expenditures in many of the southern states were substantially lower than in northern states where schools were not formally segregated.

Once the scores of cognitive function were corrected for reading level the majority of the significant differences between the ethnic groups disappeared. Differences between the two groups on fluency and the Rosen drawing task remained significant, but the effect size was reduced after accounting for reading level. In sum, perhaps because there were discrepancies between years of education received and educational level achieved in a large study of this type, race effects persisted after adjustment for years of education. Once quality of education was accounted for by measuring reading levels, the differences were no longer significant (Manly JJ, et al. J Int Neuropsychol Soc 8 [forthcoming], 2001).

Currently, African Americans and Whites are being followed longitudinally with reading levels and cognitive performance measured throughout the study. In an earlier study using the sample from the lower Manhattan Aging Project, Dr. Richard Mayeux reported that African Americans and Caribbean Hispanics have a higher incidence of Alzheimer's disease (AD) as compared to Whites across the age range. Possible reasons for these differences in incidence include genetic, environmental or other biological factors that could differ between the ethnic groups. However, it is also possible that the cognitive tests used to diagnose AD in elders might be a factor that contributes to the differences in incidence rates. For the current study, investigators will reexamine the incidence of AD in the various ethnic groups after correcting for quality of education.

Additionally, the investigators plan to formally test their assumption that reading level reflects quality of education. Dr. Manly has acquired data on per pupil expenditures, teacher-student ratios and length of school year dating back to 1911 on African-American and White schools in the south and schools in the north.

In discussion, Council members asked why cognitively normal African Americans are classified as cognitively impaired by current practices. Dr. Manly pointed out that by current standards, a mean is developed for a particular age group, and that impairment would be determined as one standard deviation below the mean. This normative group is the national standardization sample, so it is based on the population of the United States. Whereas we could expect that a small percentage might be misclassified as impaired, the percentages are very high for African-Americans and Hispanics.

Dr. Manly noted that although there are not many autopsy studies of African Americans, in those that have been published African-Americans do not reveal disproportionate Alzheimer's-like neuropathology.

Council members pointed out that assessing quality of education may be valuable in all the Alzheimer's Research Centers. Members suggested that neuroimaging studies will help answer questions about brain changes in parallel with cognitive changes and whether differences might be observed among various ethnic groups. Members pointed out that other health disparities (e.g., in vascular disease, stroke, white matter abnormalities, and socioeconomic status (SES) may complicate the specificity of performance outcomes.

Dr. Manly was asked if there was any insight as to why the figure-matching task turned out to show significant ethnic differences in performance. She stated that African mericans and Hispanics were much more likely to make errors with respect to rotation and position. She interpreted this as a difference in understanding what it means to pick the same figure.

B. Dr. Karlene Ball, of the University of Alabama at Birmingham, reported on research supported by the Behavioral and Social Research Program. Dr. Ball discussed highlights of results from their Center for Research on Applied Gerontology, illustrating the roles of basic, applied and translation research outcomes related to the safety and mobility of older drivers.

The basic research of Dr. Ball and Center investigators has focused on understanding the mechanisms for age-related decline in everyday visual and cognitive tasks, as well as mechanisms for improvement using a variety of interventions. A 1990 case-control study of 306 older drivers launched a series of applied studies aimed at understanding the risk factors for crash involvement among older drivers. This study showed that deficits in the Useful Field of View, a measure of visual attention and processing speed, were predictive of elevated crash involvement independent of age. Results also indicated that individuals could fail the Useful Field of View test due to either impaired visual function or slower processing speed. Subsequent intervention studies, funded through the Center, evaluated these findings further.

In this applied research, several new research tools were developed, including a measure of the time required to perform Instrumental Activities of Daily Living (TIADLs), several new measures of mobility, including the life space questionnaire, and a new method for evaluating the Useful Field of View. A prospective follow-up study evaluating the relationship between Useful Field of View and crash risk demonstrated an elevated relative risk (Owsley C, et al. JAMA 279: 1083-1088, 1998). Further analysis indicated that the risk for injurious crashes was even greater, with those older adults demonstrating the worst impairment (>60 percent reduction) 22 times more likely to experience an injurious motor vehicle crash. With respect to cognitive training interventions to reduce crash risk, it was found that training resulted in fewer dangerous maneuvers in on-the-road evaluations, improved hazard detection in driving simulator evaluations, faster reaction times to road signs, improved mobility, and improved performance on timed instrumental activities of daily living. These results led to further projects funded by NIA, General Motors, and the Federal Highway Administration, and collaborative relationships between several Departments of Motor Vehicles, Medical Advisory Committees, private corporations, AARP, the American Occupational Therapy Association, automobile manufacturers, insurance companies, and the National Highway Transportation Safety Administration (NHTSA). With respect to visual impairment, Center results indicated that those with cataract which resulted in significant contrast sensitivity loss were eight times more likely to be involved in a crash. Cataract surgery, however, resulted in a two-fold decrease in crash rate.

Finally, a field study of the Center evaluated a brief assessment battery, including subtest 2 of the Useful Field of View test, in Maryland Motor Vehicle Administration (MVA) field sites (Owsley C, et al. Ophthalmic Epidemiol 5 [2]: 101-113.279, 1083-1088, 1998). Several of the cognitive measures were significantly related to an increased risk of crash involvement in the subsequent two years, and those with poorer Useful Field of View performance experienced four times the crash risk. This field study led to a change in policy in the Maryland MVA with respect to drivers referred to the Medical Advisory Board, and may ultimately result in proposed legislation. Follow-up longitudinal studies are planned to evaluate the progression of both cognitive decline, and prevention of decline following training. Furthermore, studies are planned to analyze the relationships between mobility and health care costs among older individuals. In general, these studies indicate that basic and applied research on aging can lead to the development of new measurement tools, multidisciplinary collaborations, changes in public policy, and the ultimate translation of results to improve the health and quality of life of older adults.

A Council member asked both whether any cognitively-impaired participants were part of the sample examined and whether such individuals could benefit from the training given to the general group. Dr. Ball indicated that cognitively-impaired participants were included, that their performance on the useful-field-of-view test was more predictive of subsequent driving crashes than any dementing diagnosis, and that some of the impaired participants did benefit from training, though they failed to maintain the performance improvement as long as normal participants.

C. Dr. Philip Ades, Department of Medicine, Division of Cardiology, University of Vermont College of Medicine, presented his Geriatrics Program-supported research on Cardiac Rehabilitation and Secondary Prevention of Coronary Heart Disease (CHD): Focus on the Elderly.

Rehabilitation is defined by the Public Health Service as “comprehensive, long-term programs involving medical evaluation, prescribed exercise, cardiac risk factor modification, education, and counseling.” Goals include enhancing the physical, psychosocial, and vocational status of the patient, including stabilization and/or reversal of the atherosclerotic cardiovascular disease process. In the elderly, the prevention and treatment of disability is a primary goal.

Dr. Ades and colleagues have documented the safety and effectiveness of exercise training in older coronary heart disease (CHD) patients (Ades PA, et al. Circulation 94; 323-330, 1996). These patients can improve their fitness as much as younger CHD patients although the physiologic mechanisms differ, with training-induced adaptations in the elderly limited to skeletal muscle. An important functional benefit of exercise in the elderly is its role in preventing and treating cardiac disability. Dr Ades' group has shown that strength training is of particular benefit in disabled, older, female CHD patients where the performance of daily activities, including walking and stair-climbing, is limited due to lack of muscle strength.

Dr. Ades and colleagues have now begun to examine another special population with studies on the treatment of obesity in the cardiac rehabilitation setting . Ades, PA. Cardiac rehabilitation and secondary prevention of coronary heart disease (Ades, PA. N Eng J Med 345: 892-902, 2001). Over 75 percent of CHD patients are overweight, with most patients characterized by the presence of abdominal obesity, hyper-lipidemia, hypertension, and insulin resistance or type II diabetes (Ades, PA, et al. Amer Heart J 143: 151-156, 2002). Current cardiac rehabilitation exercise programs do not lead to a significant loss of weight or improvement in obesity-related risk factors (Brochu M, Ades, PA. J App Physiol 92: 672-678, 2002). Dr. Ades' preliminary data suggest that a novel training program termed “high-caloric training,” characterized by frequent, long bouts of walking, is associated with significant weight loss and improvement in cardiovascular disease risk factors. The investigators believe that this approach to the treatment of obesity in CHD patients has the potential to alter cardiac rehabilitation exercise protocols delivered to over 200,000 individuals across the U.S.

Members' questions included whether the exercise group modify their diet to compensate for increased energy usage; whether the benefits of exercise vary with degree of obesity; whether individuals who exercise are at increased risk of falling; and whether cognitive assessments were made. Dr. Ades responded that exercisers do not normally modify their caloric intake. Therefore exercise leads to some weight reduction. Exercise alone, though, is insufficient to reduce weight substantially. Physically fewer calories are burned per unit of distance the lighter the load (or weight) of the individual. Speed of travel has little effect on calories burned. The study did not track falls, though the participant group is at low-risk of falling using national comparison data. The study did not employ cognitive testing.

D. Dr. Campisi discussed her BAP-supported paper on "Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging" (Krtolica A, et al. PNAS USA 98: 12072-12077, 2001). This report provides a possible mechanism for the fact that age is the major risk factor for cancer.

Cellular senescence has long been recognized as a tumor suppressor mechanism that helps prevent the development of cancer in mammals (Sager R, Environ Health Persp 93: 59-62, 1991; Campisi J. Trends in Cell Biol 11: S27-31, 2001). It has also long been appreciated that senescent cells acquire functional changes, but little was known about the consequences of these changes. The recent work from the Campisi laboratory shed new light on the consequences of cellular senescense, and the evolutionary relationship between cancer and aging. This work showed that even though cell senescence is a tumor suppression mechanism early in life, senescent cells in the body may actually promote tumorigenesis of nearby cells later in life. This tumor-promoting activity was due to the functional changes that occur in senescent fibroblasts, specifically their secretion of growth factors and extracellular matrix components, and was limited to pre-neoplastic epithelial cells. Thus, cell senescence is an example of antagonistic pleiotropy, where a process that is beneficial in a young individual and therefore is preserved by natural selection, may turn out to have negative consequences later in life once natural selection is no longer operative (Kirkwood TB, Austad SN. Nature 408: 233-238, 2000). Dr. Campisi also described recent work in her laboratory on ways to shutdown the properties of senescent cells that facilitate tumorigenesis, including inducing cell death in senescent cells.

In response to member questions, Dr. Campisi acknowledged that all the functional consequences of inducing cell death in senescent cells must be understood prior to testing interventions based on this approach. To clarify, she repeated that senescent cells, unlike presenescent cells, secrete growth factors that appear responsible for facilitating tumorigenesis. A member drew some parallels between secretions of metastatic cells and of senescent cells. Dr. Campisi acknowledged the parallel but stressed their differing cellular origins.

7. Review of the Intramural Research Program

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). 1

8. Adjournment

The 85th meeting of the National Advisory Council on Aging was adjourned at 2:30 p.m. on January 30, 2002. The next meeting is scheduled for May 21-22, 2002.

Attachments:

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

9. Certification

I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete. 2

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

Prepared by Miriam F. Kelty, Ph.D.

Attachment A

MEMBERSHIP ROSTER
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING
(All terms end December 31 with the exception of those names marked with an * which were extended until June 30, 2002)

Chairperson

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Wise, Phyllis M., Ph.D. (2003)
Dean, Division of Biological Sciences
University of California Davis
Davis, California

Ex Officio Members

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

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

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

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

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

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

2 These minutes will be approved formally by the Council at the next meeting on May 21-22, 2002, and corrections or notations will be stated in the minutes of that meeting.