Council Minutes - September 1998

NATIONAL ADVISORY COUNCIL ON AGING
The Seventy-fifth Meeting

Summary Minutes:
September 24-25, 1998

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

CONTENTS

1. Call to Order
2. Review Issues
3. Working Group on Program
4. Biology of theAging Program (BAP)
5. Positively Aging: Choices and Changes
6. Report of the Minority Aging Task Force
7. Report of the Task Force on Training
8. Program Highlights
9. Comments from Retiring Members
10. Review of Applications
11. Adjournment
12. 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
September 24-25, 1998

The 75th meeting of the National Advisory Council on Aging (NACA) was convened on Thursday, September 24, at 2:00 p.m. at the Natcher Building, Conference Room D, 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, September 24, from 2:00 p.m. to 4:30 p.m. and again on Friday, September 25, from 8:00 a.m. to 12:30 p.m. The meeting was closed to the public on Thursday, September 24, from 10:00 a.m. to 1:00 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.

Council Participants:

Dr. Helen M. Blau
Dr. Elizabeth Barrett-Connor
Dr. Fred H. Gage
Dr. Patricia S. Goldman-Rakic
Dr. Mary S. Harper
Dr. William Hazzard
Dr. James S. Jackson
Dr. Gerald E. McClearn
Dr. John W. Rowe
Dr. Dennis Selkoe
Dr. James W. Vaupel
Dr. Eugenia Wang
Dr. Jeanne Y. Wei
Dr. David A. Wise

Absent:

Dr. Jeffrey Bluestone
Dr. George F. Fuller
Dr. Richard Goldsby
Senator Mark Hatfield

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

Members of the Public Present

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

Dr. Michael Micklin, Center for Scientific Review
Dr. Paula Skedsvold, OD/OBSSR

1. Call To Order

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

Future Meeting Dates

• February 3-4, 1999 (Wednesday-Thursday)
• May 27-28, 1999 (Thursday-Friday)
• September 23-24, 1999 (Thursday-Friday)
• February 8-9, 2000 (Tuesday-Wednesday)
• May 25-26, 2000 (Thursday-Friday)
• September 27-28, 2000 (Wednesday-Thursday)
• February 6-7, 2001 (Tuesday-Wednesday)
• May 22-23, 2001 (Tuesday-Wednesday)
• September 25-26, 2001 (Tuesday-Wednesday)

Consideration of Minutes of Last Meeting

The minutes of the May 21-22, 1998 meeting were approved as submitted.

Director's Status Report

Dr. Hodes announced that Dr. Richard Suzman has been appointed Associate Director for Behavioral and Social Research at NIA. Senior staff who are new to the Institute were introduced. Nancy Nadon, Ph.D., has joined the Biology of Aging Program (BAP) as a Health Science Administrator responsible for the Animal Resources Program.

Jeffrey Chernak, Ph.D., has joined the Scientific Review Office as a Scientific Review Administrator in the neuroscience area. Stephanie Clipper has joined the Public Information Office.

Dr. Hodes directed members' attention to the budget mechanism table. The NIA budget grew from $484 million in FY 1997 to $518 million in FY 1998. For FY 1999, the President's budget, House of Representatives mark, and Senate appropriations mark show a 7, 9 and 15 percent increase, respectively. The Senate increase for NIA is slightly above the NIH average. Budget differences for the FY 1999 budget, however, are being resolved by a conference committee, and it is likely that the new fiscal year will begin under a short-term continuing resolution.

To help plan how to spend an anticipated increase, Dr. Hodes reported that he reviewed NIA grant application success rate data from 1993-1998. In that time the success rate has increased from 23 percent of submitted applications to approximately 30 percent. With a success rate between 25 percent and 30 percent, he advised that the Institute can plan to spend a portion of the increase on special initiatives that will address gaps and scientific opportunities. Also, some scientific areas, are designated in Congressional report language. They include calls for increased training and career development in demography, increased investment in Parkinson's' Disease research, a prevention initiative on Alzheimer's disease, increased support of research on pancreatic, prostate and colon cancer, research on arthritis in the elderly, and increased support of cardiovascular research. The Pepper and Roybal Centers are mentioned, as is collaboration with the Office of Alternative Medicine to support clinical trials on gingko, support for cognitive psychology research, and participation in a multi-institute initiative to expand support for the National Disease Research Interchange. In recent years, similarly expressed interest from the House and Senate in particular activities has provided encouragement without being prescriptive.

Council members questioned why NIA is identified with initiatives that appear more appropriate for other Institutes and whether such language had been interpreted as directive in the recent past. Dr. Hodes responded that similar language often appears in the Congressional report for several Institutes.

Recognition of Public Information Office for Award

Dr. Hodes brought to the attention of Council the recent award of an Emmy from the Academy of Television Arts and Sciences to the National Institute on Aging in the Public Service Announcement category. The award, the first Emmy ever presented to a Federal agency, recognized the achievement of NIA's Public Information Office for its production of a campaign advising the public about products that claim to be effective against aging and indicating where the public can receive reliable information about aging and about these products.

2. Review Issues

Presentation by Dr. Ellie Ehrenfeld: Director, Center for Scientific Review
Dr. Ehrenfeld indicated that she would both update Council on changes that are ongoing at the Center for Scientific Review (CSR) and address the questions that were specifically raised by Council members.

She described how, after talking to various constituencies, she and senior staff at CSR had identified areas in need of change. Among these was the organization of study sections. The need for review expertise changes with advances in science. Study sections should reflect changing needs to avoid imbalance, such as a disproportionate amount of the best science concentrated in a few study sections or retention of substantial expertise in areas of science that are no longer current or active. An organizational structure designed 50 years ago may not be well-shaped for today's science.

CSR continues to rely on the Initial Review Group (IRG) structure that was established in response to a need to reduce numbers of committees in the Federal government. The IRGs are groups of six or seven study sections in a broad scientific area. The individual Scientific Review Administrators (SRAs) of the study sections work as a team to assign applications within the IRG to particular study sections for review and can share reviewers among different panels where appropriate. The IRG can shift resources internally to reflect changing areas of importance. A group of outside advisors is being established for each IRG. This working group provides advice to the IRG on the changing nature of the research field and on appropriate pools of expertise for review. The working groups also will monitor consistency of practice among the different panels within the IRG.

Another group of senior advisors is working to develop intellectually defensible and scientifically sensible rules and guidelines to use when clustering applications for review. Their recommendations are expected in twelve months.

Dr. Ehrenfeld reported on the status of the reorganization of Neuroscience review groups following integration of the Alcohol, Drug Abuse and Mental Health review with CSR. Twenty-one new panels in ten neuroscience areas have been formed and have held their first meetings. An informal review of that first round identified a few areas where improvement is needed, but generally the reviews went smoothly. Dr. Ehrenfeld emphasized the need for a formal evaluation after several rounds of review.

The Behavioral and Social Science integration is currently being designed. Following the model used to redesign Neuroscience review, outside consultants advised on appropriate clusters and an initial map of the proposed study sections has been made available for comment until October 9th. A final plan is expected by November. The first review under the new structure is planned for the June 1999 round. An outside advisor, Dr. Leonard Epstein, is working with CSR staff as community liaison during the transition process.

In considering questions identified by Council members, Dr. Ehrenfeld first addressed the issue of review of clinical research applications. In meeting with outside groups, she had identified three areas where change seemed warranted: Clinical research, bioengineering, and behavioral research. For clinical research, Dr. Ehrenfeld appointed Dr. Michael Simmons, a professor of pediatrics, to advise CSR on review of clinical applications. His report recommended clustering of clinical applications. CSR has responded by developing Special Emphasis Panels in clinical oncology and in clinical cardiovascular research. Dr. Epstein, who is advising CSR about the reorganization of Behavioral and Social Science Research, is soliciting opinions on the structure of review in this area. For bioengineering, the problem is different: the community is disparate and applications are often multi-disciplinary. Rather than a single liaison, a working group has been established to discuss review issues and develop recommendations.

A second set of questions from Council members focused on study section behavior. The major concern was limited attention from reviewers to the impact and importance of the research as opposed to its feasibility or the minutiae of experimental detail. Dr. Ehrenfeld traced the problem to the years of tight budgets at NIH in which only a small percentage of applications were paid. At that time, study sections became very conservative, putting emphasis on research that had more predictable outcomes as opposed to riskier but perhaps more important work. Several strategies are in place to change this mind set. Explicit review criteria have been established including one on the overall impact of the research. New training procedures are in place both for study section Chairs and for SRAs. The IRG working groups can be expected to help in this regard. Innovative ways are being introduced to recruit senior scientists to serve on panels. Their presence can help reviewers to focus on important issues in the research rather than on details.

In addressing locus of review, Dr. Ehrenfeld indicated no preference on whether program projects should be reviewed by CSR or by the Institutes. On the related question of whether individual panels can be expected to review a mix of mechanisms, she indicated that a strong SRA or Chair can draw the panel's attention to differences in mechanisms that may affect review and instruct reviewers in appropriate review criteria. On educating panels to emerging research areas or technologies, she indicated that she is an advocate of closer interaction between Institutes and CSR and encourages program staff to present to study sections when, for example, applications from a new program announcement are being reviewed. On reducing the time from receipt of application to award, Dr. Ehrenfeld favors reform of the current "cumbersome" system of processing applications and supports the planned shift to electronic receipt of applications.

Council members had raised questions about the use of triage. Since 1995, applications in the lower half of the review groups' distributions have been triaged. Dr. Ehrenfeld reviewed the reason why this change had been introduced – to allow more time for those applications that particularly need discussion. She also noted a number of questions that have arisen since its introduction – such as effects on morale of young investigators, and changing funding lines that would imply a need to score a higher percentage of applications. She indicated that she strongly supports the need for an evaluation. The decision, however, to change triage does not rest with CSR - it is an NIH-wide decision.

In discussion, Council members affirmed that an evaluation of triage is appropriate. They also raised a concern over the quality of reviewers and urged CSR to find ways to attract well-known scientists to serve on panels. Dr. Ehrenfeld indicated that CSR is considering several approaches including using the working groups established for each IRG, working with professional societies, and varying the length of term on panels. Members raised the need for SRA vigilance in making certain that review criteria are followed and that review does not become mired in minutiae. Dr. Ehrenfeld described training programs designed to focus the review in the manner described. Members also asked whether CSR tracks the validity of the scoring system by any outcome measures. Dr. Ehrenfeld indicated that among funded applicants who apply for competing renewals those with better scores in the initial competition tend to have better scores in the review of renewal applications than those with poorer scores in the initial competition.

 

3. Working Group On Program

Dr. McClearn, Chair, Working Group on Program (WGoP), presented the report. The first item discussed was a request from NIA that the Statement of Understanding with Council be modified to allow a subset of applications to receive expedited review by Council. The expedited review would involve voting approval prior to the physical Council meeting on the basis of receiving information about review outcome electronically. It would allow early payment of these applications. The request stems from NIA's participation in an NIH reinvention initiative to reduce the time between receipt of application and award. The set of applications eligible would be those within the 20th percentile, with direct costs less than $250,000 per year, and with no NIH policy concerns that would require special consideration by Council. Staff explained that if any member were to have a concern about any application, then that application would go to the full Council for review.

Council members noted that some applicants for competing renewals might not want early award and that applicants may target their budget at $250,000 to take advantage of the expedited award option. Members requested an evaluation of the initiative. The amendment to the Statement of Understanding was approved.

Dr. McClearn stated that the WGoP recommended that the Institute conduct a review of minority aging research. He asked Dr. Jackson to describe the plan for the review which involves a presentation at the September 1999 meeting and a written report at the January 2000 meeting. Dr. Jackson indicated that the work would be coordinated through a staff working group and that an external group of advisors, including Council members would serve as reviewers. Likely topics include issues of training new minority researchers, defining the important questions in minority aging research, and assessing whether NIA is addressing them successfully. He indicated that the question of "exceptionalism" (pursuing minority research because it is research on an underrepresented group) versus intrinsic scientific interest (pursuing research on minorities because it sheds light on questions of general scientific interest) would be addressed. The Council was asked to approve the plan for review.

Council members asked about the role of poverty in understanding ethnic differences in late life, and about the selection criteria for external advisors. They also observed that the review must encompass all four extramural programs of the NIA. Dr. Hodes indicated that a tentative list of external advisors would be presented to Council in January, and agreed to give consideration to the resources needed to accomplish the review. Council approved the plan for the review unanimously.

The statistical package for the current round was examined. The package had been modified in response to Council members' requests. A new table now shows how applications have fared in review over the past three Council rounds. Dr. Barr pointed out that Small Grants (R03s) have been separated from other research project grants to show numbers of R03 applications received and numbers of Small Grant awards made. Council members noted that Small Grants now constitute a significant percentage of the portfolio of some programs and discussed the need to evaluate whether they are serving their purpose. Dr. Hodes indicated that such an evaluation is planned.

4. Report Of The Biology Of Aging Program (BAP)

Dr. Gerald McClearn, Chair, Program Review Committee, presented the report to Council. He described the overall objective of the program as elucidating the biochemical, genetic, and physiological mechanisms of aging and age-related changes in human and animal models. The program reviewers commented on the breadth of the program mandate and the consequent demands placed on staff. He reported that the program reviewers strongly praised the staff of the program both for their responsiveness to applicants' concerns and for their own contributions to the field.

The prior review from four years ago had urged the program to increase activities in resource development. Reviewers learned that developing resources for conditional gene expression systems and the necessary infrastructure for high throughput technology are being considered as initiatives by the program and that the staff intends to renew the Nathan Shock Centers of Excellence in Basic Biology. Also, staff are considering expanding and enhancing the aging cell repository. Reviewers questioned whether BAP might help to stimulate a national population-based autopsy record and start to bank tissues and cells collected from biopsies, surgeries, and autopsies.

Council discussion of resource development activities focused on the need to balance participation in those activities which are much larger than can be supported by NIA alone with the need for NIA to target research on the biology of aging directly. The latter research could be advantaged by such biological resources and by the emerging revolution in technology but should not be held back by the need to support the resources. Members distinguished between focused collection efforts for specific needed tissues versus broad-based efforts that would be more resource-intensive.

Regarding existing animal resources, reviewers appreciated efforts to identify utilization rates of different strains of animals maintained through NIA contracts. They urged staff to consider developing heterogeneous stock while recognizing the additional expense of such an undertaking. They also urged staff to consider expanding the diversity of species maintained as resources.

Reviewers focused on the Longevity Assurance Gene (LAG) initiative and the Biomarkers initiative because of their importance to the program's overall portfolio. The LAG initiative is playing a central role in the development of functional genomics at NIA and is allowing BAP to collaborate with other Institutes to promote new quantitative methods and searches for the genes for complex diseases and for the genetic and molecular basis of longevity. Reviewers saw the initiative as a model for success in science and for generating collaboration among investigators.

The Biomarkers initiative, now terminating, was an attempt to identify detector variables, other than mortality, that would serve as accurate proxies for measuring anti-aging interventions. The Review Committee strongly recommended that an evaluation be conducted of the success of this initiative and that no further follow-up activity be initiated without the results of that evaluation. Dr. McClearn cautioned that the evaluation must be sensitive to the necessary limitations of the design – such as using inbred strains of mice.

Reviewers endorsed plans for future initiatives in caloric restriction, menopause and osteoporosis, the comparative biology of aging, and stem cell biology. They discussed the need for initiatives that focus on gene-environment interactions with a particular emphasis on exploring feedback relationships in the causal flow of action from gene to outcome. Dr. McClearn related this concept to the emerging need for an integrative science of biology and to the new tools in mathematics and computer science that facilitate such a scientific approach.

Reviewers raised some concern that the initial review committees for biology of aging applications do not contain appropriate expertise on aging research. They also emphasized that it is imperative to fill staff vacancies quickly and to consider increasing the number of professional staff positions despite constraints on staff expansion at the present time. In discussion, Council members noted the need both to train researchers in the emerging techniques and fields engendered by the new technologies and to ensure that professional staff are allowed to acquire training to remain current in their fields.

Following Dr. McClearn's presentation, Council discussed whether the review might benefit from collection of formal data on outcome of initiatives, such as number of publications and the extent to which the work is cited by others. Dr. Hodes indicated that the Institute is working on developing a plan for such an assessment and offered to provide a progress report to the Working Group on Program at the February 1999 Council meeting. Dr. McClearn indicated that formal outcome measures could be added to the written report of the BAP program review.

5. Positively Aging: Choices And Changes

Dr. Warner, Acting Associate Director, Biology of Aging Program, introduced a presentation by Dr. Michael Lichtenstein and Ms. Linda Pruski of the University of Texas Health Sciences Center at San Antonio (UTHSCA), Texas. The presentation described work supported under a grant to build science education in schools. The project, supported by NIA and the National Institute of Dental Research, is part of the Science Education Partnership Program whose chief sponsor is the National Center for Research Resources at NIH.

Dr. Lichtenstein described the aims of the curriculum supplement program, which is targeted at middle school children, to empower adolescents to make healthy choices about their own lives, to improve knowledge and skills in mathematics and science, and to help students develop sensitivity to the concerns of an aging population. The program has been based in a school district in San Antonio that has a large Mexican American population and has a significant percentage of children eligible for free or reduced cost school lunches. The grant provides funds to develop and pilot test evaluation instruments, to test the program in a controlled intervention, and to disseminate the program more broadly.

Ms. Pruski described how the curriculum supplement program is taught. Ms. Pruski, though now at UTHSCA, was the middle school teacher who was most responsible for building and introducing the curriculum supplement into the Anson Jones Middle School, the primary site for the pilot work on the project. The program was developed as a vehicle for teachers to use to integrate and illustrate the existing elements of the curriculum in mathematics and science rather than to add new curriculum elements. It takes advantage of the team teaching approach, now being adopted and used broadly in middle schools, in which groups of different specialist teachers plan a single theme around which their different curriculum elements can be taught.

She illustrated the 12 elements of the program by focusing on the element on bone health. She showed how teachers of science, mathematics, reading, English, social studies, and home economics can each draw examples and themes from the curriculum materials to illustrate middle school concepts such as genetic and environmental influences on health, the concept of density, the evolution of language, and the cultural significance of the skeleton. She also demonstrated teaching aids that are used to enhance learning experiences in classrooms.

Ms. Pruski reported that evaluations from teachers and students have been enthusiastic. She also reported that teachers who have used the materials and moved on to other schools are eager to have the materials in their new schools. Council members asked Dr. Lichtenstein about further plans for dissemination of the supplement program and encouraged the team to continue the important work.

6. Report Of The Minority Aging Task Force

Dr. Jackson, Chair of the Task Force, reminded Council members of the plan for the upcoming review of minority aging research and training at NIA. He also asked Drs. Stahl and Harden, both of NIA, to describe existing programs and initiatives on minority aging research. Dr. Stahl described the work of the Resource Centers on Minority Aging Research (RCMARs) in mentoring new minority investigators addressing measurement issues in minority aging and developing recruitment strategies to include minorities in research. Dr. Harden described the Summer Institute on Aging Research, regional meetings that target minority aging research, and an upcoming Technical Assistance Workshop to be held in collaboration with the Gerontological Society of America at its annual meeting. Dr. Jackson further illustrated the work of the RCMARs by showing how attendees at the last Technical Assistance Workshop have now been linked through the internet with the network of minority researchers supported through the RCMARs.

In discussion, Dr. Harper asked whether the planned review of NIA minority research will address where the major gaps in knowledge of minority aging are and whether attention is being given to the need for printed materials rather than web-based materials for the smaller colleges that are unable to afford web access. Dr. Jackson indicated that identifying the gaps in knowledge and addressing them is a central part of the RCMARs activities. In addition, investigators have worked to distribute materials via CD-ROM technology to provide low cost data to colleges around the country. Ms. Harootyan, of the Gerontological Society of America (GSA), described a publication of the Society on the topic of minority aging that is a collaboration between GSA and NIA.

7. Report Of The Task Force On Training

Dr. Helen Blau provided an update on the work of the Task Force indicating that the committee expects to make its final recommendations to Council at the meeting in February 1999. She described the recommendations for training in the life sciences of a recently released report, Trends in the Early Careers of Life Scientists. This report, published by the National Academy of Sciences (NAS), argues that more Ph.D.s are being produced in the life sciences than there are appropriate academic and research positions for them. The report details a set of recommendations aimed at keeping supply and demand in balance.

The Task Force is working on recommendations to substantially increase stipends for National Research Service Awards, to use program announcements to expand the definition of aging research, and to create multidisciplinary programs. In keeping with the report published by the NAS, the Task Force is looking at ways to expand the use of career awards to allow more top quality young researchers to transition to full independence. One possibility being explored is that the staff scientist position in universities may be expanded to include adequately trained scientists who are now working as senior postdoctoral fellows.

In discussion, Council members stressed the importance of working with other Institutes to develop a common plan concerning training initiatives.

8. Program Highlights

Dr. Andre J. Premen, program administrator for cardiovascular research in the Geriatrics Program, described a study by Singer and colleagues ( Journal of the American Medical Association , 279 , 657-662). The investigators examined the causes of excessive anticoagulation, the tendency of the blood not to clot, in older patients. They focused on acetaminophen as a possible contributor to excessive anticoagulation in patients taking the drug Warfarin. In a case control study where cases showed a marked tendency towards anticoagulation and controls were within the normal range, 56 percent of the cases were identified as having taken acetaminophen in the week before blood was drawn as compared to 36 percent of the controls. On average, cases consumed 21 tablets compared to 9 tablets in the controls. The authors also identified a strong dose-dependent relationship between the amount of acetaminophen consumed and the tendency towards excessive anticoagulation.

The clinical significance of this work lies in the potential of drug-drug interactions preventing effective treatment or causing complications in treatment. The investigators focused on the drug, Warfarin. It is used effectively to reduce the likelihood of ischemic stroke in high-risk patients with atrial fibrillation. Yet, excessive anticoagulation with a therapeutic dose of Warfarin may occur in the presence of other drugs (e.g., acetaminophen) which potentate the action of this anticoagulant. Singer and colleagues concluded that acetaminophen use in older patients is an under recognized cause of excessive anticoagulation in the outpatient setting. Better monitoring of potential drug-drug interactions will enable older patients to benefit from Warfarin treatment without serious bleeding complications.

Dr. Morrison-Bogorad, Associate Director, Neuroscience and Neuropsychology of Aging Program, introduced Dr. Patricia Goldman-Rakic, a Council member and neuroscientist, who described her work on understanding the neuronal processes that underlie working memory. She described working memory as the kind of memory used to retain necessary information temporarily while engaged in a task – such as holding the subject and verb of a sentence in mind while reading the sentence. She is exploring the role of dopamine, a neurotransmitter, in modulating working memory function.

Her group has trained rhesus monkeys in a spatial memory task in which the monkeys see a target presented at a particular location, must wait for a short period of time, then respond by identifying the location at which the target was presented. Neurons have been identified in the prefrontal cortex that show particular patterns of responding in this task. Some neurons turn on when the target is presented and turn off when it disappears. Other neurons turn on when the response is made. A third set of neurons turn on when the stimulus goes off and remain on until the response is made. Dr. Goldman-Rakic indicated that when these neurons are not consistently on during the memory interval, the animals make mistakes. The neurons appear to be the neural substrate of this element of working memory.

Performance of these neuronal cell systems is thought to be modulated by neurotransmitters such as serotonin and dopamine. The memory cells studied contain dopamine receptors. Dr. Goldman-Rakic explored whether dopamine influences performance of these cells by giving monkeys a drug that down-regulates the dopamine receptor preventing its uptake by the memory cells. With chronic treatment, the down-regulation impaired the monkeys' performance in the working memory task; thus, this memory function appears to be plastic and modifiable through changes in neurotransmitter levels. Her team is now studying an intervention in aging monkeys to determine whether their deficient memory function will be enhanced by a dopamine agonist.

Council members asked questions about whether dopamine had yet been demonstrated to enhance working memory and about the columnar organization of the memory cells.

Dr. Richard Suzman, Associate Director, Behavioral and Social Research Program, introduced Council member Dr. James Vaupel. Dr. Vaupel presented findings showing the malleability of mortality rates across time and across species, and as a consequence of planned intervention. He described data from three recent publications in Science ( 280 , 855-860; 280 , 986; 281 , 996-8) that were authored by his group.

He first reported that there have been sharp declines in mortality rates since 1950 among older adults in the United States and in many other developed countries. According to his projection, half of the girls born in developed countries in 1998 will reach age 100.

He next reported on research examining the belief that mortality rates increase exponentially with increasing age. He found that mortality curves fitted to data from ages ranging from 80 to 120 do not fit the exponential model. Instead, the rate of increase in mortality decelerates after age 80, and, although the number of points is small, mortality rate may level off at very advanced ages (105 to 110). Given the surprising nature of these findings, he and his colleagues explored mortality curves in different animal species to identify whether similar trends emerge. He reported the same pattern of mortality deceleration for different species of fruit fly, wasps, worms, and yeast. His group also reported mortality (or scrapheap) deceleration for very old cars. The phenomenon appears to be a property of complex systems.

Dr. Vaupel's group also asked whether it is possible to manipulate mortality rate as a function of age - to alter the timing of the biological clock. Using medflies, Dr. Vaupel and James Carey, a collaborator, fed different groups sugar-only diets and then introduced protein at different points in their lives. On the sugar diet the flies showed a typical mortality curve in which death rate per day began close to zero at day 1 and then accelerated. In one group, at day 60, the researchers introduced protein to the diet. The death rate declined to near zero before again accelerating. In a second group, protein was introduced at day 90. Again, death rate declined to near zero before beginning to increase again. Dr. Vaupel suggested that the research raises questions about the nature of biological clocks.

Council members discussed alternative hypotheses for the observed deceleration in mortality rate with increasing age. A selective survival account was contrasted with an account assuming that aging itself slows down. Dr. Vaupel outlined a method to test such explanations.

Dr. Anna McCormick, a program administrator in the Biology of Aging Program, described research by Dr. Michal Jazwinski and his colleagues on cellular mechanisms of longevity assurance. The work is supported through the Longevity Assurance Gene initiative. Because the team is part of an interactive network of investigators in this initiative, the work is being rapidly extended.

The research team noticed that a group of yeast cells, called "petites", show extended longevity relative to other yeast cells. The investigators considered two mechanisms that may be responsible for the increased longevity of these cells. The first possible mechanism follows from the fact that the petites do not have mitochondria capable of providing energy through respiration. A lesser role in providing energy means being less subjected to oxidative stress. The investigators, in two interventions, sought to eliminate oxidative stress from yeast cells. Neither intervention extended longevity – a finding contrary to the view that protection from oxidative stress is the reason why petite cells show enhanced longevity.

The investigators next considered the phenomenon of retrograde regulation. This process refers to the way some mitochondria signal to the cell nucleus to alter the way that the cell is providing energy. Retrograde regulation appears to be a feedback loop that allows the cell to respond appropriately to changed environments. The process has been identified in petite cells. With retrograde regulation, a yeast cell can survive longer than its normal counterparts. Jazwinski and his colleagues were able to delete the genes involved in retrograde regulation in petite yeast cells. With these genes deleted the petite cells no longer showed extended longevity; thus, retrograde regulation – a process allowing cells to adapt to changing environments – appears to be the mechanism responsible for extended longevity in these cells.

Dr. McCormick indicated that work is now rapidly proceeding within the LAG initiative on whether retrograde regulation occurs in mammalian and other cells. In this regard, the initiative is fulfilling its purpose of developing biologically plausible mechanisms for longevity in short-lived species that can then be examined in mammals and, eventually, humans.

Questions from Council members were concerned with extending the biological plausibility of the proposed mechanism through exploring whether in other species there are genetic homologues for the specific genes controlling retrograde regulation in yeast, and through exploring the upstream biological mechanisms that induce retrograde regulation.

9. Comments From Retiring Members

Dr. Hodes thanked both Dr. McClearn and Dr. Wang whose terms on Council expire prior to the next meeting. He offered them both the opportunity to make remarks to the group. Both expressed their appreciation for the opportunity to work with their colleagues on Council.

10. 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 737 applications requesting $591,597,546 for all years was reviewed. Council recommended 514 for a total of $395,605,087 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.

11. Adjournment

The 75th meeting of the National Advisory Council on Aging was adjourned at 12:30 p.m. on September 25, 1998. The next meeting is scheduled for February 3-4, 1999.

Attachments:
A. Roster of Council Members (Not available)
>B. Director's Report to the NACA (Not available)

12. 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.