May 23-24, 2004
Attachment A - Roster of the National Advisory Council on Aging Attachment B - Director's Status Report
The 92nd meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, May 25, 2004, at 8:05 a.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 Monday, May 25, from 12:45 p.m. to 2:15 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, May 25, from 8:00 a.m. to 12:45 p.m.
Council Participants:Dr. Marie A. Bernard Dr. John Cacioppo Dr. David Espino Dr. Linda P. Fried Dr. Alan M. Garber Dr. F. Michael Gloth, III Dr. Eugene M. Johnson, Jr. Dr. Lewis H. Kuller Dr. Ronald D. Lee Dr. Virginia M.Y. Lee Dr. Stanley Prusiner Ms. Judith RiggsDr. Gary Ruvkun Dr. Leon J. Thal
Ex-officio Participants: Dr. James Burris (VA)Dr. Kenneth G. Pugh (Navy)Mr. Donald Grantt for John Wren (AOA)
Absent: Dr. Elizabeth H. Blackburn Dr. Melissa M. BrownDr. Spero MansonDr. Peter W. Nauert
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. Nicholas Christakis, Harvard UniversityMs. Alicia Doherty, MasiMax Resources, Inc.Dr. Marc Goldstein, American Physical Therapy AssociationMs. Linda Harootyan, Gerontological Sociology of AmericaMs. Mary Jo Hoeksema, Population Association of America & Association of Population CentersMr. Kevin Kinsella, U.S. Bureau of the CensusMs. Diana Lawry, Administration on AgingDr. Rose Maria Li, Rose Li and Associates, Inc.Dr. Russell Morgan, Spry FoundationMr. Tim Perrin, American Association for Geriatric PsychologyDr. Kitt Petersen, Yale UniversityDr. Mercedes Rubio, American Sociological AssociationDr. William Sansalone, Georgetown UniversityDr. Viviana Simon, Society for Women’s Health ResearchDr. Jonathan Tilly, Massachusetts General Hospital
Dr. Hodes called the meeting to order at 8:05 a.m. on Tuesday, May 25, 2004, and welcomed members. He circulated a notebook compiled by the NIA Public Information Office of press materials generated from coverage of NIA research since the last Council meeting.
Director’s Status ReportDr. Hodes began by presenting an update of the NIA and NIH budget and the implications for research support and planning over the next few years. The double-digit increases over a 5-year period have been followed by 3 percent increases for FY2004 and FY2005 (projected). Beginning in FY1996 and through FY2003, the NIA budget increases have been associated with relatively stable success rates, ranging from about 26 to 32 percent, despite relatively large fluctuations in the rate of budget increase. This is no longer the case in FY2004.
Dr. Hodes reported that at NIA the proportion of research program grants (RPG) has remained constant at about two-thirds of the budget. Thus, even during the doubling of the NIA budget, there has not been disproportionate use of other mechanisms at the expense of research project grants. What was not predictable in retrospect was that NIA experienced a 38 percent increase in the number of new and competing applications seeking funding in FY2004, enough to reduce the success rate substantially. The total dollars requested increased by 40 percent; historically, over the past decade or so, there has been approximately a 6 percent increase in average cost. However, among applications which scored in the fundable range, the average cost increased substantially, far greater than the average cost of all applications received. These forces combined to produce an estimated FY2004 success rate at the 15th to 17th percentile. Further adjustment in the pay line may be made as the fiscal year proceeds. The NIA funding level is about average in comparison to other NIH Institutes and Centers.
In order to reach this lower payline, NIA instituted an average 18 percent reduction to funding levels recommended in peer review, with reductions handled on a case-by-case basis. For FY2005, a similar situation is anticipated. To buffer the impact of funding constraints, NIA announced a new policy capping new and competing continuation P01 applications at $1.5 million in direct costs. There was no cap in previous years. Only in exceptional circumstances will deviations to this new policy be considered.
Dr. Hodes updated Council members on a number of other developments. There has been an active period of legislative activity, with Drs. Hodes and/or Salerno testifying in seven different House and Senate hearings over the past few months. These hearings, which Dr. Hodes described as uniformly positive in a bipartisan fashion, provided an opportunity to inform Congressional leaders about NIA supported research. One Council member observed that seven hearings is remarkable and represents an unusual recognition by Congress that aging is an important area.
Funding decisions for the NIH Roadmap initiatives are beginning to be made and will be reported on at the next Council meeting.
Dr. Elias Zerhouni has taken the lead to address questions about outside activities by NIH staff. Shortly after concerns were first raised by the press and Congressional leaders, a process for review of all outside activities for NIH staff was instituted, and was coupled with the convening of a Blue Ribbon panel chaired by Norman Augustine and Bruce Alberts that reviewed current policies and made 18 recommendations (available electronically upon request). Since the time of this report, there have been additional Congressional oversight hearings, some of which have expressed the perspective that the recommendations of the group and the panel may not have been sufficient to address all of the concerns. Dr. Hodes reassured Council members that these issues are being taken seriously across the NIH. NIH is attending to maintaining the credibility and integrity of NIH employees, particularly to avoid real or apparent conflicts of interest with official duties arising from outside activities. NIH also appreciates that active NIH scientists should be permitted to function productively as part of the academic or research communities. Dr. Hodes welcomed input from Council members and constituencies on this issue.
Discussion began with questions about the funding situation and implications for training. One Council member anticipated that the number of grant applications would increase because fewer are being funded, leading to a greater number of resubmissions. With respect to modeling out-years, Dr. Hodes conjectured that the financial picture may remain highly constrained until FY2006, after which the situation is projected to improve because of grant turnover. It is likely that the real impact of low success rates or training cut-backs this year would not surface until 10-12 years from now. However, Dr. Hodes added that the level of funding for fellowships (F’s) and training grants (Ts) is not expected to fluctuate widely because NIA did not scale up funding for these mechanisms during the budget doubling period. However, a phased increase in stipends was initiated, which may not be completed because of budget constraints.
Another Council member observed that the doubling in the NIH budget gave young people hope that there is a great future in biomedical research. The current situation has had a discouraging effect, particularly for the future leaders 10 or 15 years down the road. Dr. Hodes reassured Council members that NIA has committed to maintaining funding for fellowships, will not cut career development and training awards, and will monitor success rates for new investigators.
Dr. Hodes acknowledged Council members past and present who have been particularly active in bringing to the Institute’s priority the need for providing training and career development, in particular for clinical investigators in the area of aging research. The new RFA for the Beeson Scholars Program is a partnership program funded by the NIA, the Hartford Foundation, Atlantic Philanthropies, and the Starr Foundation, with several other foundations expressing interest in joining that partnership. The first group of 13 awards has been made and an RFA will be issued for next year. The Beeson fellowship represents an expansion of training and career development above current levels, and reflects an important partnership at a time when the NIH budget is constrained. NIA leadership was congratulated for establishing such an exciting and productive program for scholars that cements careers and investigation in aging, particularly clinical investigation. Dr. Salerno noted that the Beeson program has sparked interest across the NIH to develop similar initiatives. Dr. Hodes credited the Council for providing the initial impetus for the program, and announced that NIA is planning to develop a similar program for medical students with an RFA anticipated in the next year so that the first medical students would be funded a year from this summer.
Following up on earlier discussion about training, one Council member identified the need for a very substantial expansion of investigators working on aging precisely during this period of budget constraints. The need remains particularly acute for clinical investigators.
In response to a question about apparently greater growth in intramural versus extramural program funding, Dr. Hodes stated that both the intramural and extramural program total budgets are increasing at about the same 3 percent rate. The number of intramural personnel is constant and the 3 percent increase is largely for salaries. The intramural program remains less than 10 percent of the total NIA budget.
Concerns were raised about the need to better translate research findings. There has been a quantum leap in recent years in the science base in aging which has important implications for improving the health and quality of life of older people. Most of the public focus seems to be on difficulties, Medicare, and drug pricing rather than on enhancements of new knowledge. More needs to be done to convey the successes to improving the quality of life and health of older people. Dr. Hodes acknowledged the challenges in communicating findings in a useful way, and added that NIA makes every effort to help investigators publicize advances in ways that make clear their relevance to the public. He welcomed input from Council members about how to encourage stronger communication strategies. Staff from NIA’s Office of Communications and Public Liaison (OCPL) noted that the news environment is very competitive. Even when NIA findings do not appear as headlines in the major news outlets, they are appearing more frequently on the Internet and in small community papers that older people tend to read.
Future Meeting Dates
Consideration of Minutes of Last MeetingThe minutes of the February 2004 meeting were considered. A motion was made, seconded, and passed to approve the minutes.
Dr. Lewis Kuller reported on the deliberations of the Working Group on Program (WGOP), which met on May 24. Budget and funding issues dominated the WGOP discussions.
A. Advisory MeetingsDr. Elisabeth Koss summarized the outcome of a trans-NIH (NIA, National Institute on Drug Abuse [NIDA], National Institute on Alcohol Abuse and Alcoholism [NIAAA], National Institute of Mental Health [NIMH], and National Institute of Neurological Disorders and Stroke [NINDS]) workshop on Executive Function that was held in June 2003. The Workshop produced 10 recommendations and a variety of actions are planned. NINDS plans an initiative to develop new tasks to measure Executive Functioning. NIA will collaborate with NINDS to define common objectives, prioritize Executive Function’s domains of interest, and standardize measurement procedures. NIA is taking the lead in organizing a Steering Committee of experts in Executive Functions to explore and categorize the domains of Executive Functions that are most relevant to the aging process and to determine which existing tasks and instruments map those domains. NIA will consider an initiative to target existing longitudinal studies on aging to add measures of Executive Functioning to establish normative data, e.g., in terms of age, comorbidities, race/ethnicity. A suggestion was made to focus particularly on vascular disease and associated risk factors, and to focus on younger (middle-aged) population. There is a need to understand the relationship between Executive Function or dysfunction and puzzling health behaviors. Dr. Kuller noted that opportunities should not be overlooked to add Executive Function to data collection efforts that are not longitudinal, where one could relate executive function to brain activity using available data from MRIs or cardiovascular function, or adherence to drug therapies. Dr. Andy Monjan added that a number of NIH Institutes are participating in the Healthy Brain initiative which has produced a catalog of ongoing cross-sectional and longitudinal studies.
No new advisory meetings are scheduled at this time.
B. RFA Concept ClearanceDr. Evan Hadley summarized a request for concept clearance of an RFA on Aging Through the Life Span: Longitudinal Data Analyses. This is an early but crucial step in an ongoing initiative to increase the contribution that longitudinal studies can make to some important aging questions. NIA has convened a Longitudinal Data on Aging (LDA) Working Group consisting of leading researchers from major longitudinal studies and other experts in aging, as well as population diversity and disease outcomes. The kinds of questions that could be addressed by longitudinal studies include the sequence of changes over the life course from early life to late life that result in health issues late in life. That some people age exceptionally well and stay quite healthy in late life points to an important phenotype that can be studied in addition to disease outcomes.
There is also strong interest in translating findings from basic research on animals to humans. Dr. Kuller underscored the importance of these rich data resources, and noted that the incubation period for many chronic diseases can be very long. Dr. Hadley clarified that although the RFA focused on observational data, clinical trials may also be considered. Because there are several long-term clinical trials that lasted 7-10 years, many of the people in the trials are now advanced in years. Both observational data and clinical trial data are available. The request for RFA concept clearance was unanimously approved.
Dr. Ronald Lee began his report of the Behavioral and Social Research Program (BSR) Review by describing the review process. The BSR Review Committee, which was chaired by Dr. Ronald Lee, included five members from Council (Ron Lee, John Cacioppo, Linda Fried, Alan Garber, and Spero Manson), three previous Council members (James Jackson, Andy Smith, and David Wise), and two outside experts (Danny Kahneman and James Smith). It adopted a structure of 12 subgroups involving committee members as well as 18 outside experts, with each subgroup producing a short report addressing its assigned topic. These reports constitute the core of the review. The topics were developed in conjunction with Committee members, BSR staff, and NIA leadership, and were not meant to be exhaustive. Some of these areas were identified because they were thought to be particularly promising or dynamic; other areas were identified as ones where staff sought guidance from the Committee on future directions. The Committee considered the short reports on the 12 content areas, as well as comments on a number of cross-cutting areas, to constitute the core of the review. This material, coupled with a substantial amount of background materials produced by BSR staff, provided the basis for the Committee’s deliberations which took place through three teleconferences and two in-person meetings. Primary emphasis was placed on promising scientific areas for future research, and less on evaluating past accomplishments.
The general view of the Committee was that BSR is creative, dynamic and takes risks aggressively, reflecting in good part the leadership of its director, Dr. Richard Suzman. Because interdisciplinarity is a defining characteristic of the BSR Program, which was seen as entirely appropriate, contact with other programs raises some issues, including conflicts over applications at the boundaries. The Committee recognized that some conflict is inevitable as the natural outgrowth of scientific developments. However, it believed that the ambiguity and conflicts that arise at the boundaries should be addressed to reduce the costs for staff yet maintain sufficient flexibility so that the programs can adapt as the science evolves. NIA should embrace the opportunity to share expertise across programs, and encourage BSR to support the most appropriate methodologies, which increasingly involve behavioral genetics and neuroimaging, to address cutting-edge research questions. Applications that address BSR topic areas should not be allocated on the basis of methods and techniques that are being used, but rather on the substantive issues that those projects are trying to address.
Dr. Lee reported next on several general areas identified as needing additional attention.
BSR staffing issues, particularly key vacancies and HSA work overload, need to be addressed. The Committee recognized that BSR is heavily involved in collaborative research efforts that can be particularly time consuming and not reflected in the grants to HSA ratio. It also underscored the importance of recruiting a Deputy Associate Director with strong administrative and scientific credentials. The Committee conveyed their appreciation of the dynamism, interdisciplinarity, and impressive research accomplishments of the BSR Program, which they considered to reflect the work, ideas, creativity, and judgment of the staff to launch new initiatives and move science forward despite staffing constraints. Dr. Suzman expressed a desire to fill at least one of the key vacant positions by the end of the summer.
The Committee endorsed the appointment of another advisory group to consider the adequacy of the grant application review process as the topic was considered too complex to be addressed adequately in the time available. Dr. Lee elaborated on the difficulty of securing an appropriate slate of reviewers, including participation by interdisciplinary scientists credible across multiple disciplines as well as sufficiently experienced researchers to discern overall value and innovation. In the population field, there have been intermittent complaints about the breadth of science covered by study sections with the result that disproportionate weight may be given to one person representing a particular disciplinary perspective for the duration of a four-year term. A systematic assessment of the review process was beyond the scope of the program review.
The Committee noted the investment (about $30 million/year) to support data collection efforts, and observed that BSR’s achievements in meeting data needs serve as a model for other countries. It recommended that a dedicated group review the data collection portfolio to consider areas outside of health and economic behavior of the elderly that are ripe for greater investment.
Training programs in psychology need to be examined, particularly whether new developments are incorporated in the training. There has been some concern that the top departments in psychology generally do not have T32 training grants. Because more data are needed to assess the issues, the Committee recommended a special review group to focus on this topic.
Dr. Lee mentioned each of the selected topics:
Some of the topic areas were presented in more detail by the Council member subgroup leaders to provide the full Council with a better idea of the flavor of the review and program scope.
Biodemography (Lee)Biodemography has been an active area that BSR has promoted effectively, generating some important findings. One of the earliest and most striking findings was of pervasive plateaus in mortality. It had been thought that mortality increased exponentially with age, but it has since been discovered in various biological models that, in fact, mortality levels off and declines at extreme old ages. This area of biodemography continues to be a vital line of inquiry. Another area within the biodemography portfolio has been the introduction of biological and genetic data into ongoing or new surveys. There are currently at least 16 BSR grants that are in part gathering biological and genetic material, representing the seeds of an exciting and new research agenda. One of the newly funded grants is a National Bureau of Economic Research (NBER) project on the heritability of economic phenotypes, e.g., wealth accumulation. The biodemography study group recommended that BSR continue this work, and identified areas within genetic aspects of biodemography as particularly promising.
Cognitive Aging (Cacioppo)How cognitive functioning changes with age has been a major focus of BSR and the Neuroscience and Neuropsychology of Aging Program (NNA) over the past decade. In 1999, NIA asked the National Academy of Sciences’s (NAS) National Research Council to identify areas of opportunity in the field, which led to the publication of The Aging Mind in 2000. The Cognitive Aging study group consulted with outside leaders in the area of cognitive aging, including contributors to the Aging Mind volume.
The committee emphasized that although aging is associated with impaired cognitive functioning, some aspects of cognitive functioning are spared or possibly improved. Translational research can be undertaken on how to use retained cognitive functions to accommodate losses in other areas. A related need is to understand the adaptive processes that influence cognitive functioning and performance during aging; how differences in socio-cultural context bring systematic variation in cognitive functioning and performance, and how to develop the knowledge needed to design effective human factors technologies based on advances in the technology of sensing and information processing to improve the lives of older adults.
It was the consensus of the Committee that BSR should encourage use of new research tools, e.g., neuroimaging, to enhance understanding of cognition and cognitive function. In terms of data collection, the NAS committee recommended a large-scale multi-site population-based longitudinal study of cognitive aging to better understand the needs of an increasing proportion of the US population. The study group saw this as a remaining need that BSR might pursue.
Psychological Development and Integrative Science (Cacioppo)Integrative science, or interdisciplinary perspectives, is a hallmark of the BSR Program. The study group recognized that one of the realities of science is that the leading researchers across various disciplines generally want control over their own projects. For this reason, R01 mechanisms may not be well suited to multidisciplinary teams. BSR has been responsive by supporting program projects (P01s). Peer review of large-scale multidisciplinary P01 applications may be compromised if individuals bring disciplinary perspectives that do not appreciate cross-disciplinary applications. The study group encouraged attention to special needs for high quality review of multidisciplinary applications. Finally, it was noted that BSR cannot support large-scale projects alone; collaboration is necessary and brings concomitant demands on staffing.
Behavioral and Social Interventions (Fried)Several comments emerged from deliberations on future behavioral and social interventions, particularly, on endpoints. Important research is proceeding in parallel at the individual and the population levels so that innovations at the individual level, perhaps in measurement of cognition, could be translated into population level measurements.
Maintaining cognitive and physical function, resiliency, and reserves is of particular concern. The subgroup thought it appropriate for BSR to provide leadership in understanding these areas, and to complement ongoing efforts by the Geriatrics and Clinical Gerontology Program. BSR is encouraged to increase its investment in research to improve physical function as well as cognitive outcomes. There is potential to invest in and mine ongoing longitudinal studies, particularly population-based epidemiologic studies, to deepen understanding of health dynamics and how they translate into declines in function as people age. In addition, there are emerging problems like obesity, where longitudinal studies are critical to understanding factors contributing to obesity and how these translate into adverse health outcomes as people age. The subgroup believe it critical that BSR provide leadership, in collaboration with other programs, to identify the most important prevention opportunities for the future, and to provide guidance to the scientific community in terms of targets to prevent physical, functional, and cognitive decline.
The Committee praised the BSR-led initiatives for cross-disciplinary research and suggested some consideration of new structures to further support this kind of work. Centers might be considered, such as for integrative studies of aging to foster multidisciplinary teams working on highly integrative research areas, and emphasizing integration across social, psychological, biologic and economic spheres as well as specific areas of health expertise in response to needs in particular target areas.
Finally, there is mounting interest in community interventions, and how to translate research findings back to the community. The challenge is that many community-level interventions have been disappointing in terms of their impact. Dr. Fried noted the ENRICH intervention as an example of a study for which there were high hopes that were not met.
Dr. Cacioppo added that executive functioning was discussed extensively by both the cognitive aging and the behavioral economics groups. It is one of those emerging areas where both the questions and the methodologies are relevant to both NNA and BSR. In this case it is clear that the two programs would benefit from the complementarity of research perspectives. The convergence of program focus on common problems and methods was seen as a strength rather than a weakness, although there comes a point when joint program development can be impaired by demands on staff time.
Dr. Hodes asked for clarification about the overlap issue and whether the boundaries are perceived to need clarification. Dr. Lee elaborated on two potential concerns regarding boundaries related to the study of social and behavioral outcomes involving imaging or genetics: (1) assignment of projects based on techniques used instead of research question studied; and (2) program conflicts over application assignments due to ambiguous referral criteria. Dr. Garber observed that these are transitional problems because the new research challenges, tools, and techniques are crossing traditional boundaries and raise issues of application assignment. Dr. Thal echoed the sentiment that research should not be categorized by techniques used, and provided an example of the pervasiveness of molecular biology in mainstream biomedical research studies.
Analytic Methods and Translational Research (Fried)The ability to translate basic or clinical findings back into communities, including through interventions, is an emerging area where methods development is needed, particularly to understand negative findings, and to enhance the ability to make causal inferences, or to decide at what point data are sufficient to warrant translation from one level of science to another (e.g., from basic to clinical investigation, or from observational to interventional data studies). There is a critical need to develop effective methods to inform efforts to change behaviors. Outcome measures appropriate in observational studies may not be sensitive to well-tailored interventions in communities. Thus, off-the-shelf methods that historically may have been meaningful should not be used without clear scientific rationale.
This study group recommended that BSR take the lead in supporting development of analytic methods. Methods development would support the accomplishment of NIA’s strategic plan through 2005 in many areas, including quantitative methods for modeling dynamic system changes physiologically, survey methods for looking at missing data, or quantitatively analyzing multifactorial risk factors or multifactorial outcomes. The study group recommended that NIA reissue the current Program Announcement PA-02-072 for methods development in aging research and, in addition, consider including methods for both translation and dissemination of findings to underscore the next challenge in translation—to make the results of scientific findings comprehensible to the public and to scientists in different disciplines who then could be translating those findings to a next generation of research.
Health Services Research (Garber)The subgroup that addressed health services research noted that the area is not well defined. Health services research applications at times seem outside NIA’s mission. However, agencies whose mission includes health services research, the Agency for Healthcare Research and Quality (AHRQ) and The Centers for Medicare and Medicaid Services (CMS), have limited funds to support investigator-initiated applications. Nonetheless, the subgroup acknowledged that most health resources are expended on chronic diseases of older persons and that health services research is related to aging.
Although exciting research opportunities abound in this area, the subgroup focused on how to confine the problem to provide useful guidance. Dr. Garber noted that the subgroup, which was composed of four Committee members and eight external consultants representing the fields of psychology, sociology, economics, geriatrics, general internal medicine, and less defined disciplinary backgrounds, held a diversity of views. The group emphasized the principle that NIA research support for health services research should reflect the unique strengths and the interests of NIA. Thus, any health services research supported by NIA should have implications for the elderly, and the substantive areas should be within the domain of NIA interests and ideally related to current NIA initiatives. If the topic is only sporadically funded by other agencies, it should receive special NIA consideration. As an example, if NIA is supporting behavioral interventions, some of NIA-supported health services research ought to address those interventions, whether it is done as part of these trials or as an external study. Medicare is another obvious focal area for NIA support.
The subgroup recognized that measurement techniques for outcomes are important, albeit not unique to health services research. At a prior Council meeting, there was discussion about the IOM report on testosterone and whether the NIA should support a large scale randomized trial of testosterone for men not defined as hypognadal. Given the interest in enhancing performance, and maintaining high levels of cognitive and physical functioning, health services research must be able to deal with such scientific and financial issues. It is plausible that our society is shifting from one where most health dollars for the elderly are spent on those who are severely disabled to one dominated by younger elderly trying to maintain high levels of functioning. The research agenda must be prepared to cope with such trends and the need for better instruments for measuring higher level functional and cognitive status as well as well-being.
Dr. Garber noted the subgroup's listing examples of research areas that should not be funded by the BSR program. These areas included trials of pure clinical interventions (which belong most appropriately in other extramural programs) and studies only incidentally related to aging. NIA should support studies at the core of its interests. Thus, a study about the benefits of carotid artery stenting for stenosis would be appropriate for NIA support because it is primarily an intervention applied in the elderly. The difficulty will be to balance the portfolio so as not to overwhelm it with this kind of subject. It will be particularly challenging to set priorities in light of the current budget situation.
Dr. Hodes thanked Dr. Lee and the BSR review committee for a superb effort and a substantive presentation, and considered the process a model for future program reviews in terms of providing guidance to staff in the form of issues and recommendations. He suggested that an appropriate time be set aside at the next Council meeting for further discussion.
A. Biology of Aging: Adult Germline Stem Cells and Female Reproductive Aging
Dr. Frank Bellino introduced Dr. Jonathan L. Tilly, an NIA grantee since the mid-1990s, who has been studying hormonal controlled apoptosis in ovarian follicles leading to follicular atresia and ultimately menopause. Dr. Tilly is currently the Director of the Vincent Center for Reproductive Biology and Chief of the Division of Research, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, as well as Associate Professor of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical School.
A basic doctrine of reproductive biology has been that females of most mammalian species, including mice and humans, lose the capacity for germ cell renewal during fetal development. As such, a finite reserve of oocytes enclosed within granulosa cells as follicles is endowed shortly after birth, and it is from this reserve that the entire reproductive needs of the female must be met. However, with support from the NIA (R01-AG12279), Dr. Tilly and his research associates provided several lines of evidence from studies in mice that challenge the validity of this dogma (Nature 2004 428: 145-150). In these experiments, Dr. Tilly showed that both germ cell mitosis and germ cell meiosis persist in juvenile and adult mouse ovaries, and that these proliferative germ cells are required to routinely renew the follicle pool. He found that treatment of prepubertal female mice with busulfan, an agent known to cause spermatogenic failure by specifically targeting germline stem cells (GSCs) in the testis, was shown to eliminate the primordial follicle reserve within 3 weeks in the absence of cytotoxic actions on the existing primordial follicle pool or increased primordial follicle growth activation. Dr. Tilly further showed that wild-type adult ovaries grafted into transgenic female mice with ubiquitous expression of green fluorescent protein (GFP) form hybrid follicles consisting of GFP-positive oocytes surrounded by wild-type granulosa cells. From these investigations, Dr. Tilly concluded that female mice, like females of less-evolved species, retain GSCs that replenish the oocyte pool during postnatal life. Results from as-yet unpublished studies from the Tilly laboratory indicate that significant progress has been made in isolating pre-meiotic germ lineage cells from the postnatal mouse ovary that are currently being evaluated as candidate GSCs. Furthermore, using both pharmacological and gene knockout approaches, Dr. Tilly has already generated mouse models in which the postnatal oocyte pool can be expanded in the absence of a change in the incidence of atresia, suggesting that GSC-driven oocyte production can be enhanced by various approaches. Finally, Dr. Tilly presented evidence that oocyte and follicle production occur in the adult primate ovary, collectively supporting the contention that GSC-based technologies may represent a novel and exciting new strategy to combat female infertility and ovarian failure. Given that depletion of the oocyte-containing follicle pool heralds the onset of the menopausal transition in women, future studies with adult female germline stem cells may open a number of new possibilities for sustaining ovarian function, and thus improving the health and well-being of women as they age.
A question about the possibility of applying this technology to prolong the period of fertile lifespan for women prompted Dr. Tilly to distinguish between application of this technology for fertility versus quality of life during menopause. If this technology could be further developed, he envisioned that it could be useful for a short prolongation of fertile lifespan, i.e., among the 40-something group. Mouse studies from the late 1990s suggest that simply sustaining ovarian function is not sufficient to ensure pregnancy; ovaries can continue to function while the animals age, but the animals cannot become pregnant by natural means. However, the application of the technology for other purposes such as improving quality of life is a real possibility for older women.
Further discussion centered on whether there were any compensating effects or tradeoffs (e.g., more rapid aging or more rapid decline in functioning) as a result of producing more oocytes in vivo. Although the answer remains uncertain, Dr. Tilly reported evidence from animal studies suggesting that changes in the rate of atresia can have long term implications. When his team knocked out a gene (Bax) that essentially slows depletion of the oocyte pool, it was associated as well with preventing an age-related decline in germ stem cell numbers in the ovary, contributing further to a prolongation of ovarian function (Perez et al., Nature Genetics, 1999, 21 (2): 200-3). Further investigation found that while fertility among wild-type mice tended to plummet as they age, the knockouts had very poor fertility in young adult life and then achieved 90+ percent fertility at 8 or 9 months of age. An intriguing question is whether this shifting of the entire fertile life period among the knockouts is associated with changes in the quality of the oocyte pool.
Continuing along this line of research, Dr. Tilly’s team has been studying aging in mice, having completed an examination of bone density, lean body mass, fat deposition, cataracts, sensory perception, and other factors. Dr. Tilly concluded that the ovaries do convey a very significant health advantage to females as they age, at least in the female mouse model, and the issue is not necessarily fertility so much as sustaining ovarian function and postponing menopause.
B. Neuroscience and Neuropsychology of Aging: Discovery, Physiological Function, and Pharmacological Potential of GDNF Family Ligands (GFL) Neurotrophic Factors
Dr. Brad Wise introduced Dr. Gene Johnson, an NIA Council member and Professor in the Departments of Neurology and of Molecular Biology & Pharmacology at Washington University in Saint Louis. He is a co-director of the Alzheimer’s Disease Research Center at Washington University and is an NIA MERIT awardee. Dr. Johnson’s work has focused on the role of neurotrophic factors in the nervous system, particularly the function of nerve growth factor and the mechanisms controlling neuronal cell death.
In carrying out experiments to determine the ability of two proteins to inhibit neuronal death, Dr. Johnson’s team observed that such an activity was produced by Chinese hamster ovary (CHO) cells, a commonly used cell line. This activity was traced to a protein that was then purified from CHO-conditioned media, partially microsequenced and the cDNA sequence determined. This novel protein, which was named neurturin, was found to be similar to Glial-cell line-derived, neurotrophic factor (GDNF). This discovery defined a new sub-family of neurotrophic factors related to transforming growth factor (TGF) β superfamily. Subsequently, two additional family members were discovered (artemin and persephin) using genetic approaches. The receptors for the factors consist of the signal transducing tyrosine kinase, Ret, in association with GPI-linked binding co-receptors (GFRα1-4) selective for each of the four members of the family. The family of factors became known as the GFLs. One or more of these factors were found to act on a variety of neuronal types including certain CNS neurons (dopaminergic, cholinergic, motor), and sympathetic, parasympathetic and enteric neurons in the periphery.
Null animals were generated for neurturin, artemin, and persephin, and the associated GFRαs. Phenotypes of the ligand knockout and co-receptor knockouts were virtually identical indicating precise pairing in the physiological setting. Neurturin (or GFRα2) animals show atrophy and hypofunction of the parasympathetic neurons, enteric neurons, and subsets of sensory neurons (i.e., neurturin is required for the functions of these populations in the adult animal). Artemin (or GFRα3) knockout animals show migration and axon guidance defects in the sympathetic nervous system, which leads to hypoinnervation of several organs. Persephin (or GFRα4) animals show no phenotype under normal conditions, despite extensive analysis. However, work by other researchers has shown that these animals are extremely sensitive to CNS damage in response to ischemic insults.
Neurotrophic factors are required to maintain neuronal function in adult animals. In addition, when administered pharmacologically, they are able to prevent or ameliorate damage caused by a variety of mechanical, toxic, or metabolic insults. Therefore they have been proposed as potential therapeutic agents. GFLs have been shown to be effective in several animal models, including those for Parkinson’s disease, neuropathic pain, diabetic neuropathy, Huntington’s disease, and drug addiction. The agents are in clinical development in Parkinson’s and in preclinical development for other indications. Although many hurdles remain, GFLs may prove of clinical utility in several neurodegenerative conditions.
In response to a question about why multiple ligands combine to the same receptor system, Dr. Johnson observed that one of the important physiological features of neurotrophins is its unique receptor organization. That is, the binding subunit is a GPI anchored protein, so it has a sugar linkage to the membrane, which allows molecules to be localized into what are termed “lipid rafts.” These are subdomains in the plasma membrane, which give it selective access to certain signal transducing molecules. GDNF (the alpha subunit) normally sits in the raft of a cell. When a ligand binds to the alpha it recruits Ret to the raft and gives it access to signal transducing mechanisms that are concentrated in the raft. One particularly important transducing mechanism is the src family of tyrosine kinases, which appears to be much more important for GFLs than it is, for example, with the nerve growth factor family.
C. Geriatrics and Clinical Gerontology: Mitochondrial Dysfunction in the Elderly and Possible Role in Insulin Resistance
Dr. Chhanda Dutta introduced Dr. Kitt Petersen, an assistant professor in the Department of Internal Medicine at Yale University School of Medicine. Dr. Petersen studies the mechanisms underlying insulin resistance, a major factor in the pathogenesis of type 2 diabetes, using nuclear magnetic resonance (NMR) spectroscopy. She presented results from recently published articles on the mechanism of insulin resistance in the elderly (Petersen et al., Science, 2003, 300: 1140-2) and in insulin-resistant offspring of patients with type 2 diabetes (Petersen et al., New Engl. J. Med., 2004, 350: 666-73).
Dr. Petersen’s team studied healthy, lean elderly (age: 70±2 years) and young (age: 27±2 years) subjects matched for: BMI (~25 kg/m2), fat mass (~28 kg) and activity. Proton magnetic resonance studies were performed to assess intramyocellular and intrahepatic triglyceride content and DEXA scanning to assess lean and fat mass. Hyperinsulinemic-euglycemic clamps, in combination with infusions of glucose, glycerol, and microdialysis measurements of glycerol release in subcutaneous fat, were performed to assess insulin action in liver, muscle and fat. A novel NMR technique was used to noninvasively assess rates of mitochondrial oxidative and phosphorylation activity in muscle. Elderly subjects were markedly insulin resistant compared to the control subjects, which could be attributed to ~40 percent reduction (P<0.002 versus controls) in insulin stimulated muscle glucose metabolism. These changes were associated with ~45 percent increase in intramyocellular triglyceride content (P=0.035 versus control) and ~225 percent increase in intrahepatic triglyceride content (P=0.038 versus control). These increases in tissue triglyceride content were associated with ~40 percent reduction in both mitochondrial oxidative and phosphorylation activity (both P<0.004 versus control). There were no differences in basal or insulin suppression of systemic or localized rates of lipolysis. These results demonstrate that insulin resistance in the elderly is associated with a marked increase in both intramyocellular and intrahepatic triglyceride content which can be attributed to a 40 percent reduction in mitochondrial oxidative and phosphorylation activity.
Because insulin resistance is the best predictor for the development of diabetes in the offspring of parents with type 2 diabetes, Dr. Petersen’s team has also been studying healthy, young, lean 20-year-old college students who have one or two parents with type 2 diabetes. These offspring were age-height-weight-activity matched to insulin sensitive control subjects. Subjects underwent hyperinsulinemic-euglycemic clamps, in combination with infusions of glucose to assess liver and muscle insulin sensitivity. Proton magnetic resonance spectroscopy studies were performed to assess intramyocellular lipid and intrahepatic triglyceride content. Rates of whole body and subcutaneous fat lipolysis were assessed by measuring rates of glycerol turnover in combination with microdialysis measurements of glycerol release from subcutaneous fat. Magnetic resonance spectroscopy studies were performed to assess rates of mitochondrial oxidative and phosphorylation activities in muscle. Results showed that insulin stimulated muscle glucose uptake was approximately 60 percent lower (P<0.001 versus control) in the insulin resistant offspring than the insulin sensitive control subjects and was associated with an approximately 80 percent increase in intramyocellular lipid content (P=0.005 versus control). This increase in intramyocellular lipid content could be attributed to mitochondrial dysfunction as reflected by an approximately 30 percent reduction in both mitochondrial oxidative and phosphorylation activities (P=0.01 versus control) in muscle since there were no differences in systemic or localized rates of lipolysis or plasma concentrations of tumor necrosis factor α, interleukin-6, resistin, or adiponectin. These data support the hypothesis that insulin resistance in skeletal muscle of insulin resistant offspring is due to dysregulation of intramyocellular fatty acid metabolism due to an inherited defect in mitochondrial oxidative-phosphorylation activity.
Dr. Petersen concluded by describing her most recent studies in obesity and weight loss. In this case it is not the mitochondria but an overload of the fat cells and an increase in the delivery of fat to the muscle cell overwhelming the ability to oxidize fat. Fat accumulates, causing insulin resistance. In studies conducted with the NIH involving patients with lipodystrophy, who effectively have no fat cells, a substantial amount of fat enters muscle and the liver, causing insulin resistance associated with very early onset of type 2 diabetes in these populations.
In summary, with aging, individuals appear to acquire a mitochondrial defect that inhibits the ability to oxidize substrates. As a result, fat will accumulate in the muscle, accounting for the insulin resistance associated with aging. Insulin-resistant offspring of parents with diabetes have an inherited defect in mitochondrial number. Some of the most recent studies have been examining the factors responsible for regulating mitochondrial biogenesis, and these factors are nuclearly encoded.
In response to a question about changes in mitochondrial function or other parameters in the presence of physical activity, Dr. Petersen clarified that both of the presented studies were conducted in sedentary people. An earlier study (Perseghin, Price, Petersen et al., New Engl. J. Med., 1996, 335: 1357-62) demonstrated that insulin resistance can be reversed after a period of exercise training, and subsequent studies have shown fat to melt away from the muscle. Dr. Petersen’s team is currently studying two groups of older subjects aged 65-70, one moderately active (four to eight miles per day of different activities, including aerobic exercise such as walking or running) and the other engaged in more strenuous activities (e.g., marathon running) to examine the effects of more extreme forms of exercise. Her team is concurrently studying aging rats, and measuring AMP kinase activity and the number of mitochrondria in them. Unfortunately, there may be an age-related inability to stimulate the factors that produce more mitochondria.
D. Behavioral and Social Research: Hospice Care, the Widower Effect, and Social Networks at the End of Life
Dr. Richard Suzman introduced Dr. Nicholas Christakis, Professor of Medical Sociology at Harvard Medical School. Trained as both a physician and a sociologist, Dr. Christakis has melded demographic and health services research methods to conduct a series of interrelated projects on hospice care, the “widower effect,” and inter-individual health effects near the end of life.
In setting the context for his research, Dr. Christakis observed that 40-70 percent of Americans die in pain. Over 80 percent die in institutions rather than at home as many prefer, and 25-55 percent significantly burden family caregivers near the end of life. Hospice care has been put forward as one possible clinical and policy response to the poor quality of end-of-life care in our society. Over 80 percent of hospice care in the United States is reimbursed under Medicare at a cost of over $2 billion per year.
Dr. Christakis’ initial work documented the short median length of stay, roughly 3-4 weeks, in various inception cohorts of patients admitted to hospices in the 1990s. Initial interest was directed at understanding the timing of hospice referral, followed by the development of a national sample of 184,843 hospice patients newly admitted to hospices throughout the US in 1993. Pertinent variations in the role of individual, provider, and market factors in the timing of hospice use prompted a broader look beyond numerator-based samples of hospice users, to encompass denominator-based samples of seriously ill patients at risk of hospice. Using raw Medicare claims, another data set was developed consisting of 1,343,295 patients newly diagnosed with one of 13 serious illnesses in 1993 and followed until 1999. With these data, Dr. Christakis and his team were among the first to document diagnostic variation in the probability of hospice use and to explore a variety of individual-level, provider-level, and market-level factors that influenced whether and when hospice is used. Small area variation in hospice use showed that, in some counties in the US, 40 percent of all decedents use hospice care whereas, in others, fewer than 2 percent of decedents use hospice. Even after adjusting for individual-level attributes of people residing within those counties, variation persisted across counties in the probability of hospice use. The probability of hospice use was not explained by a number of standard health care market attributes, including number of hospitals or doctors per capita.
In addition to exploring determinants of whether and when hospice is used, Dr. Christakis has also explored the consequences of hospice use through a set of studies on how hospice use by a decedent affects the health of the surviving spouse. Analyses of data on a cohort of 200,000 couples show that hospice use by a decedent meaningfully reduces the risk of the survivor dying during bereavement. For example, wives of men who died without hospice care had a 6.2 percent risk of dying by 18 months after their husband’s death whereas wives of men who died with hospice care had a 4.9 percent risk of dying by 18 months after their husband's death. The unadjusted odds ratio was 0.78 and the adjusted odds ratio was 0.92 in favor of hospice use.
These findings on the impact of hospice use on spouses of patients raise broader issues regarding health “externalities” that can arise as a result of a patient’s embedment in social networks. Health care delivered to one person can have substantial health implications for individuals to whom that person is connected. For example, hip replacement may allow a person to better care for a partner and reduce health care consumption or improve health in that partner. Similarly, a weight loss or smoking cessation intervention delivered to one individual may have multiplier effects in others to whom the person is connected.
Related research focuses on the “widower effect” in the elderly. Using new statistical techniques that control for the problem of endogeneity, Dr. Christakis documents the variation across time during bereavement in the excess mortality associated with bereavement, with peak risk periods occurring within the first six months and after the first year following bereavement.
Dr. Christakis concluded that end-of-life care (e.g., whether and when hospice is used) varies in discernible ways and that it is relevant to achieving patients' objectives regarding the end of their lives (e.g., for pain relief or home death). In addition, the type of health care delivered to patients may affect the health status of family members and thus the cost effectiveness and social value of medical interventions used near the end of life may need to be re-evaluated.
Discussion centered on sex differences in bereavement effects, specifically the prior literature suggesting that death of a partner is more deleterious for men than women. Dr. Christakis noted that prior work has not systematically examined the temporality of effects. It could be that some event has caused the death of both partners (e.g., years of exposure to radon, common smoking behavior, common obesity conditions) so that a death can be interpreted as a marker for shared health habits or environmental exposure. A related factor may be positive assortive mating on health where one can imagine the tendency of (un)healthy individuals to marry other (un)healthy individuals early in life, which can lead to mortality correlations later in life. The older age of the man relative to the women must also be considered. Dr. Christakis has controlled for these types of factors using a fixed effects model. The odds ratio of a man dying after the death of his wife goes up by 50 percent, but reaches a nadir around six months where the odds of death is increased by about 15 percent compared to other points in life, and then begins to rise again going out to about three years. He interpreted these results in a stress and social support framework. Loss of one’s wife increases the odds of death immediately, but is followed by a composite of two counteracting effects: (1) adaptation to the loss that returns the odds almost to baseline, and (2) loss of social support. Similar patterns are seen for both men and women, which contrast with the previous literature that has shown a difference in effect between men and women.
This portion of the meeting was closed to the public, in accordance with the determination that it concerned matters exempt from mandatory disclosure under Sections 552b(c)(4) and 552b(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix).2
A total of 1,060 applications requesting $1,007,423,464 for all years underwent initial review. Council recommended 711 for a total of $716,501,050 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.
The 92nd meeting of the National Advisory Council on Aging was adjourned at 12:45 p.m. on May 25, 2004. Dr. Hodes closed the Council session by thanking all speakers and the Council members for their participation. The next meeting is scheduled for September 22-23, 2004.
I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete. 3
______________________________________ Richard J. Hodes, M.D. Chairman, National Advisory Council on Aging Director, National Institute on Aging
Prepared by Miriam F. Kelty, Ph.D. with the assistance of Rose Li and Associates, Inc.
MEMBERSHIP ROSTERNATIONAL ADVISORY COUNCIL ON AGING NATIONAL INSTITUTE ON AGING (Terms end December 31)
Chairperson
Richard J. Hodes , M.D. Director, National Institute on Aging National Institutes of Health Bethesda , MD
Marie A. Bernard , M.D. (2005) Donald W. Reynolds Chair Department of Geriatric Medicine University of Oklahoma College of Medicine Oklahoma City , OK
Elizabeth H. Blackburn , Ph.D. (2006) Professor Dept of Biochemistry & Biophysics University of California San Francisco , CA
Melissa M. Brown , M.D. (2006) Director Center for Value-Based Medicine Flourtown , PA
John T. Cacioppo , Ph.D. (2007) Blake Distinguished Service Professor Department of Psychology University of Chicago and Institute for Mind & Biology Chicago, IL
*David V. Espino , M.D. (2004) Professor and Vice Chair Dept. of Family & Community Medicine Division of Community Geriatrics University of Texas Health Science Center San Antonio , TX
Linda P. Fried , M.D., MPH (2006) Professor, Medicine, Epidemiology & Health Policy Director, Division of Geriatric Medicine & Gerontology Director, Center on Aging and Health The Johns Hopkins Medical Institutions Baltimore , MD
Alan M. Garber , M.D., MPH (2007) Director Center for primary Care and Outcomes Research Center for Health Policy Standford University Standford, CA
F. Michael Gloth , III , M.D., (2005) President Victory Springs Senior Health Care Reisterstown , MD
*Eugene M. Johnson, Jr. , Ph.D. (2005) Norman J. Stupp Professor, Department of Neurology Professor, Dept. of Molecular Biology & Pharmacology Co-Director, Alzheimer's Disease Research Center Washington University School of Medicine St. Louis , MO
*Lewis H. Kuller , M.D., DrPH, MPH (2004) University Professor of Public Health Professor of Epidemiology Department of Epidemiology University of Pittsburgh Graduate School of Public Health Pittsburgh , PA
Ronald D. Lee , Ph.D. (2005) Professor, Department of Demography College of Letters and Science University of California Berkeley , CA
Virginia M.-Y. Lee , Ph.D. (2007) Professor Dept of Pathology & Laboratory Medicine University of Pennsylvania School of Medicine Philadelphia, PA
Spero M. Manson , Ph.D. (2006) Professor of Psychiatry and Head American Indian & Alaska Native Programs University of Colorado Health Sciences Ctr Aurora , CO
Peter W. Nauert, J.D. (2005) Principal Insurance Capital Management Chicago , IL
Stanley B. Prusiner , M.D. (2004) Director and Professor Institute for Neurodegenerative Diseases School of Medicine University of California San Francisco , CA
*Judith A. Riggs , M.A. (2004) Washington , DC
Leon J. Thal , M.D. (2005) Professor and Chair Department of Neurosciences University of California San Diego School of Medicine (and Staff Physician, Neurology Service,
San Diego Veterans Medical) La Jolla , CA
*WGoP Member
Tommy G. Thompson Secretary Department of Health and Human Services Hubert H. Humphrey Building Washington , D.C.
Elias Zerhouni , M.D. Director National Institutes of Health Public Health Service Bethesda, Maryland
James F. Burris , M.D. Deputy Chief Research & Development Officer Office of Research and Development Department of Veterans Affairs Washington, D.C.
John Wren Director, Office of Program Development Administration on Aging, DHHS Washington , D.C.
[ 1 ], [ 2 ] For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions, or (b) in which a conflict of interest may have occurred. This procedure only applied to applications that were discussed individually, not to "en bloc" actions.
[ 3 ] These minutes will be approved formally by the Council at the next meeting on September 22-23, 2004, and corrections or notations will be stated in the minutes of that meeting.
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