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Council Minutes - May 2006

The 98th Meeting
May 23–24, 2006

CONTENTS

  1. REVIEW OF APPLICATIONS
  2. CALL TO ORDER
  3. REPORT: TASK FORCE ON MINORITY AGING RESEARCH
  4. REPORT: WORKING GROUP ON PROGRAM
  5. PRESENTATION: NIH ROADMAP
  6. PRESENTATION: NIH AT THE CROSSROADS
  7. PROGRAM HIGHLIGHTS
  8. ADJOURNMENT
  9. CERTIFICATION

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

The 98th meeting of the National Advisory Council on Aging was convened on Tuesday, May 23, 2006, at 3:00 p.m. in Building 31, Conference Room 6, National Institutes of Health (NIH), Bethesda, MD. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA), presided.

In accordance with the provisions of Public Law 92–463, the meeting was closed to the public on Tuesday, May 23, from 3:00 p.m. to 5:00 p.m. for the review, discussion, and evaluation of grant applications in accordance with the provisions set forth in Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code and Section 10(d) of Public Law 92–463.2

A total of 1,217 applications requesting $1,184,753,172 for all years underwent initial review. The Council recommended 642 awards for a total of $798,667,943 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.

II. CALL TO ORDER

Dr. Hodes welcomed members to the open session of the National Advisory Council on Aging and called the meeting to order at 8:45 a.m. on Wednesday, May 24, 2006.

A. Director’s Status Report

Dr. Hodes presented the total budget for the NIA, in both current and constant dollars, for fiscal years (FY) 1996 to 2006. The NIA appropriation level for 2006 is $1,037,278,000, of which 67 percent is devoted to research project grants, 10 percent to intramural research, 8 percent to centers, 6 percent to contracts, 4 percent to research management and support, 3 percent to other research, and 2 percent to training, The budget peaked in FY 2003, has declined in constant dollars every year since then, and appears to be at risk of decreasing again in FY 2007.

NIA grant application success rates from FY 1996 to 2003 fluctuated between 26.2 and 33.8 percent. Success rates were relatively insensitive to increases in budget during this period. However, in FY 2004, the success rate decreased to 20.8 percent from 28.6 percent in FY 2003. The drop was attributed mainly to a 40-percent increase in new and competing applications during the year and secondarily to the increasing average size of awards during a period with no imposed limits on average costs. This circumstance was different in FY 2005 when average costs were artificially suppressed in response to pressure on the success rate. Since then, the average cost of NIH grants has been constrained by legislative policy. The success rate dropped to 18.8 percent in 2005 and is estimated to be 17.9 percent for 2006.

Dr. Hodes reviewed NIA’s Financial Policy for Grant Awards. In order to reach approximately the 15th percentile in FY2005, NIA has been imposing an average reduction to competing grants of 18 percent below reviewer-recommended funding levels. Reductions for other non-research project grant (RPG) mechanisms are negotiated on a case-by-case basis. Overall, the number of RPGs or grants supported has increased with the NIH budget, from 27,621 in FY 1998 to 32,720 in FY 2005, reflecting a 35-percent increase. Despite the decline in success rates, the NIH expects to make approximately 9,337 new RPG awards in FY 2007, an increase of 275 from the number of new awards in FY 2006. Approximately 90 percent of RPG competing awards originate as unsolicited applications. Success rates are lower for applications submitted in response to a Request for Applications (RFA). The success rate for unsolicited, competing applications fell from a high of 32 percent at the height of the budget doubling, to 18.9 percent during FY 2005.

Discussion ensued about the budget and application trajectories beyond FY 2006, and implications of declining success rates. Council members expressed concern about issues such as maintaining the work force to take advantage of scientific opportunities and the retention of new investigators. According to Dr. Hodes, how long the constraint on average costs will continue has been a topic of discussion among NIH Institute and Center Directors. The concern is that artificially suppressing average costs in the face of 4- to 5-percent annual inflation ultimately will compromise research progress, lead to more modest expectations and applications, and encourage the manipulation of funding mechanisms to reach artificial targets that are not in the best interest of science.

One Council member inquired about the competitiveness of U.S. biomedical research in comparison to other nations, for example in terms of dominance in journal publications.
Dr. Hodes responded that the U.S. share of biomedical research support is decreasing, although it is difficult to determine the optimal level of U.S. investment. He recognized that NIA research investment ought to have highly leveraged payoff in terms of spending for Social Security, Medicare, and Medicaid, and that this aspect is raised frequently. Another Council member relayed an increasing urgency to accelerate research to improve the health of older adults and, in turn, meet the growing challenges of an aging population.
In response to a question about the NIA budget by funding mechanism in the Director’s Status Report to Council, Dr. Hodes and NIA staff clarified that numbers of awards refer to new awards or competitive renewals and do not include noncompeting continuation awards. In the case of minority biomedical research support, no awards are posted, but the dollar amounts shown reflect NIA cofunding toward a program administered by the National Institute of General Medical Sciences. It was suggested that future tables be annotated to reflect these clarifications.

Dr. Hodes circulated for Council information a compendium of last quarter’s public outreach activities of the Office of Communication and Public Liaison.

B. Future Meeting Dates

September 26–27, 2006 (Tuesday and Wednesday)
January 30–31, 2007 (Tuesday and Wednesday)
May 15–16, 2007 (Tuesday and Wednesday)
September 25–26, 2007 (Tuesday and Wednesday)

C. Consideration of the Minutes of Last Meeting

The minutes of the January 2006 meeting were considered. A motion was made, seconded, and passed to approve the minutes.

REPORT: TASK FORCE ON MINORITY AGING RESEARCH

Dr. Taylor Harden, Assistant to the Director for Special Populations, summarized the meeting of the Task Force on Minority Aging Research that was held on May 23. Dr. Harden reviewed the areas in which NIA has been concentrating efforts to address disparities in terms of minority health and underscored renewed efforts to improve recruitment and retention of minorities in clinical research. In FY 2004 and 2005, NIA reported approximately 600,000 minority participants in clinical research, about 70 percent of whom were White. In 2006, the Task Force conducted a review and concluded that NIA is making a difference in terms of methods and practices used in the recruitment and retention of minority elders in aging research. This success was attributed in part to the efforts of the Resource Centers on Minority Aging Research and their partnering with many other NIA-supported centers, such as the Alzheimer’s Disease, Pepper, and Roybal Centers.

Dr. Harden next summarized the presentation by Dr. Diane Brown, Executive Director of the Institute for the Elimination of Health Disparities at the University of Medicine and Dentistry of New Jersey, an invited guest to the Task Force meeting who spoke on emerging knowledge about the factors that can impact recruitment and retention of minorities in clinical research. The Task Force discussed issues related to incentives, including timing, adequacy, coerciveness, and differential efficacy by subpopulation in terms of response rate. Continuing challenges include the need to (1) develop evidence-based recruitment and retention models and theoretical frameworks, (2) develop analytical studies and evaluate recruitment as a planned part of research, (3) recruit minority and diverse investigators, (4) determine inclusion and exclusion criteria related to multiple morbidities that can disqualify members of certain groups disproportionately, (5) research the recruitment and inclusion of “old-old” (aged 85+) participants outside of caregiving studies, and (6) include older male minority research participants.

In conjunction with NIA and the greater community, the Task Force intends to organize a workshop to explore further the issue of incentives, as well as the concept of navigators to help people through the network of potential research projects at any one clinical site. Dr. Harden pointed to the “Outreach Notebook for the Inclusion, Recruitment, and Retention of Women and Minorities Subjects in Clinical Research,” which NIA had a leadership role in developing in 2003 on behalf of the NIH. NIA intends to build on this toolkit and perhaps adapt it for use by the community of scientists in aging research. The Task Force also is exploring the possibility of an express award to evaluate this body of literature to distill best practices.

Council members raised a number of issues about the need for the workshop and its planned products. The express evaluation award will go some way towards addressing these concerns.

A motion was made to defer consideration of the workshop until the September 2006 meeting so that NIA staff can prepare a more detailed plan for the workshop incorporating the express evaluation proposal.

REPORT: WORKING GROUP ON PROGRAM

In reporting on deliberations of the Working Group on Program (WGOP), which met on May 23, 2006, Dr. Linda Fried began with a discussion of whether new training/career development programs are needed. This topic extends from an ongoing discussion presented at the January 2006 Council meeting, reflecting concerns about the relative dearth of physicians conducting aging research despite several innovations that the NIH and/or NIA has implemented. With the support of NIA leadership and others, a workshop was held three years ago that identified a number of areas where interventions could be potentially effective. There was consensus to continue to track at the WGOP level the effectiveness of these interventions and determine whether other interventions are needed to ensure an adequate science workforce to address the needs of the aging population.

The WGOP also reviewed data that Dr. Robin Barr had compiled to show the different grant mechanisms available throughout an investigator’s career, that is, mechanisms for predoctoral candidates, postdoctoral candidates, and junior faculty, and by Ph.D., M.D., or Ph.D./M.D. track. Many of these programs are new; therefore, their effects on the number and quality of physician investigators are not yet known. The NIA Web site will be revised to reflect the grant mechanisms available along the career trajectory. Dr. Barr will develop a profile of new R01 investigators. The WGOP established a career development working group that includes Drs. Kenneth Brummel-Smith, Albert Siu, Mary Ganguli, and Melissa Brown, which planned to meet by teleconference before the next Council meeting, to consider the role of physician investigators in clinical research, the important clinical issues that physician investigators need to address, and whether these issues are being addressed adequately. Dr. Fried invited recommendations for other areas of focus.

A.  Advisory Meetings, Conferences, and Workshops

Unexplained Anemia in the Elderly
The Geriatrics and Clinical Gerontology Program is planning an advisory workshop on unexplained anemia in the elderly and opportunities for clinical trials. Epidemiological data show that unexplained anemia in older people accounts for about one-third of all cases of anemia and is associated with increases in mortality, morbidity, falls with injuries, and decreased quality of life. The first day of the two-day workshop, to be held October 5 and 6, 2006, will be dedicated to a review of issues related to etiology, pathogenesis, current state of science in unexplained anemia, and available treatment options. In the second day, the group will review designs for a possible future clinical trial, outcome measures, and statistical implications.

Data Review Committee
The NACA review of the Behavioral and Social Research (BSR) program in 2004 recommended that NIA appoint a special group to undertake a more detailed view of BSR’s investment in social and behavioral data collection to inform the next decade of investments. The BSR Data Review Committee is chaired by Dr. Lisa Berkman, a social epidemiologist at Harvard University, and Dr. James Smith, an economist at the RAND Corporation. The committee includes former and current Council members, some of whom are familiar with the BSR portfolio, and some with fresh perspectives. The first committee meeting is scheduled for September 19 and 20, 2006, to be followed by a series of teleconferences and possibly a second meeting, with a report expected in 2007.

A motion was made, seconded, and passed unanimously to approve the two advisory workshops as recommended by the WGOP.

B.  RFA Concept Clearance

Three requests for RFA concept clearance were presented, all of which were recommended for approval by the WGOP, and approved unanimously by Council voice vote.

Thrombosis and Hemostasis in the Elderly
Dr. Susan Nayfield presented for concept clearance an RFA soliciting R21 and smaller R01 applications focused on thrombosis and hemostasis in older patients. A total of $1.5 million per year for four years has been set aside. Disruption of the clotting system leads to problems such as venus thrombosis and pulmonary embolisms, arterial thrombosis, atherosclerosis, acute coronary syndrome, and myocardial infarction. Clotting systems and advances in this area were addressed by a State-of-the-Art Symposium held by the American Society of Hematology in April 2005. Experts from this group will meet in June 2006 to develop a research agenda on thrombosis and hemostasis in the elderly, in collaboration with NIA and the National Heart, Lung, and Blood Institute. There was overall enthusiasm for this topic and WGOP discussion about the appropriate scope for an RFA.

Neuroeconomics of Aging
Dr. Lis Nielsen presented for concept clearance an RFA proposal to solicit R21 exploratory developmental applications in neuroeconomics with particular relevance to aging. The RFA will focus on both the social and psychological processes, and the neurobiological mechanisms of economics behavior that are of particular relevance to the well-being of middle aged and older adults in terms of savings behavior, health insurance decisions, health choices, and social influences on these types of decisions.

Membrane-Associated Signaling Defects in Immune Cells with Aging
Dr. Rebecca Fuldner presented for concept clearance an initiative to apply various biophysical techniques to examine the role of plasma membrane microdomains in impaired signal transduction in aged T-lymphocytes. The Biology of Aging program convened a workshop this past fall that brought together experts in various biophysical techniques to discuss how these could be applied to understand and define how the plasma membrane changes with age, which is important to the immune system but also has relevance to other cell types from different tissues where signaling efficiency tends to decrease with cellular aging. NIA seeks to fund approximately six to seven R21 developmental and exploratory projects in 2007 via this RFA.

C.  NACA’s Role in Recent Policy Debate Concerning NIH Initiatives and Planning

Dr. Fried turned next to a topic that was not discussed fully during the WGOP meeting for lack of time. As background, the Council has responsibility for shaping the research agenda by identifying issues that are of highest priority. Council members have expressed interest in contributing to NIA on a broader level in terms of considering directions for aging research and societal needs. A scarcity of funds has heightened awareness of the need to communicate the importance of the Nation’s investment in biomedical research to the public, bringing consideration of future directions into sharper focus.

The WGOP has requested that NIA program staff develop talks for future NACA meetings that will help communicate where and why research is absolutely critical to the health of an aging society. The WGOP also charged NIA leadership with considering the development of partnerships to facilitate Council understanding of how public awareness of aging research can be enhanced. Three proposed activities were mentioned: (1) Solicit input from Friends of NIA in terms of its research agenda, (2) consider a workshop with representatives from top pharmaceutical companies (“Big Pharma”) on what they see as the most pertinent problems to be addressed, (3) consider partnering with the American Association of Retired Persons (AARP) to champion healthy aging and improve the mutual understanding about the heterogeneity of health status needs and relevant issues.

Council members echoed the concern of the WGOP about the mismatch between research needs and the current funding climate, particularly in light of the increasing number of grant applications. Council members also sought an appropriate role for addressing this issue, if any. They were keenly aware that the needs of the country are not being served. Examples of how basic research is cost-effective in terms of reducing health burdens would be very helpful. Others underscored that older people are healthy and productive and represent one of the greatest resources in this country. One Council member stated that any media blitz that underscores the need to support research should include the issue of participation in research. Strategic partnerships with the insurance industry also could be pursued.

Dr. Hodes clarified the distinction between advocacy and education. Council members can participate in activities that include advocacy but not as a part of Council activities. A presentation from the recently reformed, re-energized Friends of the NIA may be helpful to Council, and presentations by the NIA Office of Communications and Public Liaison (OCPL) and the AARP official responsible for health education may help to facilitate discussion about appropriate public education and outreach efforts that Council members could undertake. It is appropriate for Council members to provide feedback to programs and the OCPL on the products of NIA communication.

PRESENTATION: NIH Roadmap – Re-engineering the Clinical Research Enterprise

Dr. Robert Star, Senior Scientific Advisor, National Institute of Diabetes and Digestive and Kidney Diseases, works on clinical research issues for the NIH Roadmap, and co-chairs the Trans-NIH Clinical Research Workforce Committee. Dr. Star acknowledged the earlier efforts of Dr. Lawrence Friedman (now an NIA Council member), as well as Dr. Judith Salerno, Dr. Robin Barr, Dr. Neil Buckholtz, and Dr. Evan Hadley. After a brief introduction about the NIH Roadmap, he highlighted a few of the activities he considered relevant to NIA.

The idea of the NIH Roadmap is to speed the translation of basic and clinical discoveries into clinical practice and explicitly to address roadblocks that slow the pace of medical research in improving the health of the U.S. population. Today, the United States is faced with the urgency of an aging population, emerging infections, as well as chronic conditions. The NIH Roadmap is a vision for a more efficient, innovative, and productive system of biomedical and behavioral research. It has launched a set of initiatives that addresses a number of challenges in the area of clinical research, including the recruitment and retention of clinical researchers, regulatory burdens that are increasingly difficult to surmount, and budget cuts that undermine earlier infrastructure investments.

The vision for a new strategic plan for biomedical research was developed with input from more than 300 scientists from around the country. By prioritizing the input received into those that were the most transforming, the most critical to undertake, and that required trans-Institute collaboration, the NIH Roadmap provided a framework of priorities that the NIH as a whole must address in order to optimize its entire research portfolio. The Roadmap also can be viewed as an incubator space for compelling new ideas.

Dr. Star related from personal experience his traversing the “valley of death” to get from proof of concept to compound in the clinic. The Roadmap established an important bridge, the NIH Rapid Access to Investigational Drugs, by providing a competitive process for accessing resources for the preclinical development of small-molecule therapeutics. These resources include advice on how to effect the translation, formulate an agent, assay an agent, and assess toxicology—all preliminary steps that are needed to excite the venture capitalists, the biotechnology companies, and industry. Intellectual property and project controls remain with the originating institution and investigator.

Another project, Patient-Reported Outcomes Measurement Information System (PROMIS), seeks to take self-reported outcome measures or scales (e.g., for chronic pain, fatigue, anxiety, depression) and apply them in the design of clinical trials across an entire range of diseases. PROMIS uses computerized, adaptive testing technology to administer “tailored” questionnaires that measure a patient’s self-reported health status across a wide range of chronic diseases. Item banks and scores will be validated across patient conditions and then distributed to the research community. For example, the test, Quality of Life Outcomes in Neurological Diseases, was developed for children and adults with major neurological conditions and may help Alzheimer’s disease patients in assessing neurological and behavioral functions. PROMIS is noteworthy because it has become self-sustaining and is no longer reliant on NIH Roadmap funds.

Dr. Star next described a project to integrate clinical research networks and informatics, an interoperable “network of networks,” to enable the generation of new research hypotheses, rapid scaling-up of trials over a shorter period of time, and harmonization of data, as well as to ensure that patients, physicians, and scientists form true “communities of research” to accelerate translation. As part of this effort, the NIH summarized the practices of about 150 clinical networks to identify best practices that will be presented at a national meeting to be held May 31 through June 1, 2006. Dr. Star reported on a number of pilot informatics projects designed to expand or merge existing networks across medical disciplines, settings, ages, and locations.

After describing the tools and some of the infrastructure of the networks, Dr. Star turned next to training because an entire new generation of researchers and specialists must be recruited to support future clinical research projects, including clinicians, basic scientists, pharmacologists, medicinal chemists, imaging specialists, biostatisticians, engineers, and technology transfer and regulatory affairs specialists. A new training model requires that specialists learn to work together in teams, to lead teams, and to bridge cultures. Each member of a team must have a viable career path to enhance retention. This critical aspect has been difficult because of the demands of clinical care, the culture of academic health centers, and the lack of an intellectual “home” that provides stature and promotion or tenure potential. The NIH Roadmap seeks to develop a national cadre of well-trained clinical investigators and team members, and to integrate clinical research training and career development programs across an institution. The Roadmap supported several pilot projects toward this end, including ten Predoctoral Clinical Research Training Programs (T32) aimed at medical, dental, and nursing students, to form a viable pipeline of people drawn to clinical research by coursework, seminar series, and summer experiences.

The next challenge was to develop a multidisciplinary career development program (K12) that would allow institutions sufficient funds to train individuals in multidisciplinary clinical research. Twelve sites were funded in response to two RFAs to provide formal training in standard clinical research methods, including proteomics, genomics, regulatory requirements, clinical trial design, and biostatistics, as well as training in becoming a team member and a team leader. In the second year of the program, scholars will become affiliated with a project and, through several mentors, will start a research project that will provide preliminary data for writing a grant application. Funds can be requested for pilot and feasibility projects, as well as for access to shared resources such as biostatistical and study coordination help, etc. The 12 sites are being run as a national program with monthly phone calls and in-person meetings once or twice a year to share their practices. Innovative approaches to teaching clinical research have resulted from this endeavor, and a position paper is being prepared on the topic. Many of the projects being undertaken by the scholars concern topics of interest to NIA, such as dementia.

Single training programs are not sufficient to effect the necessary culture changes at institutions. The NIH Institutional Clinical and Translational Science Awards (CTSA) were developed to provide the academic home and integrated resources needed to advance the new intellectual discipline of clinical and translational sciences; create and nurture a cadre of well-trained investigators; encourage partnerships with industry, foundations, and community physicians; and advance the health of the Nation by transforming patient observations and basic discovery research into clinical practice. The idea was to lower the barrier between disciplines and to encourage institutions to develop their own plans for what makes sense locally to catalyze change within their own institutions. The process of writing CTSA applications already has had an effect on institutional cultures and has focused attention on building from the ground up based on needs. For example, many of the NIH’s previous training programs only allowed for the training of M.D.s or dentists. Now an institution is free to propose training for study coordinators or project managers. CTSA applications will be reviewed soon, and the process is expected to yield results in five or six years.

Discussion ensued about the necessary cultural shifts at the NIH in terms of how multi- or interdisciplinary training and research grant applications are reviewed. The multiple Principal Investigator (PI) initiative was designed to stimulate collaboration by multiple investigators on team science efforts. Recognizing multiple PIs means there must be a leadership plan included in the application to indicate how the team will function and how resources will be allocated if the team were to dissolve. The NIH also has begun to consider alternate approaches to reviewing inter- and/or multidisciplinary projects, including supplementing existing review groups with additional expertise, holding telephone reviews, and introducing five-page applications where applicants are required to communicate their research plan succinctly to a diverse audience. There is recognition that the NIH review must adapt to new research demands.

In terms of training, the emphasis seems to have been on physician-scientist training. One Council member asked whether more attention should be given to training Ph.D. scientists in medicine. Dr. Star noted that there has been no shortage of applicants to the K12 program and that roughly ten percent of selected scholars hold Ph.D.s. A rigorous evaluation of the K12 program is planned to track scholar retention in clinical research.

Although more CTSA applications were submitted than expected, Dr. Star acknowledged initial concerns about finding suitable PIs to lead CTSA grants, which is seen as a huge experiment. As a result, the NIH set out to fund 50 planning grants for institutions that needed more time to develop their leadership and execution plans. One Council member suggested that the NIH organize leadership training for CTSA directors rather than leaving it entirely up to academic health centers.

PRESENTATION: NIH at the Crossroads—Myths, Realities, and Strategies for the Future

Dr. Elias Zerhouni, Director, NIH, began his presentation by thanking Council members for their participation. He noted that more than 31,000 scientists come to the NIH every year as members of advisory councils, boards of scientific advisers, and peer reviewers. He also recognized
Dr. Hodes as an institutional leader. Dr. Hodes serves as a member of the Steering Committee of the NIH, a structure created by Dr. Zerhouni to realize synergy across Institutes, especially in making strategic decisions during challenging times.

Many have described the NIH budget as facing a “perfect storm”—growing Federal and trade deficits, post-September 11th defense and Homeland Security needs, hurricane Katrina, and the $7.1 billion needed for preparing the country for a pandemic flu, in addition to ill-defined, post-doubling effects, a growing focus on physical sciences, and biomedical research inflation outstripping general inflation. Some have argued that the lack of sustained investment in science and education training is undermining U.S. competitiveness. Challenging times, which are cyclical, need to be considered in context, with attention to facts, and addressed with adaptive strategies.

Dr. Zerhouni dismissed the following three myths in explaining the reasons behind declining success rates:

  • Myth 1: The NIH is placing more emphasis on applied science as opposed to basic science. In recent years, the proportion of funding devoted to basic research has hovered around the 50-percent mark (55.8 percent in FY 2006), applied research around 40 percent, and other (e.g., infrastructure) around 3 percent.
  • Myth 2: The NIH has shifted toward solicited research (RFAs and Program Announcements) at the expense of unsolicited, investigator-initiated research. In FY 1995, about 9 percent of applications were solicited. In FY 2005, about 7 percent of applications were solicited. This proportion has remained consistently below 10 percent during the past decade.
  • Myth 3: The NIH Roadmap is to blame. In FY 2005, the Roadmap represented about 0.8 percent of the NIH budget ($237 million). By comparison, $27.5 billion went to non-Roadmap activities. The proportion of NIH funds devoted to the Roadmap is expected to stabilize at about 1.5 or 1.7 percent, depending on the budget situation. The NIH Roadmap is not a single initiative but oversaw more than 345 individual awards in FY 2005 that can be categorized as basic (40 percent), translational (40 percent), and high risk (20 percent).

Dr. Zerhouni pointed to three fundamental drivers of NIH’s current funding situation with the first being the most important:

  1. Large capacity building throughout U.S. research institutions and an increase in the number of tenure-track faculty that were stimulated by the doubling of the NIH budget. A large increase in applicants and applications occurred after 2003.
  2. Budget appropriation increases below inflation after 2003, even as the cost of grants has increased by a factor greater than inflation.
  3. Budget cycling phenomenon, which obligates funds in outyears to projects initiated in past years. New projects can be funded only from uncommitted funds.

The bottom line is that the demand for grants “took off” just as the NIH budget was “landing.” The proposed budget for FY 2007 again is expected to be flat.

The NIH managed well despite small budget increases in FY 2004 (2.9 percent) and FY 2005 (2 percent) by converting funds appropriated by Congress for “one time” expenses in 2003 to fund grants in 2004. Hurricane Katrina requirements led to a flat FY 2006 NIH budget, while the rest of the Department underwent a 2.5-percent cut. The budget cycling effect will improve demand versus supply of grants in FY 2007, but the public needs to be educated about the need for sustained research.

Dr. Zerhouni clarified that the payline is not synonymous with success rate. The success rate per application understates the funding rate per applicant because applicants on average apply 1.4 times. For FY 2005, the success rate for applications was 22.3 percent but 27.6 percent for applicants. For FY 2006, the success rate for applications is estimated to be 19.8 percent but about 25 percent for applicants.

In terms of next steps, Dr. Zerhouni emphasized the need to rely on facts and proposed a number of adaptive strategies. First, particularly in hard times, an organization must adhere to its core values and fundamental mission in making decisions. He considered it paramount to protect the essential knowledge and discovery mission of the NIH. Second is the need to manage the main drivers affecting the supply and demand of grants. Importantly, the NIH must preserve its future by supporting new investigators and encouraging early, independent research careers.

The third strategy is to convey a unified message about the positive impact of the NIH at local, regional, and national levels and the extraordinary return from investment at the NIH. He cited a number of examples of pathbreaking research supported by NIA: (1) Creation of the Pittsburgh Compound B, which makes it possible to view the amount of amyloid in the brains of living Alzheimer’s disease patients; (2) U.S. Food and Drug Administration approval in March 2004 of paclitaxel-coated stents shown to reduce the incidence of restenosis in humans safely, thus accelerating the healing process so that scar tissue does not build; and (3) declining disability across the country for seniors during the past 20 years. Basic research and technology development today provides the foundation for clinical applications. When considering the $95 per American per year that the NIH spends compared to the $7,000 per capita spent every year on health care, the discoveries supported by the NIH represent real value.

The fourth strategy is to promote an exciting vision for the NIH, which Dr. Zerhouni sees as the transformation of medicine from curative to preemptive, that is, more predictive and more personalized with participation by communities and patients. Support comes less from past accomplishments than from future potential. It is important to convey the message that the NIH has a coalition. It cannot be all things to all people. The NIH focuses on basic research and technology development for research but must balance its portfolio with translational research (about 25 percent) and clinical research (about 15 percent).

The need to transition from curative to preemptive medicine is exemplified in the challenge of caring for older adults with multiple chronic diseases who are frail and disabled. Costs can be minimized while quality of life improved through the NIH’s research. Council members were eager to learn how they could be helpful in terms of educating the public and leaders about the important work being done by NIA and the NIH.

Dr. Zerhouni distinguished between the health care delivery system and the health care that is actually delivered. He saw the latter as more in line with the NIH’s role. After 50 years of general clinical research centers, the next phase, reflected in the CTSA program, is a more community-based participatory research model that is intertwined with the health care system to permit research on a population basis with the ability to quickly define best practices. He believes that enormous support for the NIH remains but acknowledged that the need for medical research must be communicated more effectively. He reported data showing that 85 percent of the American public supports medical research, yet only 11 percent knows that the NIH has anything to do with it. Forty percent of legislators have never heard from their local scientists.

A Council member remarked on the challenges facing NIA in particular. Virtually every other Institute that started as a disease-oriented institute has a major public constituency. Aging, theoretically, is not a problem, especially given the alternative. He noted that 80 percent of Hurricane Katrina casualties were over age 65, indicating the vulnerability of the group. Dr. Zerhouni acknowledged the diffuseness of aging, recognizing that it occurs across all Institutes, which makes it all the more important to define clearly a vision for aging research. He expected increasing support from constituencies, such as the AARP and Alzheimer’s Association, in the science of aging.

In response to a question about reducing the number of Institutes, Dr. Zerhouni described two ways for an organization to grow: (1) A structural approach where divisions are merged, changed, or moved; and (2) a functional approach where mechanisms are created to effect synergy with the ability to serve the mission without losing the decentralization, that is, the identity, that usually is contained within a structure. Dr. Zerhouni subscribes to the functional approach, and the NIH Roadmap exemplifies this. He believes in the need to have a common platform for addressing overlapping problems, identifying the overall scientific roadblocks and opportunities of the times, and working together to address them.

Dr. Zerhouni also recognized the intramural program as critical for sustained efforts in far-ranging areas of science where chances for success can be low. Academic institutions appear to have a decreasing ability to run very risky, very advanced protocols like those undertaken by the Clinical Center. He sees the intramural program remaining at about ten percent of the NIH budget for the foreseeable future.

VII. PROGRAM HIGHLIGHTS

The Neuroscience and Neuropsychology of Aging presentation on “Early Diagnosis of Alzheimer’s Disease—Time to Revise Criteria?” by Dr. John C. Morris was postponed to September Council because of time constraints.

A. Geriatrics and Clinical Gerontology: Metabolic Adaptation in Response to Six-Month Caloric Restriction in Humans

Dr. Eric Ravussin from Pennington Biomedical Research Center in Baton Rouge, LA, spoke about the results of a pilot study on metabolic adaptations to caloric restriction in humans. Caloric restriction extends lifespan and retards age-related diseases in rodents and lower species. Several biomarkers of longevity have been identified in rodents and monkeys, but whether these are affected as a result of prolonged caloric restriction in humans is unknown and the mechanism through which caloric restriction increases lifespan is also unclear. One hypothesis is that metabolic rate is reduced beyond that expected from reduced metabolic mass, leading to reduced oxidative damage and possibly improvement in mitochondrial function. The goal of the randomized clinical trial was to examine the effects of six months of caloric restriction, with or without exercise, in overweight, nonobese men and women.

Findings from the study of 48 healthy, sedentary, nonsmoking, overweight men and women suggest that two biomarkers of longevity (fasting insulin level and body temperature) are decreased by prolonged caloric restriction in humans and support the theory that metabolic rate is reduced beyond the level expected from reduced metabolic body mass. Whether this metabolic adaptation translates into overall reduced oxidative damage remains to be determined. However, the increased mitochondrial content in association with a decrease in whole body DNA damage is an important indication that caloric restriction improves mitochondrial function in human skeletal muscle. Studies of longer duration are required to determine if caloric restriction attenuates the aging process in humans.

In response to questions posed by Council members, Dr. Ravussin explained that using a hip-waist ratio is a better indicator of obesity than body mass index (BMI), but the latter was used in this pilot study for convenience, as BMI was part of the inclusion criteria. In future studies, more precise indicators of body fat will be used. He also stated that caloric intake of trial participants was measured precisely over four weeks to derive the targeted reduction, and subjects’ distribution of caloric intake followed that of the American population. Finally, Dr. Ravussin commented that the decision not to pursue the caloric restriction with exercise arm of the trial was driven mostly by rodent work. The combination of caloric restriction and exercise in rats or mice results in an increase in mean average lifespan but not in maximum lifespan. Furthermore, given the limited number of subjects in each arm of the study, drawing conclusions on the interrelationship between caloric intake and exercise would have been challenging. Finally, the main goal of the pilot was to study the mechanism of caloric restriction.

B. Biology of Aging: Autophagy and Aging—More Than Keeping Cells Clean

Dr. Ana Maria Cuervo, from the Albert Einstein College of Medicine, Bronx, NY, began her talk by describing how damaged and abnormal proteins that accumulate in most cells and tissues with age are deleterious to cellular function. Protein accumulation results in part due to the failure of systems that normally take care of their removal. Dr. Cuervo’s research primarily focuses on chaperone-mediated autophagy (CMA), which mediates selective targeting of cytosolic proteins to lysosomes for their degradation. Degradation via this pathway requires the presence of a targeting motif in the substrate protein that is recognized by cytosolic chaperones. Once this complex is formed, it binds to a receptor protein on the lysosomal membrane. Subsequently, lysosomal chaperones aid in the transport of the substrate protein into the lysosome.

CMA activity declines with age and in some age-related disorders such as familial forms of Parkinson’s disease. Blockage of CMA in culture cells diminishes their ability to adapt to most types of stresses (e.g., oxidative stress, ultra violet light, heat shock) and promotes the formation of protein aggregates. Using this model, it also was shown that crosstalk takes place among different protein removal systems; in response to diminished CMA activity, cells activate other forms of autophagy that compensate for CMA failure temporarily. However, replacement of the highly selective CMA with less selective mechanisms (e.g., macroautophagy) has detrimental consequences for cell functioning; the resulting accumulation of undegraded products inside the cell results in increased apoptosis and cellular death. This crosstalk is of particular relevance in aging and age-related disorders where declined activity in one of these proteolytic systems may be compensated for temporarily by another. Understanding these compensatory mechanisms is essential for any future therapeutic attempt aimed at restoring normal proteolytic activity in aging and age-related disorders.

In the case of CMA, Dr. Cuervo’s laboratory has identified that the decline in function with age is due to a decrease in the levels of the lysosomal receptor that mediates substrate translocation. Different approaches to restore normal CMA activity in old rodents are being developed by Dr. Cuervo’s research team. To this end, a bitransgenic mouse model has been generated in which the levels of the lysosomal receptor in the liver can be regulated by administration of tetracycline, a common antibiotic. Through this animal model, it has been demonstrated that CMA can be restored in livers from old mice by increasing lysosomal receptor levels to normal values. Sustained levels of CMA activity dramatically diminished the accumulation of oxidized proteins in the old transgenic mice. The improvement in CMA in this transgenic mouse model also appears to maintain the activity of other autophagic pathways through the latter stages of aging. Currently, Dr. Cuervo’s laboratory is developing a similar transgenic mouse with broader expression of the receptor to target multiple organs. Together, these models will help to further evaluate the importance of maintaining proper protein removal until advanced ages.

In response to queries from Council members, Dr. Cuervo clarified that although a transcriptional strategy was used to sustain lysosome receptor (LAMP-2A) levels in mice, a nontranscriptional mechanism is responsible for the LAMP-2A deficiency. She also stated that the effect of restored LAMP-2 expression levels on longevity will be studied in the second transgenic mouse model currently being developed in which the transgene is targeted to major tissues. To this end, mice will be followed for at least two years.

C. Behavioral and Social Research: Loneliness Causes Declines in Health—Evidence From the Chicago Health, Aging, and Social Relations Study

Dr. John Cacioppo, a Council member, and the Distinguished Service Professor in the Department of Psychology at the University of Chicago, is President-Elect of the Association for Psychological Science. Loneliness afflicts approximately 20 percent of Americans and is approximately 48 percent heritable, with no age or gender differences. A variety of studies associate loneliness with lack of independent living, alcoholism, increased depressive symptoms, impaired sleep, increased suicide, lower self-rated health, a higher number of chronic conditions, and elevated blood pressure. Normal correlates of social pain are in the same area of the brain, the dorsal anterior cingulate, as is activated during physical pain.

The literature on a related variable, social support, is now quite large. Although research on social support and on loneliness has been viewed as closely related, conceptual and empirical distinctions between loneliness and social support have been clarified, and studies of loneliness have revealed associations and effects that are not evident from the perspective of social support. For instance, Dr. Cacioppo and his colleagues examined the relationship between loneliness and subsequent changes in depressive symptoms in a sample of 229 individuals aged 50 to 67 years residing in Cook County, including whether the association between loneliness and depressive symptoms could be explained in terms of socioeconomic status, low social support, demographic characteristics, hostility, perceived stress, or physical health status. The results demonstrated that baseline levels of loneliness and gender were unique and specific predictors of subsequent changes in depressive symptoms in middle-aged and older adults.

To better understand the role of loneliness in older adults, Dr. Cacioppo and his colleagues began the Chicago Health, Aging, and Social Relations Study (CHASRS) in 2001, a population-based longitudinal study of African American, Latino American, and Caucasian American adults born between 1935 and 1952. Dr. Cacioppo’s prior research has shown that loneliness is relatively stable over time and is associated with heightened total peripheral vascular resistance (TPR) in normotensive young adults. If the elevation in TPR in young adults contributes ultimately to higher systolic blood pressure (SBP), then individual differences in loneliness should be related to SBP in middle-aged and older adults. Results from CHASRS provide support for this hypothesis. Preliminary data show that lonely individuals evince larger increases in the morning rise in cortisol and in RNA transcripts indicative of glucocorticoid resistance, suggesting altered activation of the hypothalamic pituitary axis.

Finally, Dr. Cacioppo reasoned that loneliness may weaken the restorative effects of processes that serve to repair and maintain physiological functioning, foster recovery from stress, and contribute to the expansion of physiological capital and capacities as a function of adaptive transactions with the environment. He and his colleagues found evidence that a prototypic restorative behavior—sleep—is marked not by differences in time in bed or in sleep duration but in its efficacy: Lonely individuals evinced poorer sleep efficiency and more time awake after sleep onset than nonlonely individuals. Subsequent research indicated that lonely individuals reported poorer sleep quality and higher daytime dysfunction on the Pittsburgh Sleep Quality Index, an effect that was found in young and older adults in the CHASRS.

In response to questions from Council members, Dr. Cacioppo stated that acute effects from newly lonely individuals (e.g., in widowhood or widowerhood) seem to have the same kinds of consequences as chronic loneliness and that the association between loneliness and introversion is weak.

VIII. ADJOURNMENT

The 98th meeting of the National Advisory Council on Aging was adjourned at 1:45 p.m. on May 24, 2006. The next meeting is scheduled for September 26 and 27, 2006.

IX. CERTIFICATION

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

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

Prepared by Robin Barr, D.Phil.
With assistance by Rose Li and Associates, Inc.


Attachment A: Roster of the National Advisory Council on Aging

MEMBERSHIP ROSTER
NATIONAL ADVISORY COUNCIL ON AGING

NATIONAL INSTITUTE ON AGING

(Terms end December 31)  (*WGoP Member)

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

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

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

Kenneth V. Brummel-Smith, M.D. (2009)
Professor and Chair
Department of Geriatrics
Florida State University College of Medicine
Tallahassee, FL

*John T. Cacioppo, Ph.D. (2007)
Blake Distinguished Service Professor
Department of Psychology
Director, Center for Cognitive and Social Neuroscience
University of Chicago
Chicago, IL

Carl Eisdorfer, Ph.D., M.D. (2009)
Knight Professor and Director
Center on Aging
University of Miami
Miami, FL

*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

Lawrence M. Friedman, M.D. (2009)
Independent Consultant
11712 Farmland Drive
Rockville, MD

Mary Ganguli, M.D., M.P.H. (2009)
Professor of Psychiatry, Neurology, and Epidemiology
Department of Psychiatry
University of Pittsburgh
Pittsburgh, PA

Alan M. Garber, M.D., Ph.D. (2007)
Director
Center for Primary Care and
   Outcomes Research
Center for Health Policy
Stanford University
Stanford, CA

Paul Greengard, Ph.D.  (2008)
Vincent Astor Professor
Laboratory of Molecular & Cellular Neuroscience
The Rockefeller University
New York, NY 

*Virginia M.-Y. Lee, Ph.D. (2007)
Professor
Dept of Pathology & Laboratory Medicine
Univ 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

Mills, Terry L., Ph.D. (2008)
Associate Dean for Minority Affairs
and Special Programs
Office for Academic Support 
and Institutional Services
University of Florida
Gainesville, FL

John C. Morris, M.D. (2009)
Professor
Washington University School of Medicine
St. Louis, MO

Gary B. Ruvkun, Ph.D. (2007)
Professor, Molecular Biology
Massachusetts General Hospital
Boston, MA

Gerald P. Schatten, Ph.D. (2009)
Professor, Pittsburgh Development Center
Magee-Womens Research Institute
University of Pittsburgh
Pittsburgh, PA

Albert L. Siu, M.D., M.S.P.H.  (2008)
Ellen and Howard C. Katz Professor
Chairman, Brookdale Department
of Geriatrics and Adult Development
Mount Sinai School of Medicine
The Mount Sinai Medical Center
(and Director, Geriatric Research, Education, and Clinical Center, Bronx Veterans Administration)
New York, NY

*Mary E. Tinetti, M.D.  (2008)
Gladys Phillips Crofoot Professor
Department of Internal Medicine, Epidemiology, and Public Health
Director, Program on Aging
Yale University School of Medicine
New Haven, CT

EX OFFICIO MEMBERS

Michael O. Leavitt
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.
Chief Consultant
Geriatrics & Extended Care Strategic
   Healthcare Group
Department of Veterans Affairs
Washington, D.C. 

Kenneth G. Pugh, M.D.
Commander, MC, U.S. Navy
Department of Medicine
National Naval Medical Center
Bethesda, MD

John Wren
Director, Center for Planning & Policy Development
U.S. Administration on Aging, DHHS
Washington, D.C

 

 

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

  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. (Back to text.)

  3. These minutes will be approved formally by the Council at the next meeting on September 26-27, 2006, and corrections or notations will be stated in the minutes of that meeting. (Back to text.)

Page last updated Sep 26, 2008