The 113th Meeting
May 24–25, 2011
- REVIEW OF APPLICATIONS
- CALL TO ORDER
- REPORT: Task Force on Minority Aging Research
- REPORT: Working Group on Program
- INITIAL REPORT: NIA Funding Policies and Scientific Review Branch Council Review
- PROGRAM HIGHLIGHTS
The 113th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, May 24, 2011, at 3 p.m. in Building 31, Conference Room 6, National Institutes of Health (NIH), Bethesda, Maryland. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA), presided.
In accordance with the provisions of Public Law 92–463, the meeting was closed to the public on Tuesday, May 24, from 3 p.m. to 5 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 the Public Law 92–463.1 The meeting was open to the public on Wednesday, May 25, from 8 a.m. to 1:30 p.m.
Council Participants (* Provisional Members appointment pending at the time of the meeting):
Dr. Lisa Berkman
Dr. Hugh C. Hendrie
Dr. Andrea LaCroix
Dr. Victor Molinari
*Dr. Richard Morimoto
Dr. Lennart Mucke
Mr. Daniel P. Perry
Dr. Ronald C. Petersen
Dr. Arlan G. Richardson
Ms. June Simmons
Dr. James P. Smith
*Dr. Stephanie Studenski
Dr. Susan L. Swain
Dr. Terrie F. Wetle
*Dr. Norman Anderson
Dr. Dale E. Bredesen
Dr. Robert Califf
*Dr. Eliseo J. Perez-Stable
Ex Officio Participants:
Dr. James F. Burris, Department of Veterans Affairs
Mr. Robert Hornyak, Administration on Aging
Absent Ex Officio Participants:
Dr. Kenneth G. Pugh, National Naval Medical Center
Dr. John Wren, Administration on Aging
The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as attachment A.
In Addition to NIA Staff, Other Federal Employees Present:
Ms. Judith Dulovich, Office of Human Resources, National Institutes of Health (NIH)
Dr. Heidi Friedman, Center for Scientific Review, NIH
Ms. Tonia Purkoski, Office of Human Resources, NIH
Ms. Michelle Washko, Administration on Aging
Members of the Public Present:
Dr. Kimberly Acquaviva, George Washington University
Mr. James Appleby, Gerontological Society of America
Dr. Randy L. Buckner, Harvard University
Ms. Danita Byrd, Social Scientific Systems, Inc.
Dr. Leonard P. Guarente, Harvard University
Ms. Linda Harootyan, Gerontological Society of America
Dr. Rose M. Li, Rose Li and Associates, Inc.
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Dr. Terrie Moffitt, Duke University
Dr. Virginia Neale, University of Virginia
Ms. Sue Peschin, Alzheimer’s Foundation of America
Ms. Michelle Rodrigues, SRI International
Ms. Branka Sekis, Social Scientific Systems, Inc.
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 552(b)(c)(4) and 552(b)(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 1101 applications requesting $1,571,640,209 for all years underwent initial review. The Council recommended 595 awards for a total of $ 993,409,904 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.
Dr. Hodes welcomed members to the open session of the 113th NACA meeting and called the meeting to order at 8:00 a.m. on Wednesday, May 25, 2011.
Director’s Status Report
Dr. Hodes reviewed NIA appropriations and compared the FY2011 enacted budget with the FY2012 President’s budget, which shows only a slight decrease in current dollars but an 18 percent cumulative loss in purchasing power since FY2003. He indicated uniform concern across NIH about the budget outlook for FY2012, as well as potentially greater budgetary challenges the following year. Dr. Hodes noted particular attention paid this year to the NIA payline and reported on the FY2011 paylines to date for large grant applications (greater than $500,000) and smaller grants (less than $500,000) among different types of principal investigators (PIs):
NIA Payline Percentiles to Date, FY2011
Early stage PI (R01 only)
Other new PI (R01 only)
He stated that the NIA paylines similar to those of other NIH Institutes and Centers (ICs). For example, the National Institute of Allergies and Infectious Diseases reported a 10th percentile payline, and the National Institute on Neurological Diseases and Stroke reported a 14th percentile payline.
Dr. Hodes focused the remainder of his introductory comments on two interagency initiatives. The first is the Centers for Medicare and Medicaid Services (CMS)-NIH Leadership Committee, chaired by CMS Director, Dr. Don Berwick and NIH Director, Dr. Francis Collins. This initiative aims for an enduring commitment by the two agencies to the following areas:
- NIH providing information about current research of potential interest to CMS.
- CMS providing an environment to test factors that affect physician and patient behavior in clinical practice and in successful execution of clinical trials.
- CMS providing a venue for novel implementation of research and natural experiments.
- Enhancing researcher use of CMS data.
The second initiative, which arises from passage of the National Alzheimer’s Project (NAP) Act (Public Law 111-375), establishes NAP within the Department of Health and Human Services (HHS). NAP would:
- Be responsible for the creation and maintenance of an integrated national plan to overcome Alzheimer’s disease (AD).
- Provide information and coordination of AD research and services across all Federal agencies.
- Accelerate the development of treatments that would prevent, halt, or reverse the course of AD.
- Improve early diagnosis of AD and the coordination and care and treatment of citizens with AD.
- Ensure the inclusion, in clinical, research, and service efforts, of diverse ethnic and racial populations who are at higher risk for AD or least likely to receive care.
- Coordinate with international bodies to integrate and inform the global fight against AD.
The HHS Secretary will oversee NAP and an advisory council comprised of designees from several Federal agencies and 12 expert members from outside the Federal government who will meet quarterly to advise the Secretary. Progress on NAP will be pursued by the Interagency Group on AD and Related Dementias, which comprises subgroups focused on research, clinical care, and long-term services and support.
Council discussion focused first on the NIA payline and its effect on investigators. One Council member noted that the National Heart, Lung, and Blood Institute (NHLBI) completed an analysis showing that scores after two reviews might improve by 20 percentile points, which might reflect true improvement or reviewers sympathetic to the fact that no further resubmissions are possible. Thus, NHLBI’s paylines for resubmissions are more stringent than for first submissions. Dr. Hodes responded by noting that many ICs have their larger grant applications reviewed by Special Emphasis Panels (SEPs) and their scores are not percentiled. He added that in general, case-by-case judgments are based on priority scores, rather than percentiles, and thus there is no way to know what the equivalent paylines are for large awards across ICs.
Dr. Robin Barr pointed out that although NIA had the lowest payline in FY2010 compared to other ICs, this did not equate to the worst success rate. He added that because paylines are constructed by and specific to each IC, they do not translate well across NIH. Thus, applicant success rates (i.e., total number of applications funded as a proportion of total applications submitted) might serve as a better point of comparison. Dr. Hodes and the Council agreed on the importance of communicating this distinction to investigators. Dr. Richard Morimoto suggested that even a simple email with a positive subject line, for example “NIA Success Rate Better Than You Think,” could address concerns.
In response to questions regarding flexibility in funding, Dr. Hodes noted that approximately 10 percent of funds is set aside for NIA initiatives, 80 percent is devoted to investigator-initiated research, and the remaining 10 percent is directed to a discretionary fund for high-priority applications that are slightly beyond the payline.
In response to questions about NAP and its likely effectiveness, Dr. Hodes emphasized that the scope of the NAP Act goes beyond research and is being scrutinized by many constituent groups, including those focused on the pace of developing and screening for new drugs. He added that NIA will be involved in leading the research effort and in identifying redundancies and gaps across Federal, non-Federal, nonprofit, for-profit, domestic, and international funders of AD research, but it is hard at this time to know how the project will influence research funding or public advocacy. Thus, although NIA and NIH are clear leaders with respect to AD research funding, the Act will promote greater coordination and integration of efforts. Dr. Hodes observed the rapid pace at which the NAP Act was passed as a promising sign, but cautioned that it is premature to speculate whether the HHS Secretary could be influenced to begin an appropriations action.
Dr. Hodes also noted that databases such as clinicaltrials.gov could be used to engage with the pharmaceutical and biotechnology industries for NAP. Although goodwill and interactions with networks conducting proprietary research (for example, the AD Neuroimaging Initiative) will be required for such engagement, Dr. Hodes cited NAP as an overall opportunity for industry to collaborate.
Mr. Daniel Perry raised concerns about implementation. He noted that the structure of the advisory council, which forms the core of the NAP Act, must conform to the National Advisory Committee Act. He further expressed frustration at the length of time taken so far to establish the NAP advisory council. Dr. Hodes clarified that the process to establish the committee was expected to take several months, but he also noted progress in that the council’s charter has been approved by the Office of General Counsel and might already have been signed by the HHS Secretary. Although the council is still awaiting formal approval, it has already held one teleconference and established its three subgroups.
Dr. Ronald Petersen noted that the U.S. Food and Drug Administration (FDA) is likely to approve amyloid imaging by the end of the calendar year and cited this approval as an example of information that should be communicated to CMS. Dr. Hodes encouraged others to formulate with colleagues the issue(s) for NIA to bring to the attention of CMS.
Ms. Linda Harootyan reported that the Gerontological Society of America (GSA), in collaboration with Friends of NIA and the American Geriatrics Society, is hosting a webinar on June 9 to share information about the NIA payline and success rates and allow NIA staff to answer questions. Audio from the webinar will be posted on the GSA website. Dr. Hodes thanked the GSA for its leadership in working with NIA to share information.
A binder containing media coverage was circulated among Council members. Dr. Hodes reported an increase in media clippings from 3,379 last year to 7,679 this year. He welcomed reactions from Council members about NIA’s press coverage and suggestions for areas where the NIA can do more.
Introductions of New Staff and Visitors
Dr. Luigi Ferrucci has become the new Scientific Director of the Intramural Research Program.
Dr. Max Guo has joined the Division of Aging Biology as Chief of the Genetics and Cell Biology Branch. Dr. Guo comes to NIA from the National Institute on Alcohol Abuse and Alcoholism.
Future Meeting Dates
September 20–21, 2011 (Tuesday and Wednesday)
January 24–25, 2012 (Tuesday and Wednesday)
May 22–23, 2012 (Tuesday and Wednesday)
September 18–19, 2012 (Tuesday and Wednesday)
There will be an orientation for new Council members on September 19, 2011.
Consideration of Minutes of the Last Meeting
The minutes of the January 2011 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.
Dr. Terrie Wetle’s report focused on the biomedical research workforce. She began by announcing the formation of a new NIH Advisory Committee working group, which will develop a model for a sustainable and diverse workforce in biomedical research. She then reported on a presentation by Dr. Suzanne Kunkel, of the Scripps Gerontology Center at Miami University of Ohio, on efforts to draw more undergraduates into science and gerontology in particular.
The workforce needs in gerontology education have been well established. The number of advanced degrees in gerontology is increasing, and researchers within gerontology have the opportunity to specialize in other disciplines and professions. However, recruitment to the field of gerontology remains a hard sell for high school and college students. In recognition of the importance of undergraduate programs in feeding the workforce pipeline, and to overcome difficulties in recruiting undergraduates, the University has worked to develop high-quality introductory gerontology courses, integrate gerontological content into the university curriculum (encouraging aging as a specialization or minor within other areas of study), and promote service learning. Miami University also is working to increase the number of underrepresented minorities in research by collaborating with Central State University, increasing internal recruitment of these minorities into graduate programs, and working with community agencies that have access to underrepresented minorities. Dr. Kunkel’s presentation also noted the importance of international students and students from online education and regional campuses, and the University’s emphasis on practical skills that will help its students compete in the job market or graduate admissions. In response to results from a survey of agencies, Miami University changed its curriculum to include both classroom and practical research training, with some focus on addressing health disparities. Miami University students also gain experience through research internships. Through all these efforts, Miami University has learned about the importance of meaningful collaborations across institutions, disciplines, students, and faculty, and community agencies; the strong value of mentorship programs; and the need to continue funding undergraduate innovation.
Following Dr. Wetle’s report, Dr. J. Taylor Harden presented for concept clearance a funding opportunity announcement (FOA) for FY2012 on Advancing Diversity in Aging Research (ADAR). This initiative stems partly from National Science Foundation (NSF) data showing that the proportion of underrepresented minorities decreases with each advancing step in the research workforce pipeline. In addition, the current reliance on international students and temporary residents might decline as global competitors grow and strengthen their own science and education programs. Thus NIA wishes to increase interest in aging research not just among underrepresented minorities, but also among students overall. At the high school and undergraduate levels, NIA has only two mechanisms to support research opportunities for students.
ADAR aims to add a grant mechanism that will draw more undergraduate students into the science education and aging research arena, diversify the workforce by supporting creative and innovative undergraduate education programs, and provide a pathway through baccalaureate education and into graduate programs. Outcomes for evaluation will include undergraduate retention, completion, and transition to graduate study. NIA proposes that ADAR have set-aside funding with 5 years of support, and it anticipates supporting three to four awards.
A motion to approve this proposed FOA was forwarded by the Task Force. During discussion, Dr. Hodes clarified that ADAR support also could be used to address areas of curriculum development or supplement recruitment programs. Dr. Morimoto noted the exciting opportunity to increase communication and collaboration between undergraduate campuses and medical schools and centers. Dr. Andrea LaCroix added that opportunities for research collaboration are not limited to medical schools alone; for example, undergraduate programs also can work with schools of public health. The motion was seconded and passed unanimously.
Dr. Sidney Stahl presented for concept clearance a proposal to recompete the Resource Centers for Minority Aging Research (RCMAR) program and coordinating center. He briefly reviewed RCMAR’s mission and reported that six RCMAR sites have been in place since 1997. Since the program’s inception, eight other programs at NIH have emulated RCMAR components. The RCMAR program has mentored 238 scholars and generated 27 diversity supplements, and several RCMARs have become focal points for research on minority aging. Although data are incomplete, the number of major grant awards, including R01s and P01s, has increased consistently among RCMAR scholars. These scholars and associated faculty have published an impressive number of journal articles, and many scholars who are new faculty have K awards. Dr. Stahl noted that Dr. Yvette Roubideaux, the first female director of the Indian Health Service, began her research career as a scholar with the University of Colorado RCMAR.
NIA proposed a FY2012 request for applications (RFA) to continue the RCMAR program, with a slight change in core procedures to increase flexibility with respect to the kinds of institutions that can apply. NIA expects to support six or seven core-only RCMAR center grants for 5 years. A motion to approve the concept was forwarded and seconded, and the motion passed unanimously.
Dr. Lisa Berkman reported that the working group considered concept clearances for nine FOAs.
- Leveraging Existing Data or Studies to Evaluate Safety and/or Effectiveness of Pharmacological Management of Chronic Pain in Older Adults, presented by Drs. Basil Eldadah and Wen Chen. This proposed FOA with set-aside funds stems from the need for evidence to guide safe and effective long-term treatment of older people, particularly with non-steroidal anti-inflammatory drugs and opioids. Research projects responsive to this FOA could improve understanding of healthy aging and disease and disability, develop interventions to reduce disease and disability, and reduce health disparities among older adults. The working group agreed on the importance of the concept and expressed enthusiasm. A motion to approve the concept was forwarded, seconded, and passed unanimously.
- Demonstration Projects for Systems Biology of Aging in Saccharomyces cerevisiae, presented by Drs. Ronald Kohanski and Jose Velasquez. This proposed FOA aims to encourage the use of systems biology approaches to study aging in single-cell organisms such as yeast. NIA anticipates supporting two awards for up to 5 years. During the working group’s discussion, Dr. Morimoto pointed out that yeast is a fully developed model organism and that systems biology in this context could represent an opportunity to integrate different layers of knowledge, including the proteome, transcriptome, and level of protein-protein interactions. Dr. Lennart Mucke added that many systems biology studies have yielded profiles that are hard to synthesize into insightful descriptions of biological processes. He suggested that the integration of knowledge layers should be emphasized to make this FOA worthwhile and yield more than what systems biology has produced so far. Council members also encouraged NIA staff to take advantage of the simplicity of yeast by encouraging new algorithms. Dr. Arlan Richardson added that demonstrated projects should examine natural yeast strains as well as laboratory strains. A motion to approve the concept was forwarded, seconded, and passed unanimously.
- Network Infrastructure Support for Emerging Areas of Research in the Basic Biology of Aging, presented by Dr. Felipe Sierra. The proposed FOA will provide 3 years of support to address the need for the development of a network to advance interdisciplinary research. Activities will include workshops, pilot studies, and mini-sabbaticals for investigators, and areas of interest will include integrative physiology, anti-aging interventions, inflammation, biology of aging in animal models, and translation of discoveries into the clinic. Although the working group expressed enthusiasm for the project, members expressed concerns about specificity and suggested that the focus of the FOA be clarified further. A motion to approve the concept was forwarded, seconded, and passed unanimously.
- Secondary Analyses and Archiving of Social and Behavioral Datasets in Aging, presented by Dr. Partha Bhattacharyya. This proposed FOA will provide small, 1-year grants to support short-duration and low-cost secondary analyses in NIA program areas in cognitive science, psychology of aging, economics, sociology, and demography. The working group was enthusiastic about this proposal but expressed concern about funding and the 1-year time frame. Dr. James Smith pointed out that small grants have traditionally run into difficulty because they are capped and have been subject to across-the-board reductions. Dr. Hodes noted that in the past year, the NIA’s average reduction of 18 percent represents an average, and added that ICs have discretion to cut more from some programs and less from others, so long as the average is met. Dr. Barr commented that eliminating budget reductions will result in fewer awards. A motion to approve the concept was forwarded, seconded, and passed unanimously.
- Supporting Aging Research through the NIA-CMS Data Enclave, presented by Dr. Bhattacharyya. Several NIA-funded projects use data from CMS, and researchers must pay for access each time they request data. The proposed contract solicitation aims to establish an enclave that would allow NIA researchers to access CMS data through a secure mechanism, with NIA incurring a one-time fee each year. The working group advised that the virtual environment should have adequate capacity for multiple uses and for linkage to multiple datasets. Dr. Hugh Hendrie also suggested that NIA should emphasize the need for such an environment to account for the complexity associated with obtaining and analyzing CMS data. NIA staff clarified that the enclave would not eliminate the need for data use agreement (DUA) approval, but it could assure that researchers do not have to wait until CMS pulls samples for linkage. Dr. Hodes noted that a successful project could serve as a pilot that could be extended to all of NIH. A motion to approve the concept was forwarded, seconded, and passed unanimously.
- Human Cell Reprogramming for Aging and AD Research, presented by Dr. Brad Wise. The proposed FOA will support development of human induced pluripotent stem cells (IPS) and other reprogrammed cells to study molecular and functional characteristics of age and AD phenotypes. NIA anticipates that successful projects will demonstrate proof-of-concept that human reprogrammed cells can serve as valid models of aging. Although the working group expressed enthusiasm for this concept, members also suggested that NIA emphasize reproducibility across cell lines and patients, build safeguards to ensure that funds are used to generate data and not simply to tweak technology, and encourage partnerships to allow investigators access to expertise and appropriate facilities. Council suggested that NIA could address these issues both in FOA eligibility and in program checks. A motion to approve the concept was forwarded, seconded, and passed unanimously.
- Proposed NIA Program Announcements with Set-aside on T1 and T2 Translational Research in Aging, presented by Dr. Chhanda Dutta. Sponsored by all four NIA Divisions, this initiative will support exploratory studies focused on new or improved diagnostics, care practices, and policies with respect to translational research. A motion to approve the concept was forwarded, seconded, and passed unanimously.
- Proposed NIA RFAs to Encourage Involvement of Small Businesses in T1 and T2 Translational Research on Aging, presented by Dr. Chhanda Dutta. The proposed initiative would support innovative research to advance the availability of novel interventions and products. In response to questions from Council, Dr. Dutta noted the refinement and scale-up of hip pads, the dissemination of virtual reality technology for balance training, and movement of two new therapeutics into clinical trials as examples of innovations in which SBIR grants were involved. A motion to approve the concept was forwarded, seconded, and passed unanimously.
- Analyses of Databases from Health Care Systems or Large Epidemiologic Studies to Evaluate Safety of Testosterone Administration in Older Men, presented by Dr. Lyndon Joseph. Testosterone administration has increased among older men, but much of this administration has been off label. Ongoing studies are continuing to assess the benefit of testosterone administration, but they are not powered to assess safety. The proposed program announcement, which will include a set-aside to permit resubmissions if needed, aims to address this gap. Council members questioned the narrow scope of this concept and suggested broadening the concept in the future to support analyses of the general effectiveness of drugs in older populations. Dr. Hodes noted the long history of testosterone studies, a partnership between NIA and the U.S. Department of Veterans Affairs (VA), and the increasing public health imperative resulting from increased use of testosterone, as reasons for the narrowed scope of the proposed initiative. He further clarified that the proposed initiative would support targeted studies of adverse events, with larger-scale trials taking place if positive effects are found. However, Dr. Hodes also agreed on the need to expand the initiative in the future, particularly in the context of comparative effectiveness research and alternative approaches to clinical trials, and suggested VA and health maintenance organizations as likely partners. A motion to approve the concept was forwarded, seconded, and passed unanimously.
Dr. Petersen’s report focused primarily on the payline. Amid concerns that an exceedingly low NIA payline might siphon applications to other ICs, the committee agreed that any decision making should preserve the mission of the Institute, , and should not sacrifice the next generation of investigators.
On the basis of data from the past 5 years, the committee has found that fewer small grants, defined as those lower than $500,000, have been submitted, whereas the number of “big science” grants, for example clinical trials, has increased. In addition, the average size of typical grants has increased. Changes in the proportions of awards based on grant size or mechanism differ only slightly from those of other ICs, and these differences most likely reflect differences in IC missions and funding mechanisms used. NIA does not appear to differ significantly from other ICs with respect to trends in the total budget, the proportion of budget devoted to research project grants, or the number of applications received. However, although the average cost of an R01 has increased across all ICs, it appears that the largest grants have come to NIA, which has contributed to a lower payline. However, after a steep decline, the NIA payline is now stabilizing.
The committee also assessed whether priority scores differ by type of grant mechanism. Although the priority scores for cooperative agreements (U01) and program projects (P01) are slightly lower, the committee could not agree on how to interpret that difference. However, the committee did have suggestions on the way grant applications, excluding P01s, are reviewed. At present, grants of more than $1.5 million require a program review. The committee suggested that these grants should also require Council approval, although the committee recognized that because Council meets only three times a year, there could be logistical challenges. Another option might involve the Council approving these applications after the review process, although there was some concern about investigators going through the entire process, only to be unsuccessful. The committee also noted that Council usually approves concepts without knowing their cost or impact on the overall NIA budget. To address this issue, NIA could present concepts during an open session, hold an extended closed session in which Council considers the budget and members who might submit applications recuse themselves, then return to an open session where Council would vote on the concepts. Dr. Petersen also noted that recent histories of proposed RFA concepts would give the Council a better sense of the size and magnitude of concepts on which they vote.
The committee concluded that the NIA staff has been diligent in considering issues that affect the payline and the NIA mission. The committee also agreed that the adjustments made by the Institute might be having the intended effect. The committee should see more data, get feedback from the scientific community, and follow these trends on a regular basis, perhaps annually, rather than make a large number of changes without knowing what will be effective.
Dr. Petersen closed his presentation with a brief discussion of P01s, which will now be percentiled through the NIA rather than through the Center for Scientific Review. The committee suggested that NIA provide SEPs with indications of how P01 review committees have functioned and how scores differ across committees, so that committees can self-calibrate. The committee also discussed parent committees. That is, SEPs would score the components of a P01 without giving it an overall score, whereas a parent committee would look at all P01s submitted to the Institute. However, the committee noted the differences in the science expertise across NIA Divisions, which might present a challenge in scoring P01s consistently across the Institute. Thus, the committee recommended waiting to see if percentiling within NIA is adequate to level the playing field for P01s, rather than instituting parent reviews.
Dr. LaCroix, who served on the committee, opened discussion by pointing out that the committee had considered several alternative strategies to fund science of the best quality and were unable to identify any that were better than the approaches NIA has already started to take. Other committee members commended the NIA leadership and staff for working to improve the payline. The committee agreed that NIA should focus on achieving a reasonable payline and success rate, even if that sometimes means funding more smaller grants than larger ones. Council members also suggested that Council review this data annually.
The bulk of discussion focused on ways for Council to review costs or budgetary impact as it considers concepts. By suggesting an extended closed session, the committee suggested a mechanism that would not challenge NIH policy directly, and Dr. Barr speculated that the closed session could immediately follow introduction of a concept during the meeting of the Working Group on Program. However, the committee also suggested that members recuse themselves from cost discussions if they intended to submit applications for a particular concept. Several Council members pointed out that the decision to respond to a FOA does not usually depend on the overall FOA cost or its impact to the NIA budget. Others noted that members who would be asked to recuse themselves might be the only ones with the expertise to adequately assess a concept’s cost. One Council member suggested a “divisional” closed session, which would take place before the overall Council closed session and allow members with potential conflicts to provide their expertise.
With respect to the committee’s suggestions that Council also review and approve proposed awards of $1.5 million or more, several Council members expressed concerns about eleventh-hour rejections of grant applications. Dr. LaCroix suggested that the bar should be set very high for Council to overturn a decision made in peer review. However, Dr. Hodes pointed out that an electronic book of all applications is available to Council and that members have the opportunity to raise concerns about any application. He added that NIA could facilitate its review by formalizing these books and sorting applications by cost. Dr. Hodes further noted that having Council review and approve grant awards might be problematic, because applications are submitted throughout the year. Dr. Barr added that most of these applications are driven by RFAs and would be reviewed by Council; only two or three applications costing more than $1.5 million fall outside of this category. Some Council members noted the need to avoid re-reviewing concepts that had already been cleared, especially when the system in place is already working well for those two or three applications per year.
Other Council members pointed out that reviewers are instructed not to consider funding during review and that where Council members might be helpful is in helping program staff prioritize from a set of fundable applications with comparable assessments. In such a case, Council would not evaluate the science in the application, but rather the relevance to the NIA mission given the cost proposed. However, some members expressed concern that because of the multidisciplinary nature of the Council, it will be challenging for individual members to make judgments about relevance across fields. Thus, the Council would again be in a position of overturning a decision made by the study section, which is still the best group to assess relevance.
The Council agreed to table discussion on large applications until the September meeting. By that time, NIA can provide Council with new data about the number of large applications received per year.
Division of Geriatrics and Clinical Gerontology: Testing New Interventions for Menopause Symptoms—New Findings from the MsFLASH Clinical Trials Network
Hot flashes are the leading reason for menopausal women to seek medical treatment; about 88 percent of women experience hot flashes around menopause. Hormone therapy has declined since the results of the Women’s Health Initiative (WHI) were released, and no alternative treatments have been approved by the U.S. Food and Drug Administration (FDA) for hot flashes. The MsFLASH Research Network has brought together researchers of various backgrounds and disciplines to evaluate potential interventions for hot flashes, in a way that will facilitate work on comparative effectiveness. The Network is conducting three trials.
Dr. LaCroix presented results from the first trial, which sought to evaluate the efficacy and tolerability of escitalopram (Lexapro), a selective serotonin reuptake inhibitor (SSRI), in alleviating the frequency, severity, and bother of menopausal hot flashes (JAMA 305(3), 2011). It was a multi-site, randomized, placebo-controlled, double-blind trial in which the study population (average age 54 years) was stratified by race. The Network recruited as many African American women as white women, because African American women are more likely to be bothered by hot flashes but generally have been underrepresented in clinical trials. Study participants were randomized to 10 mg/day escitalopram or placebo for 8 weeks, and those who showed no improvement in symptoms at 4 weeks underwent a blind dose-escalation to 20 mg/day. Hot flashes were assessed via daily diaries throughout the study, and treatment evaluations of hot flash frequency (number of flashes/night sweats per 24 hours) and severity (mild, moderate, severe) were made at 4 and 8 weeks, and at 3 weeks post-treatment.
Out of 205 women randomized 201 (98 percent) contributed week 4 and/or week 8 diary data. About 87 percent of the women adhered to their study doses, and 9 women (7 active, 2 placebos) discontinued participation because of adverse events. Both the placebo and escitalopram groups showed a decrease in the frequency, severity, and bother of hot flashes from baseline, as early as 1 week after initiation of treatment, but the decrease was more marked in the escitalopram group. The divergent curves by treatment and placebo for frequency, severity, and bother all converged following treatment discontinuation. Dose-escalation was required in 70 percent of women in the placebo group, compared with 51 percent in the escitalopram group, and more women in the escitalopram reported greater than 50 percent improvement at week 4. No significant differences were seen by subgroup. Adverse events were common, 52.9 percent in the escitalopram group versus 62 percent in the placebo group, but these events were generally transient and mild. No serious adverse events were reported. In accordance with new FDA guidelines, study participants were also asked about satisfaction with treatment. About 70 percent of the escitalopram group were satisfied with their treatment, compared with 43 percent in the placebo group. Sixteen percent reported no benefit in the escitalopram group, compared with 46 percent in the placebo group, and 64 percent of the escitalopram group wanted to continue treatment, compared with 42 percent of the placebo group.
Dr. LaCroix reported that the Network will conduct a trial testing the effects of yoga, aerobic exercise, and omega-3 fatty acids, compared with placebo. The Network also plans a second trial comparing low-dose estrogen and venlafaxine to placebo. Dr. LaCroix closed by describing the recruitment process for all three trials and by noting that the Network has tested commercial hot-flash monitors. The results of this study will be published later this year.
In response to questions from the Council, Dr. LaCroix noted that drug companies have had limited interest in seeking FDA approval of SSRIs for hot flashes, but she expected that results from the MsFLASH studies might elicit greater interest. She also suggested that the escitalopram study results could be immediately translated to clinical practice. The remainder of discussion focused on technical aspects of the trial, on potential mechanisms, and what could be learned from studies of SSRIs and depression.
- Division of Aging Biology: Sirtuins, Aging, and Disease
Dr. Leonard Guarente, of Harvard University, briefly presented a history of sirtuin biology and its association with aging and disease. About 20 years ago, Dr. Guarente and colleagues screened for yeast mutants that underwent more cell divisions than normal. These screens led to the discovery of silencing information regulatory protein 4 (SIR4) and 2 (SIR2), and further work showed that deletion of the SIR2 gene shortened the yeast lifespan, whereas the addition of one extra copy extended it. Dr. Guarente and colleagues also used gene duplications to identify genes that could slow aging in C. elegans and found an ortholog of SIR2. Further work with purified yeast and human SIR2 proteins showed that SIR2 is involved in protein deacetylation, and it provided links between protein deacetylation and metabolism.
There are seven mammalian sirtuins, of which SIRT1 is the ortholog of yeast SIR2. Three of these sirtuins, including SIRT3, are mitochondrial proteins. SIRT3 functions as a major mitochondrial deacetylase, triggers b-oxidation of fatty acid, and suppress the production of reactive oxygen species through several mechanisms. Recent work by Prolla and colleagues has shown that SIRT3 mediates the protective effects of calorie restriction against hearing loss and oxidative damage in mice. Moreover, overexpression of SIRT1 appears to be protective in AD mouse models. In particular, overexpression of SIRT1 affects cleavage of the APP protein to slow production of Aβ amyloid. Sirtuins also have been implicated in cancer. SIRT3 works in the mitochondria and regulates production of reactive oxygen species. Elevated SIRT3 levels suppress these species, as indicated by a failure of hypoxic conditions to induce HIF-1a. In addition, many cancers show a loss of SIRT3, and the Warburg effect is reversed by introducing SIRT3 into cancer cells.
Since these first discoveries, the field of sirtuin biology has grown, stimulated by the hypothesis that sirtuins mediate the beneficial effects of calorie restriction seen in rodents. Several studies have shown that mice overexpressing sirtuins are protected against age-related diseases and conditions, including diabetes and bone loss, and small molecules such as resveratrol, which activates SIRT1, have shown similar effects to those of sirtuin overexpression. Although the mechanisms are still poorly understood, some evidence suggests that these SIRT1 activators trigger calorie-restriction pathways. At least eight clinical trials are testing the effects of sirtuin-based drugs on metabolic and other diseases.
Questions from the Council focused on possible connections between sirtuins and neurological diseases, the point of cross-talk between sirtuins in different cellular compartments, and the evolutionary history and function of histone deacetylase activity.
- Division of Behavioral and Social Research (DBSR): Does Childhood Self-Control Predict Adult Health, Wealth, and Public Safety?
Dr. Terrie Moffitt presented results from a study of the Dunedin birth cohort, which comprises more than 1,000 individuals born in 1972 through 1973 (PNAS 108 (7), 2011). This cohort has undergone 12 follow-up assessments, and at its last assessment in 2005, 96 percent of the cohort still participated. The 38-year follow-up assessment is under way.
In the study, Dr. Moffitt and colleagues constructed a composite variable of self-control measures, including reports from parents and teachers, observational ratings made by study staff, and children’s self-reports when they were older, at ages 3, 5, 7, 9, and 11 years of age. The study team then looked at clinical assessments, substance dependencies, wealth outcomes, and criminal court convictions when cohort participants were 32 years old. Participants who exhibited higher self-control as children were less likely to experience adverse health outcomes at age 32. They also exhibited higher occupational status, more financial planning, higher income, and fewer financial struggles, and they were less likely to be convicted of a crime. Among those who had at least one child, participants who had exhibited higher self-control as children were less likely to have their child raised in a single-mother household. In addition, among social welfare participants, those who had exhibited higher self-control as children left welfare within a year, whereas those who had shown lower self-control stayed on welfare for an average of 4 years. All analyses controlled for sex, social class of origin, and childhood intelligence quotient (IQ).
To begin to isolate self-control as an “active ingredient,” Dr. Moffitt and colleagues conducted a study using data from the Environmental Risk Longitudinal Twin study, which involved 1,116 families and 2,232 twins in a nationally representative sample across the United Kingdom. Of the twins studied, 45 percent were dizygotic fraternal twins. Again, self-control measured at the age of 5 years predicted differences in smoking, school achievement, and conduct at age 12.
This study has several implications. Although one cannot change childhood IQ or socioeconomic status, self-control is independent of, and often stronger than, IQ or socioeconomic status in predicting outcomes. Moreover, as suggested from the single-parent household results, low self-control places the next generation at a disadvantage. Thus adolescent programs might not be enough to prevent poor adult outcomes. Enhancing self-control might also reduce the costs to government of crime control, health care, social welfare, and preparation for old age. Thus early intervention might provide the best cost-benefit ratio.
Dr. Moffitt closed her presentation by noting that self-control gradients in clinical trials suggest that even children with above-average self-control can benefit from learning better self-control skills and the independence of self-control as a predictor suggests that intelligent children from wealthy homes also can benefit. Thus universal enhancement of self-control skills might be more beneficial than targeting individual children. Scale-ups of these clinical trials must be tested.
The bulk of discussion focused on technical aspects of the work Dr. Moffitt presented. However, Dr. Moffitt also noted that although Head Start failed to meet its objective of increasing IQ, a follow-up of Head Start participants’ shows that they have better health, are wealthier, have less criminal involvement, and are less likely to have children raised in single-parent homes. Work is under way to tease out the “active ingredients” in Head Start. In response to questions, Dr. Moffitt indicated parent-training and delay-of-gratification exercises as potential interventions to improve self-control, and she briefly described studies suggesting heredity, prefrontal cortex activity, birth anoxia, and social environment as factors in low self-control. Dr. Lis Nielsen noted work on the relationship between conscientiousness and health, as well as recent DBSR workshops on genetic studies, aging phenotypes, and their links with life-course studies.
- Division of Neuroscience: The Boundary Between Normal and Pathological Brain Aging
The boundary between normal and pathological aging of the brain is unclear By 70 or 80 years of age, the loss in brain volume is about 0.5 percent in adults without dementia and as much as 1 percent in adults with earliest signs of dementia. Yet patients in the early stages of AD tend to have much larger brain volume, and exhibit less loss than do individuals with normal cognitive function. In addition, the most profound pathology in AD, the appearance of plaques and tangles, also has been seen postmortem in individuals who never showed any signs of dementia. There clearly are multiple mechanisms affecting brain changes. Dr. Randy Buckner, of Harvard University, discussed work exploring further changes in the aging and AD brain, and his belief that there might be a distinct molecular mechanism causing this complex set of patterns.
Dr. Buckner and colleagues identified individuals with normal cognitive function and no amyloid deposition, as well as those with substantial amyloid deposition and early signs of pathology. However, about 30 percent of the individuals imaged showed substantial amyloid deposition but were symptom free. Measurement of cortical thickness through high-contrast imaging of the brain further showed that amyloid imaging can identify areas of cortical thinning long before the appearance of early signs of clinical dementia. Dr. Buckner and colleagues have also examined the functional integrity of large-scale circuits in the brain and found changes, particularly global changes in the white matter, that appear with age, even in the absence of amyloid deposition. These studies suggest multiple, potentially related cascades that exert different potential effects and have different progression rates across cognitive states. The techniques used by Dr. Buckner and his colleagues also provide biomarkers to measure these cascades at earlier stages of pathology.
With the increasing use of amyloid imaging, researchers now can examine why certain cortical regions are vulnerable to amyloid deposition and what that vulnerability might suggest about how normal aspects of brain function contribute to the pathophysiology of AD. Dr. Buckner and colleagues examined general properties in the brain architecture and found a correlation between amyloid deposition and brain regions that show the highest basal activity in neural networks. This observation suggests a relationship between brain activity or metabolism and the upregulation of amyloid deposition. It is possible that when an action potential fires, the release of neurotransmitters is accompanied by a release of amyloid-β. Thus the use and connectivity of specific brain regions might contribute to their vulnerability to amyloid deposition. Because many of the affected regions are involved in higher cognition, it is possible that the residual metabolism supporting these functions mediates disease.
In response to questions from Council members, Dr. Buckner would not speculate whether the data he presented show that individuals develop AD if they live long enough. He also noted that although studies have suggested that high cognitive activity and higher socioeconomic status are somewhat protective against AD, it is not yet clear how topographical brain images can relate to individual differences.
The open session of the 113th meeting of the National Advisory Council on Aging adjourned at 1:30 p.m. on May 25, 2011. The next meeting is scheduled for September 20–21, 2011.
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.
- 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.)
- 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.)
- These minutes will be approved formally by the Council at the next meeting on May 24–25, 2011, and corrections or notations will be stated in the minutes of that meeting. (Back to text.)
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING
(Terms end December 31) (*WGoP Member)(**Provisional member whose appointment is not yet official)
Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
Bethesda, MD 20892
Norman B. Anderson, Ph.D. (2014)
Chief Executive Officer and
Executive Vice President
American Psychological Association
Washington, DC 20002
Lisa F. Berkman, Ph.D. (2011)
Director and Professor
Harvard School of Public Health
Department of Society, Human Development, and Health, and Department of Epidemiology
Cambridge, MA 02138
Dale E. Bredesen, M.D. (2011)
Buck Institute for Age Research
Novato, CA 94945
Robert M. Califf, M.D. (2013)
Vice Chancellor for Clinical Research
Director, Duke Translational
Durham, NC 27710
*Hugh C. Hendrie, DSC, Ph.D. (2013)
Professor of Psychiatry
Indiana University School of Medicine and Regenstrief Institute, Inc.
Indiana University Center for Aging Research
Indianapolis, IN 46202
*Andrea Z. LaCroix, Ph.D., MPH (2012)
Fred Hutchinson Cancer Research Center
Women’s Health Initiative Clinical Coordinating Center
Seattle, WA 98109
Richard I. Morimoto, Ph.D. (2014)
Bill and Gayle Cook Professor of Biology
Departments of Biochemistry, Molecular, and Cell Biology
Evanston, IL 60208
Victor Molinari, Ph.D. (2012)
University of South Florida
Department of Aging and Mental Health
Tampa, FL 33612
*Lennart Mucke, M.D. (2012)
Department of Neurology
University of California, San Francisco
San Francisco, CA 94141
Eliseo J. Perez-Stable, M.D. (2014)
Department of Medicine
University of California
School of Medicine
San Francisco, CA 94143
Daniel P. Perry (2013)
Alliance for Aging Research
Washington, DC 20006
Ronald C. Petersen, Ph.D., M.D. (2013)
Department of Neurology
Mayo Clinic College of Medicine
Rochester, MN 55905
Arlan G. Richardson, Ph.D. (2013)
Barshop Institute on Longevity and Aging Studies
University of Texas Health Science Center
San Antonio, TX 78245
June Simmons (2012)
Chief Executive Officer
Partners in Care Foundation
San Fernando, CA 91340
James P. Smith, Ph.D. (2011)
Department of Labor and Population
Santa Monica, CA 90407
Stephanie A. Studenski, MPH, M.D. (2014)
Department of Medicine
University of Pittsburgh
Pittsburgh, PA 15213
Susan L. Swain, Ph.D. (2011)
Department of Pathology
University of Massachusetts Medical School
Worcester, MA 01655
*Terrie F. Wetle, Ph.D. (2013)
Associate Dean and Professor
Brown Medical School
Providence, RI 02912
EX OFFICIO MEMBERS
Department of Health and Human Services
Washington, DC 20202
Francis S. Collins, M.D., Ph.D.
National Institutes of Health
Public Health Service
Bethesda, MD 20892
James F. Burris, M.D.
Office of Research and Development
Department of Veterans Affairs
Washington, DC 20430
Kenneth G. Pugh, M.D.
Department of Medicine
National Naval Medical Center
Bethesda, MD 20889
Office of Program Development
U.S. Administration of Aging
Washington, DC 20020