The 114th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, September 20, 2011, at 3 p.m. in Building 31, Conference Room 10, 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, September 20, 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, September 21, from 8 a.m. to 1:20 p.m.
Dr. Norman Anderson
Dr. Lisa Berkman
Dr. Dale Bredesen
Dr. Robert Califf
Dr. Hugh C. Hendrie
Dr. Andrea LaCroix
Dr. Victor Molinari
Dr. Richard Morimoto
Dr. Lennart Mucke
Dr. Eliseo Perez-Stable
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. James F. Burris, Department of Veterans Affairs
Mr. Robert Hornyak, Administration on Aging
Dr. Kenneth G. Pugh, National Naval Medical Center
The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as attachment A.
Ms. Cate Bennett, Center for Scientific Review
Dr. Chris Sempos, NIH Office of Dietary Supplements
Dr. Lawrence Tabak, Principal Deputy Director, NIH
Mr. James Appleby, Gerontological Society of America
Dr. Amy F.T. Arnsten, Yale University School of Medicine
Dr. John Christopher Gallagher, Creighton University Medical Center
Ms. Linda Harootyan, Gerontological Society of America
Mary Jo Hoeksema, Population Association of America
Dr. Lisa Kilpatrick, RTI International
Ms. Pat Kobor, American Psychological Association
Dr. Rose M. Li, Rose Li and Associates, Inc.
Dr. Valter D. Longo, University of Southern California School of Gerontology
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Dr. Joseph P. Newhouse, Harvard Medical School Department of Health Care Policy
Dr. Olivia Okereke, Brigham and Women’s Hospital and Harvard University
Dr. David Scalzitti, American Physical Therapy Association
Dr. Megan Vijiarungam, American Association of Colleges of Osteopathic Medicine
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 886 applications requesting $1,403,479,374 for all years underwent initial review. The Council recommended 470 awards for a total of $1,025,924,211 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 114th NACA meeting and called the meeting to order at 8:00 a.m. on Wednesday, September 21, 2011.
Dr. Hodes reported that no new or definitive information was available on the budget. There has been some talk about a continuing resolution, at lower levels than FY2010-11, through mid-November 2011. All agencies might be required to propose plans for significant reductions from FY2010-11. At present, however, nothing has been confirmed.
Congress has passed the National Alzheimer’s Project Act (Public Law 111–375), which establishes a committee that reports to the U.S. Department of Health and Human Services (HHS) and to Congress on a national plan to address the escalating burden of Alzheimer’s disease (AD). Council member Ronald Petersen, Ph.D., M.D., will serve as Committee Chair, and Dr. Hodes will represent NIH. The names of non-Federal members can be viewed online, but the names of Federal members have not been announced yet. Dr. Hodes expects to provide an update at the January 2012 Council meeting.
Dr. Hodes focused the rest of his report on NIA communication and outreach activities, which have become vital in a time of fiscal challenges. Because of increasing Congressional interest and the work of constituents and advocacy groups, NIA has participated in two Congressional hearings in FY2011: one focused on AD in the House Energy and Commerce Subcommittee on Health, and a second focused on international efforts to address AD in the House Foreign Affairs Subcommittee on Africa, Global Health, and Human Rights. NIA also has increased its activity from two Congressional briefings per year in FY2008, FY2009, and FY2010 to seven in FY2011. In addition, NIA has increased its outreach and visits to Congressional districts, with visits to Minnesota, the U.S. Virgin Islands, and New York.
The visit to Minnesota is an excellent prototype of the NIA outreach activities. Dr. Hodes visited Minneapolis with Dr. Petersen and Senator Amy Klobuchar, of Minnesota, and participated in both an open house and a town meeting. They appeared with advocates such as representatives of the Alzheimer’s Association to discuss the importance of AD research and answer questions from members of the audience, which included people with general interests, academics, and some individuals with early-stage AD and their families. Senator Klobuchar and Drs. Hodes and Petersen then went to Rochester to tour a facility focused on neuroimaging, with several opportunities to communicate with constituents. Dr. Hodes noted that the Senator had been well briefed and was knowledgeable on research and its potential applications. He reminded the Council of the effectiveness of this forum, and he encouraged Council members to promote these kinds of efforts when they are not working for the Federal government.
NIA communication efforts also are relying on electronic media. The redesigned NIA website should be online in the near future, and it will provide updated features, enhanced search capabilities, better resources, and increased outreach for researchers and health professionals. In addition, NIA will increase its email alerts and direct mailings, increase awareness for the revamped Spotlight on Aging Research newsletter, and discuss research priorities and funding with organizations through newsletters and journals. Dr. Hodes closed by asking for help in conveying the significance of NIA activities and the importance of continued support.
In response to questions, Dr. Hodes reiterated that community visits can be the most effective forms of outreach. Often, NIH staff have no more than “sound bites” or “elevator moments” to communicate with Congress, whereas community visits offer opportunities for real communication and relationship building. Dr. Petersen added that Senator Klobuchar had requested a visit after attending a gala for the Alzheimer’s Association and hearing remarks on relative funding for AD versus other diseases. He noted that the visit focused on ongoing research in Minnesota and proved to be rewarding for all. Mr. Daniel Perry noted that many Congressional briefings have been organized by advocacy groups, and he emphasized the importance and potential benefit of working with outside groups to organize outreach events, particularly in Congressional settings. Dr. Norman Anderson suggested that organizations spend time with NIA staff to determine the most important topics Congress needs to know about.
Dr. Hodes also noted the benefits of recognizing academic institutions within a district and pointed out that Senators or Representatives often take pride in their local institutions. Dr. Susan Swain pointed out that creating avenues of outreach is easier for someone if their university or medical center has a Center for Aging or something similar, and she asked whether some type of center designation could be established, in the absence of additional funds, to allow smaller groups to build relationships. Although Dr. Hodes was not sure centers could be designated without an attached funding mechanism, he did suggest that institutions aggressively highlight their achievements whenever they receive a center or large research award. Highlighting those local achievements can bring recognition to a representative and instill pride in local institutions.
Council members asked about the proposed National Center for Advancing Translational Sciences (NCATS) and the Cures Acceleration Network (CAN). Dr. Hodes reported that although some activities have been announced for NCATS, including a search for a director, the Center does not yet exist legislatively, because no appropriations have been made. The same is true for CAN.
A binder containing media coverage was circulated among Council members.
January 24–25, 2012 (Tuesday and Wednesday)
May 22–23, 2012 (Tuesday and Wednesday)
September 18–19, 2012 (Tuesday and Wednesday)
January 29–30, 2013 (Tuesday and Wednesday)
The minutes of the May 2011 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.
Dr. Terrie Wetle reported that the Task Force had focused primarily on the NIA Research Supplements to Promote Diversity in Health-Related Research (Diversity Supplement Awards). Notable alumni from this program include Dr. Raynard Kington, former Deputy Director at NIH; Dr. Felipe Sierra, Director of the NIA Division of Aging Biology (DAB); and Dr. Yvette Roubideaux, Director of the United States Indian Health Service.
The Diversity Supplement Awards began in the late 1980s with a series of NIH-sponsored regional meetings on minority representation in the biomedical and behavioral sciences. The first notice promoting supplements was published in 1989. The first program analysis was carried out in 2003, and in 2005 the program was expanded to include investigators with disabilities or from disadvantaged socioeconomic backgrounds. An analysis of program results from 2002 through 2009 shows that the NIA program has seen an increase in the number of female awardees, as well as an increase in the proportion of awardees supported for postdoctoral training. The largest proportion of awards has come from the Division of Behavioral and Social Research (DBSR) and the Division of Neuroscience (DN). The success rate on subsequent NIH applications from 2002 through 2009 appears to be relatively high, but when the Loan Repayment Program is excluded from the data, the success rate has averaged about 26 percent. The number of applications to all NIH Institutes and Centers (ICs) has grown over time, with the exception of a brief dip in NIA-funded applications in 2008.
NIA Diversity Supplement awardees have shown a considerable amount of success in obtaining funding from other government agencies, as well as from foundations and from their home institutions. They also have shown considerable productivity, with an average of 16 papers published and 8 papers on which they served as first author. All awardees have had publications both in the past 3 years and in the past 18 months, and these publications have been in high-quality journals. Eighty percent of awardees currently work in academic research institutions, and another 8 percent are in clinical practice. Thus, although the numbers are still small, the NIA Diversity Supplements appear to be working. They have supported a large number of promising researchers, served as an important step toward their independence as researchers, and contributed to their overall productivity. The 2002–2009 data, along with the data from the 2003 analysis, support a key role for this program to continue to advance and improve diversity in aging research.
During its meeting on the previous day, the Task Force heard presentations from two previous Diversity Supplement Awardees. Dr. Olivia Okereke, of Harvard University and the Brigham and Women’s Hospital, discussed her work exploring the impact of diabetes, lifestyle factors, and insulin-like growth factor (IGF) on cognition. Dr. Okereke has gone on to receive pilot funding from the Harvard NeuroDiscovery Center to develop a shortened clinical dementia rating questionnaire; a K08 award to look at dietary fat composition, plasma lipids, and cognitive decline; and an R01 grant to study depression prevention in the Vitamin D and Omega-3 Trial. She has authored many publications, and she is highly skilled and productive. Dr. Kimberly Johnson, now an assistant professor at Duke University, used her Diversity Supplement Award to support formal training in a master’s degree in health science, as well as informal training through conferences, national meetings, and faculty development. Her work explored why African Americans use hospice care at lower rates. Dr. Johnson has gone on to receive a Beeson K08 award and is now examining a framework to understand racial differences in hospice use, with a focus on system-wide and patient-level factors.
Dr. Wetle concluded her presentation by highlighting an NIA website that matches researchers with interested community members to improve communication, networking, and research quality.
Dr. Robert Califf asked about trends for African American men, who appear to be losing out in the academic race. Ms. Kate Nagy, who conducted that 2002–2009 analysis, responded that several African American men have received supplements and gone on to successful careers. She offered to send the data to Council members.
Dr. Eliseo Perez-Stable lauded the progress of the program and reiterated Task Force suggestions that NIH revisit the duration of these awards, even in light of the current budgetary climate. Dr. Wetle also reported on disappointment among the Task Force that more people had not applied for supplements and discussions of better ways to advertise the program. Dr. Robin Barr emphasized that the program analyses shows that the NIA Diversity Supplement Awards program works.
Dr. Wetle also reported on the recent activities of the NIH Council of Councils (CoC), which is responsible for advising the NIH Director on the policies and activities of the Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI); serves as an external panel to IC Directors during the concept approval stage of the Common Fund/Roadmap initiative review process; and provides a second-level review of DPCPSI grants such as the Transformative R01 and the Early Independence Award.
Recently CoC has approved concepts in four areas:
Dr. Lisa Berkman reported that the working group considered one advisory meeting and one request for applications (RFA) concept clearance.
The advisory meeting, Advancing Alzheimer’s Disease Preclinical Therapy Development, convened more than 60 participants from academia, the biotechnology and pharmaceutical industries, private foundations, NIH, and the U.S. Food and Drug Administration (FDA) to delineate areas of development necessary for the successful translation of AD drug efforts into the clinic. The meeting specifically focused on new research directions and technological investments, overcoming challenges associated with the use of animal models, and new public-private partnerships. Participants generated the following key recommendations:
Dr. Suzana Petanceska, who provided NACA with highlights of the advisory meeting, reiterated the participants’ emphasis that addressing these recommendations will exceed the funding capacity of NIA. Thus partnerships between NIA and industry and private foundations were encouraged.
The Council discussion focused on the inadequacy of animal models for neurodegenerative diseases. Dr. Lennart Mucke pointed out that animal models are designed to dissect diseases and look at specific factors, but many people expect these models to simulate the complexity of disease and have difficulty changing their hypotheses based on models. He suggested that compound models might be more predictive for AD and other neurodegenerative diseases.
Council members also noted meeting participants’ discussion of the lack of rigor in clinical trials [Did this comment refer to lack of rigor in human clinical trials or in preclinical animal studies?]. Dr. Califf indicated that information and reproducibility of data are important factors. Many trials are designed based on an inadequate or selective understanding of data from preclinical animal models. On the basis of his own experiences in examining research reproducibility, Dr. Califf noted the need for an informatics infrastructure for animal models and preclinical studies, an infrastructure that allows investigators to move back and forth between animal models and clinical studies. Dr. Arlan Richardson added that this problem is not unique to aging research. For example, studies of increased lifespan are usually done under refined conditions. Dr. Richardson highlighted a DAB program in which three different sites test an intervention in animal models.
Dr. Hodes commented that even if studies are well conducted and reproducible, heterogeneity in strain remains a concern. Recent reports examining genetic heterogeneity among animal models used in lifespan studies found that calorie restriction, hypothesized to extend lifespan, did so only in a third of the mouse strains tested. Another third showed no effect, and the remaining third actually showed a decrease. Thus paradigms that have been in place for decades should be considered with care.
A motion to approve the recommendations from the advisory meeting was forwarded and seconded. The motion passed unanimously.
Dr. Berkman also reported that the Working Group considered and recommended approval to renew the AD Cooperative Study (ADCS), a clinical trial consortium that is one of NIA’s largest signature programs. ADCS supports the development of new evaluation instruments for clinical trials and of novel and innovative approaches to clinical trial design. The 5-year renewal would cover years 22 through 26.
Dr. Hugh Hendrie commended NIA on including non-pharmacological approaches and mild cognitive impairment in ADCS studies. A motion to approve renewal of ADCS was forwarded and seconded. The motion passed with one abstention.
The Working Group also discussed the need to develop and nurture the interface between researchers focused on neurodegenerative disorders and those focused on the basic biology of aging. Specific recommendations included workshops to bring investigators together; RFAs focused on questions such as how to introduce aging into models of neurodegenerative disease or whether anti-aging factors can stall or block cascades underlying disease; creation of a resource enabling a greater focus on aging and neurodegenerative disease, for example a repository of aged mouse models that simulate key aspects of neurodegenerative diseases; and extension of these initiatives to other ICs and age-related conditions. Council members acknowledged ongoing dialogue between the two groups at NIA, but they called for more to be done in the larger scientific community.
In response to questions from Dr. Wetle, Dr. Mucke, who participated in drafting these recommendations, noted that an animal model repository is especially important in light of calls for more rigorous preclinical studies. He also pointed out that such a repository will require more resources than one institution can provide and that a committee will be needed to examine complex models, decide which ones are most useful, and determine how to distribute them. The cost and investment of housing and aging mouse models can be a challenge, however. On the basis of experiences with an NIA-supported mutant mouse colony, a staff member suggested that an animal model repository will require a mechanism that ties the resource to its actual use, rather than age mice with the hopes that someone will use them. Dr. Swain agreed and suggested that the Council could encourage further consideration of the expenses, the inefficiencies associated with individual investigators developing models on their own, and the challenges of aging animals. She also suggested cellular aging as a field where a demonstration project could bring together researchers from different disciplines.
Dr. Barr summarized that the Council recommended the encouragement and acceleration of existing NIA efforts to integrate work on aging biology with basic research in neurodegenerative disease, as well as the consideration of aged animal models in targeting neurodegenerative disease. Workshops, RFAs, and other strategies will be considered. A motion to approve these recommendations was forwarded and seconded. The motion passed unanimously.
Dr. Hodes acknowledged the service of four outgoing Council members: Dr. Berkman, Dr. Dale Bredesen, Dr. James Smith, and Dr. Swain.
Dr. Petersen reminded the Council that a subcommittee had been charged with examining NIA’s review process because such a review had not been done before. The subcommittee met with the Scientific Review Branch (SRB) to identify issues, then further discussed those issues among themselves and in individual interviews with Division directors. The subcommittee also reviewed data provided by the Institute.
Overall, Division directors considered their relationship with SRB to be very good, and some said that this relationship had improved substantially during recent years. The directors also considered SRB to be doing an excellent job. Scientific review officers believed that at times the Divisions did not regard them as scientists, but as administrators. However, this was not the perception of Division directors. Rapport between scientific review officers and program officers was generally good, and program officers generally believed that the best reviews are taking place. The Divisions particularly appreciated the scientific review officers’ workload and efforts to maintain high-quality reviews, especially in light of funding constraints and during the 2 years of American Recovery and Reinvestment Act (ARRA) funding.
SRB staff requested consideration of more funds to attend scientific meetings in order to stay current and to network. This request was endorsed by the Division directors and the Council subcommittee. Scientific review officers also wanted more input on the acceptance of some grants, such as initially unclaimed grants that were assigned to NIA but peripheral to the Institute’s mission. In addition, although the officers acknowledged the need for a firewall between their branch and others within NIA, they wanted to participate in more NIA activities such as retreats, program planning, and funding opportunity announcements.
Opinions about Program Project (P01) reviews were mixed, and this process is still evolving. Some scientific review officers questioned whether P01 applications should undergo an initial review by Special Emphasis Panels (SEPs) prior to review by a parent committee with representation from all Divisions. Staff also noted that P01s formed a major portion of the portfolio in some Divisions but were hardly used in others.
The composition of review panels also was raised during the SRB review. Both Branch staff and Division directors observed that applications were reviewed by relatively junior investigators, but SRB would have to send several inquiries before it could find someone willing to accept a position on a panel. Scientific review officers noted that this is an area where traveling to scientific meetings and networking would be helpful. Building in incentives for senior investigators to participate on review panels also was suggested.
Scientific review officers also expressed that R03 applications should be reviewed by NIA. R03 reviews were transferred to the Center for Scientific Review (CSR) a few years ago, when SRB was overwhelmed by the number of R03 applications. However, SRB staff commented that there is not enough expertise on aging research or that CSR treats R03 applications similarly to R01s, either of which is detrimental to the review of aging applications.
On the basis of these interviews, the Council subcommittee concluded that SRB is functioning at a high level. The subcommittee concluded that the scientific contributions of SRB staff are appreciated, but also noted integration of this staff into NIA activities as an important issue. It further called for ongoing monitoring of communication between SRB and the rest of NIA, and, in agreement with SRB staff, recommended periodic reviews of SRB. The subcommittee also agreed that R03 reviews should be brought back to NIA and that increased travel budgets for SRB should be considered.
In response to further questions about P01 reviews, Dr. Hodes reminded Council members that the current process of percentiling P01 applications against CSR is not working. Because P01s are evaluated in ad hoc reviews, and because so many applications receive good scores, a large majority of P01 applications are scored in a compressed range. Judgments about single- versus dual-level reviews will be made once the outcomes from several council rounds of single-level reviews where P01s are not percentiled against CSR are known. However, a dual-level review would resemble the process used by the National Heart, Lung, and Blood Institute (NHLBI), where the ad hoc panel would conduct a primary review with narratives, but no scores, and a parent committee would accept the subject matter expertise of the ad hoc panel but assign scores based on the strengths of the overall program project. Dr. Hodes noted that the Council would be informed of any decision about the review process, but he invited Council members to provide input before any changes were made.
Dr. Ramesh Vemuri, SRB Chief, reported that when the issue first arose, the Branch staff visited different ICs and identified two workable models. In the NHLBI model, the investigators send information 4 months before the application is submitted and the review process begins 2 months before, when abstracts on key personnel are submitted. A member of the initial review committee reports to the parent committee, and half the applications are unscored. In the CSR model, all information is submitted to the parent committee, and the first level does not provide a score. However, Dr. Vemuri noted that the second level was more general and that first-level reviewer, who might have more specific expertise, often felt frustrated and eventually dropped out of the review process. He asked NIA to consider the constraints and limitations of each system before choosing one to use.
Dr. Berkman expressed concerns that a dual-review system would place applicants in “double jeopardy,” especially if the parent committee review is not a true peer review. Dr. Mucke suggested a process whereby one or two members of the study section would participate in the site visit then discuss the initial review with the parent committee. In this way, the two reviews would be integrated. Drs. Swain and Richardson pointed out the difficulty of reviewing one project without knowing about the others, and they suggested a process where members of each Division rank applications within their own divisions. Other Council members suggested a process by which the first level would score projects based on enthusiasm, whereas the second level would evaluate overall impact. There were mixed opinions about whether NIA should have one multidisciplinary parent committee or a separate parent committee for each discipline. Dr. Mucke also suggested soliciting additional input from the field (e.g., the principal investigators on existing P01s), because these investigators might have good ideas on ways to improve review and are nervous about any changes that might be made.
Dr. Barr summarized the SRB review subcommittee’s recommendations to review travel budgets for SRB officers, bring R03 reviews back into NIA, and continue to discuss how P01 reviews can improve. A motion to accept these recommendations was forwarded and seconded. The motion passed unanimously.
Dr. Lawrence Tabak, Principal Deputy Director, NIH, noted that diversity programs at NIH aim to attract the best and brightest scientists into biomedical and behavioral research. He emphasized that these programs were designed not as social engineering but toward creating the best scientific workforce. Despite these efforts, the impact on the diversity of the NIH-funded workforce has been disappointing. In 2008, African Americans constituted 10 percent of the U.S. population, and Latinos 12 percent, but they only represented 1.2 percent and 3.4 percent, respectively, of funded principal investigators. Even among full-time medical school faculty, only 2.9 percent are African American and 4.3 percent are Latino.
To address these shortfalls, NIH has commissioned several studies. One, an evaluation of education and career outcomes, with implications for policy, has been published online by the Social Science Research Network. Another, which summarizes sex differences in application, success, and funding rates for extramural NIH programs, has shown slightly less success for applications from women. Dr. Tabak focused his presentation on a study recently published in Science on race, ethnicity, and research awards (19 August 2011, Vol. 333, no. 6045: 1015-1019).
In this study, Ginther and colleagues assessed the probability of securing first-time R01 funding from 2000 through 2006 by Ph.D. investigators, controlling for observable characteristics such as NIH training, research experience, and home institutions. Of approximately 83,000 applications submitted by 40,000 unique Ph.D. investigators, only 1,149 were submitted by black or African American investigators. Assuming an award rate similar to those seen among white applicants, 357 of these applications would have been funded. However, only 185 were awarded. The scores and rate of pay decisions by ICs were similar among groups, suggesting differences at the level of peer review. Award probabilities were correlated with the NIH funding rank of the applicants’ institution. Yet even among the top 30 NIH-supported organizations, black or African American applicants had the lowest award probability. In addition, black/African American and Latino applicants were less likely to resubmit applications, which are particularly critical in a constrained funding environment, when applications are rarely awarded on the first attempt. Moreover, participation in NIH-supported training or career development programs had a positive effect on R01 award rates, but much more for white applicants than for black or African American applicants.
In an accompanying commentary published in Science, Dr. Tabak and Dr. Francis Collins, NIH Director, declared the findings to be unacceptable, and they go on to describe NIH’s continued commitment to a diverse biomedical workforce, additional analyses that have been conducted, and steps to seek out causes of racial and ethnic differences in awards. The agency is engaging in vigorous communication with all stakeholders, with the understanding that the problem will not be solved overnight. Because review experience correlates with success, NIH has established an Early Career Reviewers program, which will increase both the diversity of review panels and the exposure of investigators from diverse institutions to the review process. NIH also will conduct experiments to identify sources of bias, for example by de-identifying applications; testing reviewers’ ability to determine applicants’ race even on de-identified applications; assessing different types and timing of training against bias; and using validated tools such as Project Implicit. NIH also will assess whether the proportion of underrepresented minorities on review committees affect outcomes and will work with academic institutions to create pre-application mentoring programs for junior faculty. NIH has funded several extramural grants to study interventions that can strengthen the pipeline in a way to improve workforce diversity, and it has established both internal and external committees focused on diversity in the biomedical research workforce.
In response to questions from the Council, Dr. Tabak noted that the Ginther study analyzed data in aggregate form but looked at scientific fields as assessed by study sections. The study sections did not show differential success rates, but Dr. Tabak noted that the vast majority, if not all, of black and African American applicants submitted applications in behavioral sciences, particularly in the area of health disparities. Almost none of these applicants submitted applications in the basic sciences. In response to questions from Dr. Andrea LaCroix, Dr. Tabak noted that the data did not parse out first-time applicants.
Dr. Perez-Stable noted that although the distributions reported by Dr. Tabak are instructive, they are not exact. For example, the category “Other/Unknown” tends to include people of color, many of whom are biracial. Dr. Perez-Stable suggested that NIH pay more attention to Census groupings to understand which groups are really affected. He further pointed out that although the success rates get the most headlines, the number of African Americans and Latinos submitting applications is equally disappointing and deserves just as much emphasis. Dr. Perez-Stable also noted the emphasis on Ph.D. investigators and the need to look more at M.D.s and social scientists. Dr. Tabak agreed, and elaborated that the number of applicants self-identifying as “Other” is increasing and that the “Other” category is doing as well as white applicants. However, he also noted that an informal analysis of M.D.s found similar trends and that people of color tend to choose careers in the community, rather than careers in academic research.
Dr. Anderson was troubled that differences still exist even after data are controlled for “reputational issues” such as institution, publications, and grant experience, and he emphasized that NIH will have to address both issues with the pipeline and those with differential success rates. However, he commended NIH for taking this issue seriously and for looking at the levels of individual investigator, reviewer, and system. Dr. Anderson particularly acknowledged the inclusion of Project Implicit and noted evidence that just taking that test increases awareness and is beneficial. He further suggested that NIH also look to the Institute of Medicine report on differences in health care, as well as to research on housing audits or salary differentials, for ideas.
Dr. LaCroix noted the frustration of many young applicants, who are likely to have their applications rejected, and she feared that many would become so ungratified that they would choose a different career path. She also noted that the review process often rewards investigators for selling themselves, rather than their project. Drawing on her experiences in mentoring junior faculty who were first-generation college graduates, Dr. LaCroix further pointed out challenges faced by mentors attempting to overcome lack of preparation, for example in writing skills. Dr. Tabak and other Council members agreed that mentorship, though critical, is becoming increasingly difficult at the local and institution level. In some places, formal and rigorous mentoring programs do not exist.
Dr. Richard Suzman, Director of the Division of Behavioral and Social Research (DBSR) added that having access to an experienced co-principal investigator can be critically helpful; this might therefore be a place for NIH intervention and encouragement. Dr. Suzman also noted that many applications from minority applicants may be more problem-oriented rather than driven by scientific issues and so may not be seen as at the cutting edge of research.
In response to questions from Dr. Marie Bernard, NIA Deputy Director, Dr. Tabak explained that the Early Career Reviewers program looks for a strong record of high-quality publications but not necessarily for a history of NIH funding. He added that NIH wants to reach out to a more diverse group of institutions to find faculty who are also strong scientists, and he encouraged Council members to suggest such faculty from their own institutions.
In both humans and monkeys, increasing age is associated with impairments in working memory, multitasking, insight, decision making, and other executive functions, as well as with an increased susceptibility to interference. Yet in the information age, these functions are becoming even more important as tasks such as career maintenance, financial management, and medication administration become increasingly complex. Dr. Amy Arnsten, of the Yale University School of Medicine, described work focused on the prefrontal cortex (PFC) of the brain, where executive functions occur.
Studies in rhesus monkeys have shown that the higher functions in the PFC arise from neuronal networks that excite each other. In highly evolved circuits, these layer 3 networks connect at the synapse, in long, thin spines, and allow gating, and it is these spines that are most vulnerable to normal aging. Dr. Arnsten and colleagues have used a spatial working memory task to further examine the physiology of the aged PFC. They have identified two populations of cells in the PFC: cue cells, which fire specifically to a cue when it comes on, through bottom-up stimulation; and delay cells, a unique population of cells that fire to that cue but keep firing during the delay period, stimulated by their networks to keep that cue in mind. The delay cells, which fire only in the direction of that specific cue, undergo robust memory-related firing in younger monkeys, but this firing is dramatically reduced with age. Thus, the ability to discriminate what should be remembered from what should not be declines with age. However, cue-cell firing and bottom-up processing remain intact.
Biochemical data suggest that the loss in the memory-related firing of delay cells arises from dysregulation of cyclic adenosine monophosphate (cAMP) signaling. Stress or fatigue promotes production of cAMP, and potassium channels open gating network connections so that persistent firing drops. In the younger brain, the elimination of cAMP by the stress enzyme PDE4A and further inhibition of cAMP by alpha 2A receptors restore control of signaling and re-establish network connections. In the older brain, however, PDE4A and alpha 2A receptors are lost. In addition, PDE4A is expressed in the necks of long, thin spines, where gating and potassium channels are found, and other cAMP signaling proteins are expressed in these spines.
Dr. Arnsten’s group has further shown that administration of the drug guanfacine, which stimulates alpha 2A receptors, can inhibit cAMP production and increase network firing. These findings are consistent with other work showing that systemic administration of guanfacine improves behavior, working memory, and resistance to interference. Although guanfacine has been on the market to treat hypertension, it also has been approved by the FDA for the treatment of attention-deficit-hyperactivity disorder, and increasing evidence suggests a benefit of guanfacine in treating Tourette’s syndrome, autism, traumatic brain injury affecting the PFC, strokes, and emergent delirium related to anesthesia. Further work is under way to determine whether this drug can improve PFC functions in older people.
In response to questions from the Council, Dr. Arnsten speculated that cellular age might play a role in age-associated declines in executive function. It is not clear, however, whether there is heterogeneity in effective aging among monkeys as has been seen in rodents. Nor is it clear whether age-associated dysregulation of cAMP signaling is a disease process or a time-related phenomenon similar to radioactive decay.
In 2008, the State of Oregon used a lottery system to randomly enroll uninsured residents into its Medicaid program. Approximately 85,000 applicants signed up for the lottery during a 5-week period, and of those, about 30,000 were selected and asked to provide additional information on income, assets, and citizenship. The Oregon Health Insurance Study, an ARRA-funded study, assessed the effects of enrollment on use of services, health outcomes, and financial outcomes. Dr. Joseph P. Newhouse, of the Harvard Medical School Department of Health Care Policy, presented data from the first year of the study.
Only 60 percent of lottery winners responded to requests for more information on assets, income, and citizenship, and only half met eligibility criteria for the Oregon Medicaid program. Slightly more than half of the lottery winners were female, and there was a wide age distribution. Chronic disease and depression were prevalent, and half of the winners did not work. Enrollment in Medicaid was associated with increases in use of preventive care, outpatient visits, and rates of hospitalization, suggesting a 25 percent increase in health care spending. Enrollment did not appear to have an effect on emergency room visits. The study is not sufficiently powered to examine effects on mortality, but first-year data suggest substantial effects on self-reported health. The proportion of individuals reporting good or very good health was higher by 13 percent in the Medicaid group, and the number of days of reported good health was higher by 5 percent. Effects on financial strain were not apparent except for a 10 percent reduction among the Medicaid group in terms of collections related to medical debt.
Dr. Newhouse noted that although enrollment of uninsured persons into Medicaid was associated with substantial improvement in self-reported physical and mental health, about two-thirds of these health gains occurred almost immediately. It is not clear then whether the observed gains merely reflect a general decrease in anxiety. In addition, the study population is similar to the population targeted by the Affordable Care Act Medicaid Expansion, but it is not fully representative of the U.S. population. Further clinical measures have been taken and will be included in future results.
In response to questions from Dr. Hendrie, Dr. Newhouse clarified that hospitalization rates increased by 30 percent and length of stays by 20 percent in the Medicaid group. There also appeared to be a large increase in the number of procedures. However, Dr. Newhouse speculated that this effect might be transient and that hospitalization rates may actually decrease overall the longer individuals are in the Medicaid program.
Dr. Smith pointed out that self-reports on health are subjective and that the observed effects could simply arise from a better feeling about life. Dr. Newhouse acknowledged the subjective nature of these reports, but he added that study measures also include more objective questions about activities of daily living, as well as a physical health scale. He further noted that this study differed from a RAND study which was the only other randomized health insurance study done in a developed country. Compared with that study, the Oregon Health Insurance Study population is a more disadvantaged population with a wider age distribution. All have income under 100 percent of the Federal poverty level, many have no supportive partners or real health providers, and many face severe financial stress, possibly as a result of poor health.
In response to questions from Dr. Perez-Stable, Dr. Newhouse noted that most of the increased hospitalizations appear to be associated with heart disease. As a result of enrollment in Medicaid, many patients were seeing a doctor for the first time, and concerned doctors were sending them to the hospital. Dr. Newhouse added that most of these patients had been able to access medical care under the safety net before. He further indicated that many in the control group reported a usual source of care but that the number increased substantially in the treatment group.
Dr. Stephanie Studenski asked whether information is available on study participants prior to their selection in the lottery, and she expressed concern that failure to randomize participants to a new health care benefit could result in declines in perceived health or actual harms. Dr. Newhouse responded that little information was available on participants prior to the lottery. He further noted that study investigators were actually concerned that improvements in perceived health would arise simply from participants winning the lottery. It is not clear whether such an effect will persist.
Dr. Valter Longo, of the University of Southern California School of Gerontology, described work in which results from yeast studies were further explored in other models and in clinical trials. Studies of yeast have shown that yeast cells switched from glucose-rich medium to starvation medium become protected against many toxins. Many of the genes controlling starvation-dependent protection are orthologs of human oncogenes, suggesting that starvation might protect normal cells from chemotherapy. This hypothesis would further suggest that cancer cells will not receive such protection because of oncogene mutations.
In a proof-of-principle study, Dr. Longo and colleagues found that a cancer-like yeast strain was killed by treatment with a chemotherapy drug, but normal yeast strains were not. These results were consistent with mouse studies in which starvation for 48 to 72 hours protected normal cells, but not cancer cells, from drugs such as etoposide, cisplatin, and doxorubicin. Further studies in mice demonstrated a role for glucose levels and expression of insulin-like growth factor 1 (IGF-1). In normal cells, stress response is associated with a reduction in glucose and IGF-1 levels, resulting in a downregulation of many proto-oncogenic pathways. However, although glucose and IGF-1 levels are reduced in cancer cells, oncogenic mutations likely prevent the stress-associated downregulation of oncogenic pathways, and these cells thus remain sensitive to chemotherapy. Studies are under way to determine whether starvation actively worsens conditions for cancer cells.
Anecdotal evidence suggests that patients who combine starvation with chemotherapy feel better and experience fewer side effects associated with therapy. However, a starvation time of 48 to 72 hours in mice translates to 5 days in humans, which is not feasible. In a company supported partly by the National Cancer Institute, through a Small Business Innovation Research grant, Dr. Longo and colleagues have developed a substitution diet based on yeast and animal studies, such that patients can receive the benefits of fasting without the risk for undernourishment. A clinical trial of this diet is planned.
In response to questions from Dr. Swain, Dr. Longo noted that fasting and chemotherapy must be timed precisely, because IGF-1 levels rebound fairly rapidly once a normal diet is reinstated. Dr. Hodes cited Dr. Longo’s work as an example of the ingenuity of investigators in making connections and translating results in an orderly way.
Vitamin D intake occurs both from diet and from absorption through the skin from ultraviolet light in the sun. Once in the body, vitamin D travels to the liver and is converted to 25-hydroxyvitamin D (25OHD), which is what is measured in the clinic. This metabolite travels to the kidney, where it is further converted into 1,25-dihydroxyvitamin D. However, there is also a catalytic step between 25OHD and 1,25-dihydroxyvitamin D that results in an inactive metabolite.
Each measurement of 25OHD costs about $150; thus population screening for vitamin D deficiencies has become a billion-dollar industry. Yet vitamin D is clinically problematic, because definitions of normal levels, insufficiency, and deficiency in vitamin D differ among groups. The Endocrine Society recommends a threshold level of 30 ng/ml, whereas the Institute of Medicine (IOM) and the World Health Organization (WHO) recommend a threshold level of 20 ng/ml. Moreover, the ability to determine whether someone has a vitamin D deficiency differs depending on whether measurements are taken in the winter or summer.
On the basis of an extensive review and an Agency for Healthcare Research and Quality (AHRQ) report by the Tufts Evidence-based Practice Center, the IOM has issued new guidelines on vitamin D and calcium intake. The report found implications for vitamin D deficiency not only in poorer bone health, but also in poorer physical performance and in diseases and conditions including cardiovascular disease, cancer, diabetes, and immune disorders. However, the report also found that the majority of findings regarding vitamin D, calcium, or the combination are inconsistent, making it impossible to establish dose-response relationships among intake of vitamin D, calcium, or both.
Dr. John Gallagher, of the Creighton University Medical Center, discussed the IOM/AHRQ review and the rationale for the Endocrine Society and IOM guidelines. He noted that the Endocrine Society recommended a threshold of 30 ng/ml because of suggestions that serum parathyroid hormone (PTH) plateaus at a serum 25OHD level of 30 ng/ml, that calcium absorption shows a threshold response at 32 ng/ml 25OHD, and that a serum 25OHD level above 24 ng/ml is necessary to prevent falls. However, across 70 worldwide studies, the AHRQ review found no consistent level of serum 25OHD associated with a PTH plateau. With respect to threshold effects in calcium absorption, more than 1,000 papers showed no threshold effects, and 1 paper included a theoretical point, rather than a measurement. When this theoretical point was removed, the threshold for calcium absorption was approximately 15 to 20 ng/ml 25OHD. Moreover, doses were not aligned correctly in the paper suggesting a threshold of 24 ng/ml, and further analysis by the IOM found that the effect of vitamin D on falls is nonsignificant.
The quality of data has been poor, and the majority of studies reviewed by the IOM and AHRQ have focused on vitamin D and calcium, not on vitamin D alone. However, evidence does support a serum 25OHD threshold of 20 ng/ml to define vitamin D insufficiency. For example, several studies have shown a significant increase in hip fractures only below 20 ng/ml. In addition, enough data were available for meta-analyses, which supported a recommended daily allowance of 400 units of vitamin D in individuals aged 50 years or older. A clinical trial is under way to further assess the vitamin D dose needed to achieve a serum 25OHD level of 20 ng/ml.
In response to questions from the Council, Dr. Gallagher speculated that in the United States, individuals’ vitamin D levels would be low only during the fall and winter months, when there is less exposure to the sun, but this should be studied further. Otherwise, the implications of the IOM guidelines on vitamin D screening are not yet clear.
The open session of the 114th meeting of the National Advisory Council on Aging adjourned at 1:20 p.m. on September 21, 2011. The next meeting is scheduled for January 24–25, 2012.
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.
(Terms end December 31) (*Member WGoP)
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 Medicine Institute
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
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
Robin A. Barr, D.Phil
Division of Extramural Activities
National Institute on Aging
Bethesda, MD 20892