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The 116th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, May 22, 2012, 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, May 22, 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 23, from 8:00 a.m. to 1:25 p.m.
Council Participants:
Dr. Norman Anderson
Dr. Laura Carstensen
Dr. Dennis Choi
Dr. Ana Maria Cuervo
Dr. Hugh C. Hendrie
Dr. Andrea LaCroix
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. Jonathan Skinner (phone)
Dr. Stephanie Studenski
Dr. Terrie F. Wetle
Absent:
Dr. Robert Califf
Dr. Victor Molinari
Dr. Jonathan Skinner
Ex Officio Participants:
Mr. Robert Hornyak, Administration on Aging
Absent Ex Officio Participants:
Dr. James F. Burris, Department of Veterans Affairs
Dr. Kenneth G. Pugh, National Naval Medical Center
Edwin L. Walker, 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:
Dr. Mercy Prabhudas, National Institute of Allergy and Infectious Diseases
Ms. Teresa Shea, Center for Information Technology
Dr. Michelle Washko, Administration for Community Living
Members of the Public Present:
Dr. Kimberly Acquaviva, George Washington University
Mr. James Appleby, Gerontological Society of America
Dr. Ulyana Desiderio, American Society of Hematology
Dr. Loretta Doan, The Endocrine Society
Dr. J. Taylor Harden, Building Academic Geriatric Nursing Capacity, American Academy of Nursing
Dr. Pat Kobor, American Psychological Association
Dr. Arthur Kramer, University of Illinois at Urbana-Champaign
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Ms. Katie Moore, The Endocrine Society
Dr. Lauren Nicholas, University of Michigan
Dr. Howard T. Petrie, The Scripps Research Institute
REVIEW OF APPLICATIONS
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 1160 applications requesting $1,431,341,567 for all years underwent initial review. The Council recommended 620 awards for a total of $826,416,467 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.
CALL TO ORDER
Dr. Hodes welcomed members to the open session of the 116th NACA meeting and called the meeting to order at 8:11 a.m. on Wednesday, May 23, 2012.
Director’s Status Report
Dr. Hodes noted that topics surrounding Alzheimer’s disease (AD) had abounded, both around NIA and in the news, during the past few months. In January 2011, the National Alzheimer’s Project Act (NAPA) was signed into law, and in February 2012, Department of Health and Human Services (HHS) Secretary Kathleen Sebelius announced that $50 million would be directed immediately toward AD research. About half of these funds will be devoted to AD genome sequencing. The $50 million also will be used to support Small Business Innovation Research and Small Business Technology Transfer grants, as well as two clinical trials, one on prevention and the other on treatment. NIH is still in the process of intense scientific planning to determine the best strategy for the funds overall.
NAPA includes a National Plan to Address Alzheimer’s Disease. Implementation of the broad goals outlined by this plan will be guided partly by recommendations from the Alzheimer’s Disease Research Summit, held May 14–15, 2012, at NIH. Dr. Hodes reported that 500 participants representing 38 States had attended the meeting and that an additional 500 individuals watched the Summit by webcast. NACA reviewed the recommendations from the Summit at a later time during the open session (see below).
Dr. Hodes further reported that NIA, in collaboration with the Alzheimer’s Association, had begun developing an inventory of AD research. The first step in this process is the development of an ontology to better identify in which areas NIA has already invested and where the gaps are. An inventory is available to the public online, in the form of an Excel worksheet, and NIA plans to convert this to database form by the summer. Dr. Hodes noted that the inventory will serve as a rich source of information about ongoing AD research, and he invited other organizations to join the effort and list their projects. He also noted a new HHS website, www.alzheimers.gov, that provides information for families and caregivers to resources related to AD and related dementias from agencies and organizations with expertise in these areas.
A reorganization within HHS has combined the Administration on Aging, the Office on Disability, and the Administration on Developmental Disabilities into a single agency, the Administration for Community Living (ACL). ACL will work to increase full participation in the community and access to community supports. On May 17–18, NIA and ACL, in collaboration with the National Institute on Disability and Rehabilitation Research (a component of the U.S. Department of Education’s Office of Special Education and Rehabilitative Services [OSERS]) and the Interagency Committee on Disability Research), held a conference on aging and disability. One product of this conference is a webinar series on AD and tools for caregivers. Dr. Hodes pointed out that the AD research agenda is not comprehensive; activities such as the collaboration between NIA and ACL will include efforts focused on patient, clinical, and long-term care.
Dr. Hodes closed his report by noting the proposal for special Council review of applications from investigators with more than $1.5 million total costs in research support. He clarified that this proposal was made in response to ongoing budgetary constraints and does not constitute a ban on increased funding in areas of importance. Rather, it calls for closer scrutiny of additional funding to these investigators. There was no discussion.
Future Meeting Dates
September 18–19, 2012 (Tuesday and Wednesday)
January 29–30, 2013 (Tuesday and Wednesday)
June 4–5, 2013 (Tuesday and Wednesday)
September 17–18, 2013 (Tuesday and Wednesday)
Consideration of Minutes of the Last Meeting
The minutes of the January 2012 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.
REPORT: TASK FORCE ON MINORITY AGING RESEARCH
Dr. Eliseo Perez-Stable reported on a presentation by Dr. Roy Wilson, recently named Deputy Director of the National Institute on Minority Health and Health Disparities (NIMHD), who described recent efforts related to the NIH Health Disparities Strategic Plan. The Plan for 2009–2013 has been updated and is now posted on the NIMHD website, and NIMHD has begun the process for the 2014–2018 Plan. Dr. Wilson outlined his goals to review the literature, identify priority areas, create internal and external advisory groups, and begin trans-NIH strategic planning. Dr. Wilson also will try to meet with directors and representatives of intramural research programs from each Institute or Center (IC).
During his presentation to the task force, Dr. Wilson elaborated on the need to create priority areas, rather than attempt to cover the entire spectrum of health disparities. He outlined an approach that would build on priority areas proposed by each constituency group. Dr. Wilson emphasized increasing dissemination of health disparities research findings and translation of those findings to practice. He also noted continuing concern about capacity in the workforce, particularly the ability to conduct health disparities research and the proportion of underrepresented minorities in the workforce. Dr. Perez-Stable reported that Dr. Wilson aims to have the NIH Health Disparities Strategic Plan for 2014–2018 completed by the end of 2013, with final release in early 2014.
Dr. Perez-Stable reported that the task force is also reviewing the NIA health disparities and diversity training portfolios. This review has involved a substantive amount of work with respect to data gathering and categorization. Teleconferences will be held over the summer to direct and continue the work, and the task force will meet in September before the Council meeting to discuss the portfolios in further detail. Dr. Perez-Stable noted that 1,680 grants from 2002 to 2010 were initially classified as related to health disparities. After further review by NIA staff, that number is now 985. Sixty percent of these grants were focused specifically on health disparities, another group of grants were focused on racial/ethnic or socioeconomic underrepresentation, and others were training grants. Dr. Perez-Stable also noted that about 35 to 40 percent of the grants did not fit into any of these categories. He expected to report more details at the September Council meeting. He acknowledged that the working group focused on this review, and he invited other Council members to participate.
In closing, Dr. Perez-Stable reported that the Summer Research Institute had accepted 35 students from among more than 100 applicants.
Dr. Robin Barr noted that the NIH Health Disparities Strategic Plan for 2014–2018 would include an evaluation component and that a methodologist has been hired to develop that component. Dr. Marie Bernard, NIA Deputy Director, added that the Plan for 2009–2013 is more of an inventory and that each IC is responsible for reporting how its inventory might have changed each year, and she envisioned that the 2014–2018 Plan would include more concrete outcomes evaluation. Dr. Perez-Stable assumed that yearly IC reports on health disparities would look similar to yearly reports from the Agency for Healthcare Research and Quality.
Dr. Richard Morimoto expressed excitement about the work under way at NIA, and he highlighted Dr. Wilson’s suggestion that the reporting and structure at NIA could perhaps guide other ICs. Dr. Bernard added that NIA has been a leader in evaluating issues of diversity and health disparities, and she noted, for example, that NIA is one of the few ICs that has reviewed its diversity supplements program.
REPORT: COUNCIL OF COUNCILS
Dr. Terrie Wetle reminded Council members that the Council of Councils (CoC) had been established through the NIH Reform Act of 2006. CoC includes representatives from the advisory councils for each of the NIH ICs, and from the Council of Public Representatives. Congress established CoC to advise on the policies and activities of the Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI); make recommendations on trans-NIH research supported by the Common Fund; and guide DPCPSI on high-risk, high-reward research. Over the years, CoC’s role has expanded to include concept reviews.
Recent budget legislation dissolved the National Center for Research Resources (NCRR) and created the National Center for Advancing Translational Sciences (NCATS), causing several organizational changes that directly affect CoC. Several NCRR infrastructure divisions, including the Division of Comparative Medicine, the Division of Construction and Instruments, the Science Education Partnership Awards, and the Office of Science Education, are now housed within the DPCPSI Office of Research Infrastructure Programs. As a result, CoC’s role has expanded to include second-level reviews of these programs. In addition, the Office of Medical Applications Research (OMAR) has been consolidated into the Office of Disease Prevention. With this consolidation, OMAR will hold consensus development conferences but at a greater frequency, and will no longer hold state-of-the-science conferences.
Dr. Wetle provided updates on several Common Fund programs. Five Early Independence Awardees have been named to the Forbes 30 Under 30 Best list. The Transformative R01 program received 750 applications during the latest round, and reviews are under way. Seven requests for applications (RFAs) have been issued under the Metabolomics Project, and three have been issued under the Single-Cell Analysis Project. The H3 Africa Project has issued RFAs for biorepositories, informatics centers, and research centers to improve the quality of genomics research in sub-Saharan Africa, and the Fogarty Medical Partnership Initiative is accepting applications for additional awards. The Rapid Access to Interventional Development program has been renamed the Bridging Interventional Development Gaps (BrIDGs) program.
Dr. Wetle also noted a new role for CoC with respect to the use of chimpanzees in biomedical and behavioral research. Although research involving chimpanzees has served an important role in advancing human health, new methods have provided alternative approaches in several areas of research, and there are several concerns about the use of chimpanzees. In December 2010, NIH commissioned the Institute of Medicine (IOM) to conduct a study to determine whether chimpanzees are or will be necessary for research, and in December 2011, IOM issued its findings and recommended that chimpanzees be used in research only if:
The knowledge gained advances the public’s health.
There is no alternative research method, or the research cannot be performed ethically on humans.
Chimpanzees are maintained in their natural habitats or in ecologically and socially appropriate environments.
IOM acknowledged that some research areas (e.g., re-emerging or new emerging diseases) might justify the use of chimpanzees. However, IOM was unable to reach consensus on the use of chimpanzees in developing prophylactic hepatitis C vaccines.
CoC has been asked to create a working group to determine how best to implement the IOM recommendations. The working group was officially charged at the February CoC meeting, and it will provide an update at the next CoC meeting on June 5. A final report is expected to be posted for public comment in January 2013.
Dr. Barr and Dr. Richard Suzman, Director of the Division of Behavioral and Social Research (DBSR), noted that the IOM recommendations on chimpanzees in research have already begun to discourage applications that propose purely observational studies. Dr. Suzman further noted that applications in the field of biodemography have been unduly hampered. Dr. Dennis Choi voiced his concern that studies with potential implications for human cognition will be erroneously disqualified as “outside the realm” of NIH’s purview but really should qualify given their relatedness to human health.
Dr. Wetle closed her report by noting that because CoC members represent 27 ICs and because the advisory council for each IC conducts secondary review in a different way, CoC has had to discuss how best to conduct its own secondary review. For example, CoC members have discussed whether members should have access to the actual applications and not just the summary statements. Dr. Wetle noted that these discussions have given her a greater appreciation of how NACA conducts its secondary reviews.
Dr. Barr pointed out that the dissolution of NCRR and formation of NCATS is not a simple switch. NIH is still working out the redistribution of programs to other ICs and the NIH Office of the Director. In response to questions, Dr. Barr noted that NIA is one of the ICs least affected by these changes.
REPORT: WORKING GROUP ON PROGRAM
Dr. Richard Morimoto reported that the working group had considered one set of recommendations, two workshops, and several funding opportunity announcement (FOA) concept clearances. Working group members described their assigned items.
Dr. Stephanie Studenski reminded the Council that the Clinical Trials Advisory Panel (CTAP) advises NIA on potentially high-impact intervention studies of substantial size, and she reported on CTAP recommendations in two intervention areas. The first is related to an ongoing study on the use of yoga, exercise, and omega 3-fatty acid supplementation in managing menopausal symptoms. Dr. Andrea LaCroix added that the study will be unblinded in July and the final paper completed by the September Council meeting. CTAP urged the network supporting this study to work further on studies and intervention trials for vaginal aging, a topic that has been little studied. The second intervention area concerns the development of a multisite clinical trial evaluating the appropriate dosing and effects of vitamin D supplementation, particularly for mobility and falls. CTAP strongly recommended moving forward with this trial and considered several scenarios of varying resource totals. The Working Group on Program motioned that the Council accept CTAP’s recommendations. The motion was seconded by Council members and passed unanimously.
Dr. Morimoto discussed a proposal for two workshops on 1) the epigenetics of aging and 2) the role of inflammation in aging and age-related diseases. Both workshops received a large amount of enthusiasm from the working group, which motioned that the workshops be accepted and recommended to NIA. The motion was seconded by Council members and passed unanimously.
Dr. LaCroix described a proposal for a secondary analysis of the CALERIE dataset and stored biospecimens to address research questions concerning caloric restriction in humans. CALERIE was a U01-supported consortium of clinical trials studying the impacts of calorie restriction interventions. Program staff are planning a meeting that will include the original CALERIE investigators and investigators interested in responding to the RFA. The use of webinars to extend outreach also was suggested. The working group motioned that Council approve the concept with a message for NIA to make the RFA as accessible as possible to the scientific community. The motion was seconded by Council members and passed unanimously.
Dr. Studenski discussed a proposal for a secondary analysis of comparative effectiveness research data, health outcomes, and costs in persons with multiple chronic conditions. Although many older adults have more than one chronic condition, clinical treatment trials are done in patients with isolated conditions. There is a need to develop evidence in patients with multiple conditions, but doing so will require large datasets and a focus on the potentially high impact of treatments. The proposed RFA, which has been developed through work by special expert panels, can advance the science in multiple chronic conditions and associated issues. The working group was highly enthusiastic about the proposed RFA and motioned that the concept be approved, with a recommendation that NIA encourage the use of universal, rather than disease-specific, health outcomes. The motion was seconded by Council members and passed unanimously.
Dr. Lennart Mucke discussed a proposal concerning the molecular mechanisms of circadian clocks in aging tissues. The human body contains several clocks that respond to light-dark cycles in the environment. The best studied of these clocks is that in the suprachiasmatic nucleus (SCN) in the brain; the RFA will encourage research into the other clocks, some of which also might be affected by aging and diseases like AD. The working group enthusiastically motioned that Council accept the concept, with two recommendations:
The RFA, while focusing on clocks other than that in the SCN, should not exclude research on interactions between extra-SCN and SCN clocks.
The RFA should emphasize the public health impact, particularly with respect to impairments, of the research it will support.
The motion and recommendations were seconded by Council members and passed unanimously.
Dr. Arlan Richardson discussed a proposed RFA to solicit comparative physiological studies of aging. The past decade has seen much progress in biological research using genetic manipulations to increase lifespan. However, most of these genetic manipulations have involved loss-of-function mutations and do not necessarily make the model more fit for its environment. In nature, animals have evolved with a wide range of lifespans. Some animals can live for an exceptionally long time for their size, and unlike genetically engineered animals, they are very fit. The proposed RFA will support small grants to investigators with various resources to conduct comparative studies. The motion to approve this concept was seconded and passed unanimously.
Dr. Ana Maria Cuervo discussed a proposed RFA that is based on an ongoing initiative to test compounds or interventions that increase lifespan or health span in mice. This initiative has yielded exciting results and motivated a large amount of research. The proposed RFA will complement that initiative by funding a similar analysis of compounds and interventions in worms (C. elegans). Genetic backgrounds vary within species, and a 2008 conference on aging emphasized that interventions that might work in one genetic background might be ineffective or even harmful in others. Accelerating research in human populations will require a vast amount of resources. Research in worms can be done in a relatively short period of time, allow for the testing of combinations, and accelerate the rate of discovery. NIA envisions this and the mouse initiative to be complementary and facilitate the translation of findings.
The working group motioned that the concept be approved, and the motion was seconded. Discussion included a question about the use of other models, such as flies and zebrafish. Dr. Cuervo responded that these models were discussed and will be considered for the future. The motion for concept approval passed unanimously.
Dr. Laura Carstensen discussed a proposal for an RFA to support secondary analyses and archiving of social and behavioral datasets in aging. The proposed RFA would support small grants to leverage major data resources and make them more accessible to a wider range of investigators. NIA has made substantial investments, both in the United States and around the world, in surveys with large representative samples of individuals followed over time. The working group motioned that the Council approve this concept. The motion was seconded and passed unanimously.
Dr. Hugh Hendrie described a proposal for an RFA to support the collection of DNA from 20,000 participants across two longitudinal aging cohorts in Africa and Asia. This collection would allow for future genetic and epigenetic studies in these populations to complement ongoing studies from the Americas, Europe, and China, and subsequent analyses would further understanding of the interplay among genetics, the environment, and health outcomes. The working group motioned that the Council approve the concept with recommendation to add sites. The motion was seconded by Council members.
In response to questions about possible collaboration and coordination with the Human Health and Heredity in Africa (H3 Africa) Initiative, Dr. Jonathan King, of DBSR, reminded the Council that H3 Africa, which is supported by the Common Fund, seeks to build genomics research infrastructure in Africa and is thus more focused on developing infrastructure and a scientific base. This RFA, on the other hand, would align with NIA’s goal of developing existing surveys. However, Dr. King speculated that this RFA would increase awareness of DBSR’s efforts and that H3 Africa might help with sample collections and issues of where these samples would be analyzed. Dr. Suzman expected that there would be close integration.
The motion passed unanimously.
Dr. Barr reported that the working group discussed the draft policy calling for special Council review of investigators with $1.5 million or more in total research funding. Dr. Mucke reiterated concerns that using total cost as a measure will discriminate against investigators at certain institutions, and he called this unfair and unwise. Drs. Morimoto and Wetle added that the amount of dollars spent should be evaluated against the investigators’ impact and that certain areas of science, such as longitudinal or epidemiological studies, require large-scale investments. Dr. Morimoto suggested that impact could be measured by publication record and how much an investigator’s work has changed the field.
Dr. Barr reviewed the statistical package and noted that for the May Council meeting, the total number of applications received by NIA exceeded the average because of the number of RFAs recently issued. Dr. Barr also acknowledged that NIA applications did not fare as well in review as they have in previous rounds. The reason for this is unclear.
In response to questions of a possible relationship to the payline, Dr. Barr confirmed that NIA saw a drop in the number of applications in 2010, when the payline was tightest. However, that number is rebounding; the number of applications received for the October round is 30 percent higher than it was last year. NIA also saw a bigger drop in 2011, compared with other ICs. In response to other questions, Dr. Barr noted that NIA has posted six paylines on its website; the paylines differ based on investigators’ career stage and requested funding level. Dr. Hodes added that unlike other ICs, NIA continues to publish its paylines because it believes it is important to inform the scientific community. He further noted that the success rate for NIA R01 applications in 2011 was 17.6 percent, which was the mode for R01s across ICs.
CONSIDERATION OF RECOMMENDATIONS FROM THE ALZHEIMER’S DISEASE SUMMIT
One of NAPA’s goals is to cure or make substantial inroads toward a cure for AD by 2025. The AD Research Summit was held to explore the state of the science in AD research, identify challenges and barriers, and make recommendations for future research. The Summit agenda included 57 speakers organized into six themed sessions, and an executive committee and writing group were formed to incorporate the speakers’ presentations and Summit recommendations into an integrated, multidisciplinary blueprint with overarching, transformative goals. The ultimate goal of the Summit blueprint is to highlight research priorities and strategies to accelerate the development of successful AD therapies.
Dr. Ronald Petersen presented a number of overarching issues that cut across many of the sessions and were seen as critical to progress in AD therapy development, and followed with specific recommendations organized by the six session themes:
Interdisciplinary Approach to Discovering and Validating the Next-Generation of Therapeutic Targets for Alzheimer’s Disease
Challenges in Preclinical Therapy Development
Whom to Treat, When to Treat, and What Outcomes to Measure
Dr. Mucke emphasized the need to intensify and broaden efforts to understand the basic pathobiology of AD. He also noted that the recommendations presented by Dr. Petersen were culled from several pages of recommendations shared with NIA. He expressed concern that an emphasis on distilling recommendations could lead to a focus on only a fraction of strategies, and he hoped that NIA will refer to the larger document as it considers the issues that rose above all others.
Dr. LaCroix mentioned the press around NAPA and referenced a quote by Dr. Peter Whitehouse regarding the need to integrate a public health approach, rather than simply focusing on “magic bullets and single molecules.” Although she supported the identification of drugs to treat AD, she also speculated that because of the heterogeneity and complexity of AD, treating or even curing the disease will likely require combination therapy incorporating different modes of action.
There was lively discussion about the emphasis on lifestyle changes. Dr. Hendrie pointed out that the scientific and medical community often considers lifestyle to be subject to individual control, when individuals who are disadvantaged might have less control. He expressed the hope that disadvantaged and minority groups would be considered as lifestyle interventions are designed. However, Dr. Mucke cautioned against being overly optimistic about non-pharmacologic approaches, particularly in light of the diversity of individuals affected by AD. He agreed that lifestyle changes should be further explored, but he was not optimistic about lifestyle changes as an effective approach. Dr. Perez-Stable expressed optimism about the clear-cut benefits of physical activity for many health outcomes, including delay of AD, and he speculated that enough evidence exists for policymakers to encourage more physical activity.
Dr. Perez-Stable also noted that the design of large, observational studies could address lifestyle interventions and the need for rigor similar to that seen with clinical trial design. Dr. Norman Anderson emphasized the importance of interdisciplinary research across all session categories, and he suggested that insights could be gained from research on other physiological processes. For example, immunological studies have explored the effects of behavioral and social factors on the immune system and the brain.
Dr. Barr shared comments from Dr. Jonathan Skinner, who was absent from the meeting. Dr. Skinner expressed concern that recommendations from the Summit have not addressed formal care for patients with late-stage AD. He pointed out that these patients are often handled poorly, bouncing between nursing homes and hospitals. Although Dr. Skinner acknowledged that intervention research is still at an early stage, he suggested that the AD research community start to think about comparative effectiveness.
A motion to accept the recommendations from the AD Research Summit was forwarded and seconded. Discussion focused on increased rigor for preclinical studies and systematic approaches for disseminating results from preclinical work. Council members noted that preclinical trials already have been standardized and registered for other areas of neurodegenerative diseases and that recommendations from the Summit acknowledged that more rigor, for example in randomization and statistical analysis, is needed for preclinical trials. These recommendations included a website, preclinicaltrials.gov, where researchers could register their trials and share their positive and negative data. The Interventions Testing Program also was cited as a model for standardized testing. Dr. Choi noted efforts under way in the health disparities field, where the Public Library of Science (PLoS) is collaborating with another journal to create a new journal with a citable, archivable mechanism that allows researchers to publish their negative results. Dr. Choi noted that the AD community could support such a mechanism and have a catalytic effect on changing scientific culture. Dr. Hodes stated that the need for more rigor should not unnecessarily delay studies, and Dr. Mucke acknowledged that increased rigor could be costly.
Council members suggested a two- or three-tiered system in which R01s could support the gathering of preliminary data, another mechanism could support some flexibility in testing, and a third system would require standardized testing. Dr. Mucke commented that proof-of-concept preclinical studies would not necessarily need to be registered, but that extrapolation of findings to humans would require an adherence to standards and the rigor seen with clinical trials.
The motion passed unanimously. Dr. Hodes indicated that these recommendations will go to the HHS Secretary, who will make decisions on implementation. He added that NIA will plan for the short to intermediate term, assuming an increase of $80 million for AD research, above and beyond the NIA and NIH budgets. He expected that the Council could see FOAs related to the highest priorities at the September meeting, and he emphasized that Council and other advisory groups will continue to be involved as NIA plans for each subsequent year.
Because of the number of concepts expected to arise from the Summit recommendations, and in light of the timing and urgency of these concepts, Dr. Morimoto suggested involving the Working Group on Program at an earlier stage of concept development to permit more time for review. Other Council members agreed, noting that NAPA represents a unique opportunity and deserves more time and attention to detail.
PROGRAM HIGHLIGHTS
Division of Aging Biology: Unraveling the Complexity of Thymic Biology and Atrophy through Global Analysis of Lymphoid and Stromal Gene Profiling
The thymus is the most rapidly aging tissue in the body, with progressive atrophy beginning as early as birth and no later than adolescence. Certain stimuli can induce quantitative re-growth, suggesting a latent regenerative potential in the atrophic thymus, but the function of T lymphocytes produced by a regenerated thymus has not been examined.
Dr. Howard Petrie, of The Scripps Research Institute, has used a genome-wide computational approach to show that accelerated thymic aging is primarily a function of stromal cells in the thymic microenvironment. He and his colleagues also have found that while overall cellularity of the thymus can be restored, many other aspects of thymic function, such as medullary islet complexity and tissue-restricted antigen expression, cannot. These findings suggest a mechanism underlying the increased incidence of autoimmune disease with age: the inability of induced thymic regrowth to restore medullary islet complexity and tissue-restricted antigen expression suggest that new T cells produced by the re-grown thymus include more autoreactive cells.
Dr. Petrie and his colleagues have further conducted global analyses of gene expression profiles and found widespread changes in Wnt signaling in the stromal cells within the atrophied thymus. Moreover, these changes are seen even when the thymus is re-grown. Consistent with these observations, the re-grown thymus itself returns to an atrophic state within 2 weeks of reaching its peak size. Thus, aging-associated thymic changes and their implications for autoimmunity persist, even when the thymus is regenerated.
Discussion focused on links between Dr. Petrie’s findings and an autoimmune regulator, as well as possible implications of these findings for interventions that might maintain immune function.
Division of Neuroscience: Take a Walk: Developing Healthy Brains and Minds
The Cognitive Enrichment Hypothesis suggests that levels of performance are open and malleable to enhancement throughout the human lifespan and that the upper levels of performance are constrained by biological aging. A large body of evidence supports exercise or physical activity as one example of an enriched environment. For example, exercise enhances learning and memory, as well as several positive molecular and cellular effects, such as increased neurotransmitter production, decreased b-amyloid production, and increased expression of genes associated with plasticity and mitochondrial function.
Dr. Arthur Kramer, of the University of Illinois at Urbana-Champaign, described his research on the cognitive effects of physical activity among older adults. He and his colleagues have found that physical activity, unlike cognitive training, exerts benefits across all cognitive tasks, although the benefit is larger for some tasks than for others. They have used magnetic resonance imaging (MRI) to show beneficial effects on brain structure, for example increased anterior hippocampal volume, among older adults who walk 3 days a week. Dr. Kramer and colleagues have used functional MRI and measures of functional connectivity to show that aerobic fitness can lead to increased connectivity and improvements in executive function. They also have found an association between exercise and improved network resilience. Similar results have been found in studies of children aged 8 to 10 years.
Prospective observational studies suggest a link between increased physical activity and a lower probability of receiving a diagnosis of AD or other dementias, as well as a relationship between physical activity and higher achievement scores in children. By creating virtual street-crossing scenarios, Dr. Kramer and his colleagues have found that highly fit children are more successful at this task, even when they are distracted, and that they make better decisions about gaps as they cross the street. Increased physical activity also appears to improve depression and increase self-esteem and efficiency.
Discussion focused on technical aspects of Dr. Kramer’s work and how to translate these and other findings into general recommendations promoting exercise. Dr. Kramer emphasized that more work needs to be done, because not enough is yet known about cognition and the brain. Dr. LaCroix noted the need for collaborations between researchers and public health departments, perhaps in randomized clinical trials, to identify factors that might promote sustained exercise.
Division of Geriatrics and Clinical Gerontology: Progress toward a Clinical Definition of Sarcopenia
In all adults, muscle mass decreases with older age. In some individuals, however, sarcopenia, or severe loss of muscle mass, can lead to weakness and poor function. Yet sarcopenia is often considered a part of normal aging, with little attention given to treatment. Thus, there is no language or diagnosis that characterizes severe muscle loss and is accepted by physicians or Medicare. NIA, NIH, and private sector investments have led to an exponential growth in what is known about muscle biology and physiology, and preclinical and early clinical studies have pointed to potential treatments. However, the lack of a clear clinical definition for sarcopenia, and the resulting inability to identify which patients require treatment, has created a bottleneck in drug development.
Clear and valid diagnostic criteria and outcome measures are needed that are acceptable to clinicians, regulators, and health insurers, including the Centers for Medicare and Medicaid Services. Also needed are opportunities to develop and test interventions on sarcopenia, as well as clinical and practice guidelines for screening, diagnosis, and treatment. Both the European Working Group on Sarcopenia in Older People and the International Working Group on Sarcopenia have proposed criteria for screening and diagnosis, but these criteria are based on expert opinion, are supported by little information, and rely upon distribution-based criteria for muscle mass.
Dr. Studenski is leading a project, supported by the Foundation for the NIH (FNIH), to analyze data on sarcopenia and develop a set of analytical strategies focused on clinical diagnosis. Several investigators and sites pooled data from large aging studies and evaluated potential criteria for sarcopenia, with the aim of defining clinical weakness and the degree of low muscle mass in a way that best discriminates individuals with poor physical performance. All the selected studies included key indicators of mobility, strength, and mass. In developing analytical approaches or diagnostic testing strategies, Dr. Studenski and her colleagues aimed for a conservative definition with strict thresholds. Their criteria for selecting measures included strong psychometric properties, validation against health indicators, feasibility in clinical practice, sensitivity to change, and wide availability in existing datasets.
Typically, an individual presents to a health profession with poor performance, and the professional must determine whether the individual is weak and, if so, whether low muscle mass is a cause of weakness. After reviewing the data, Dr. Studenski and her colleagues chose gait speed as a measure of poor physical function, because this measure met most of their criteria, and they chose a cutoff of 0.8 m/s because an analysis of survival showed that 0.8 m/s reflected the median survival for both men and women. Grip strength was chosen as a measure of weakness, because it is the most widely available and clinically feasible, and the project team found that different cutoffs offered high levels of specificity. The consideration of measures of muscle mass was marked by debates about what to measure and adjust for; Dr. Studenski and her colleagues chose appendicular lean muscle mass as the measure that best balanced feasibility and optimal discrimination. Further evaluation of the data suggests that risk for future disability was increased with the presence of weakness, despite the level of muscle mass.
Dr. Studenski reported that the results of the FNIH Sarcopenia Project were presented recently at a conference co-sponsored by NIA. This conference brought together representatives from academia, the pharmaceutical industry, NIA, the Food and Drug Administration (FDA), and professional societies to comment and make suggestions on the proposed criteria. Conference participants agreed that mobility as measured by performance and self-report is an important fundamental state for function and health in later life. Participants also agreed that loss of strength is the most clinically relevant indicator of muscular dysfunction and could result from any combination of insufficient muscle mass and loss of muscle quality. With respect to a clinical definition, findings from the FNIH Sarcopenia Project suggest that decreased mobility and weakness are core elements, but that these elements account only for a portion of the problem in terms of public health. Dr. Studenski noted that people with weakness and normal muscle mass also might need more attention.
Dr. Studenski highlighted recommendations for the project team to use its data to formally evaluate the two previously proposed sets of criteria, as well as to evaluate the effects of height and weight. Other recommendations include studying populations with higher rates of weakness or disability; using data sources to define normal muscle quality; assessing the impact of gains in muscle mass, strength, and quality on function in clinical trials; and examining the effects with diseases such as diabetes. Dr. Studenski and her colleagues have received offers of datasets, and the FDA representatives will post their conference materials on the FNIH Sarcopenia Project website.
In response to concerns from Dr. Choi about the term “muscle quality,” Dr. Studenski noted that the project team has an extensive framework accounting for all etiological pathways associated with inadequate use, and as a clinician, she expects that an educational effort would take place to guide health professionals on the differentials of weakness and how to identify the appropriate patients to receive treatment. Dr. Choi acknowledged that with exclusion of myopathy and neurogenic causes from definitions of poor muscle quality, the focus on low muscle mass is innovative. In response to questions from Drs. Carstensen and Richardson, Dr. Studenski added that the FNIH Sarcopenia Project team looked at several measures of strength in their dataset and that no other measure proved superior to grip strength. She added that the conference included presentations on muscle strength in the lower extremities.
Dr. Suzman noted that the Health and Retirement Study (HRS) includes grip strength and walking speed and that data are standardized across 30 countries. He suggested the HRS dataset to the FNIH Sarcopenia Project.
Division of Behavioral and Social Research: Regional Variation in the Association between Advance Directives and End-of-Life Expenditures
About a third of all Medicare spending is devoted to end-of-life expenditures, and this spending is driven mostly by high-intensity, aggressive life-saving efforts. These life-saving efforts often reflect provider practice styles, rather than patient preferences; surveys indicate patients might not necessarily want these procedures. Yet the question of whether Medicare should reimburse physicians for discussing patient preferences for end-of-life care is a controversial one, and advance directives therefore provide the only means for understanding patient preferences. However, advance directives are not typically a part of a patient’s health care record, and the existing literature provides conflicting evidence on whether advance directives affect end-of-life expenditures.
Dr. Lauren Nicholas, of the Institute for Social Research at the University of Michigan, described a recent study focused on the effects of advance directives on Medicare spending and palliative care and whether the effects vary across high- and low-intensity hospital referral regions. This study built on work done on the Dartmouth Atlas, which has found a variation across the United States, and even within closely linked geographic regions, in default levels of care, use of specific procedures, and Medicare expenses at the end of life. Dr. Nicholas and her colleagues interviewed relatives of deceased HRS respondents about the respondents’ end-of-life treatment and preferences, as well as whether advance directives were in place. The study team also linked these interviews and HRS data with Medicare claims to derive measures of treatment intensity at the end of the respondents’ lives. Of the 3,300 decedents who had been enrolled in fee-for-service Medicare during their last 6 months of life, 37 percent had care-limiting advance directives, and 20 percent had assigned durable power of attorney but had not prepared advance directives. Three percent of the sample had prepared advance directives requesting all care possible; these decedents were not included in the sample.
Dr. Nicholas and her colleagues found that decedents who had lived in low-spending geographic areas were more likely to have prepared advance directives, compared with those in the highest-spending regions. They also found a correlation among advance directives, lower overall spending, and lower use of aggressive procedures, particularly in higher-spending geographic regions. Advance directives also were associated with an increased probability of receiving hospice care and a simultaneous decreased probability that a patient died in the hospital, again in medium- to high-spending regions. There were no statistically significant differences in the use of life-sustaining treatment, and there were no differences in spending or treatment among decedents in low-intensity geographic regions. These data suggest that the advance directive promotes a quicker realization that all has been done and a more timely focus on the patient’s wishes for comfortable care, rather than imply denial of treatment which has been a concern in policy debates.
Advance directives would likely have a modest impact on end-of-life spending. Dr. Nicholas estimated that if an additional 6 percent of decedents in high-intensity regions had prepared care-limiting advance directives, Medicare spending would have been lowered by almost $300 million. However, advance directives could have a potentially large impact on patients and their families in terms of quality of life, and because this could result in fewer physical and emotional health effects on surviving family members, advance directives could exert strong public health effects as well.
Discussion focused on technical aspects and limitations of Dr. Nicholas’s work and potential next steps. Dr. LaCroix also expressed concern about how the study findings would be interpreted in policy debates.
ADJOURNMENT
The open session of the 116th meeting of the National Advisory Council on Aging adjourned at 1:25 p.m. on May 23, 2012. The next meeting is scheduled for September 18–19, 2012.
CERTIFICATION
I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete.3
Richard J. Hodes, M.D.
Chairman, National Advisory Council on Aging
Director, National Institute on Aging
Prepared by Robin Barr, D.Phil.
With assistance by Rose Li and Associates, Inc.
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 September 18–19, 2012, and corrections or notations will be stated in the minutes of that meeting. (Back to text.)
Attachment A: Roster of the National Advisory Council on Aging
MEMBERSHIP ROSTER
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING
(Terms end December 31)
(* WGoP Member)
(** TFMAR Member)
Chairperson Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
9000 Rockville Pike
Building 31, RM 5C35
Bethesda, MD 20892
Norman B. Anderson, Ph.D. (2014)
Chief Executive Officer and Executive Vice Chair
President
American Psychological Association
Washington, DC 20002
Robert M. Califf, M.D. (2013)
Vice Chancellor and Professor
Department of Medicine
Duke University Medical Center
Durham, NC 27710
Laura L. Carstensen, Ph.D. (2015)
Professor
Department of Psychology
Stanford University
Stanford, CA 94305
Dennis W. Choi, Ph.D., M.D. (2015)
Executive Vice-President
Simons Foundation
New York, NY 10010
Ana M. Cuervo, Ph.D., M.D. (2015)
Professor
Albert Einstein College of Medicine
Department of Development and Molecular Biology
Bronx, NY 10461
**Hugh C. Hendrie, DSC, Ph.D. (2013)
Professor of Psychiatry
Indiana University School of Medicine and Regenstrief Institute, Inc.
Indiana University Center on Aging Research
Indianapolis, IN 46202
**Andrea Z. LaCroix, Ph.D., MPH (2012)
Professor
Fred Hutchinson Cancer Research Center
Women’s Health Initiative Clinical Coordinating Center
Seattle, WA 98109
Victor A. Molinari, Ph.D. (2012)
Professor
University of South Florida
Department of Aging & Mental Health
Louis De la Parte Florida Mental Health Institute
Tampa, FL 33612
*Richard I. Morimoto, Ph.D. (2014)
Bill and Gayle Cook Professor of Biology
Departments of Biochemistry, Molecular, and Cell Biology
Northwestern University
College of Arts and Sciences
Evanston, IL 60208
*Lennart Mucke, M.D. (2012)**
Professor
Department of Neurology
University of California, San Francisco
San Francisco, CA 94141
**Eliseo J. Perez-Stable, M.D. (2014)
Professor
Department of Medicine
University of California, San Francisco
School of Medicine
San Francisco, CA 94143
Daniel P. Perry (2013)
Executive Director
Alliance for Aging Research
Washington, DC 20006
Ronald C. Petersen, Ph.D., M.D. (2013)
Professor of Neurology
Cora Kanow Professor of Alzheimer’s Disease Research
Director, Mayo Alzheimer’s Disease Research Center
Director, Mayo Clinic Study of Aging
Rochester, MN 55905
Arlan G. Richardson, Ph.D. (2013)
Director
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
Jonathan S. Skinner, Ph.D. (2015)
Professor of Community and Family Medicine
Dartmouth College
Department of Economics
Institute for Health Policy and Clinical Practice
Lebanon, NH 03755
Stephanie A. Studenski, MPH, M.D. (2014)
Professor
Department of Medicine
University of Pittsburgh
Pittsburgh, PA 15213
**Terrie F. Wetle, Ph.D. (2013)
Associate Dean and Professor
Brown University Medical School
Providence, RI 02912
EX OFFICIO MEMBERS
Kathleen Sebelius
Secretary
Department of Health and Human Services
Hubert H. Humphrey Building
Washington, DC 20202
Francis S. Collins, Ph.D., M.D.
Director
National Institutes of Health
Public Health Service
Building 1, Room 126
Bethesda, MD 20892
James F. Burris
Deputy Chief
Office of Research and Development
Department of Veterans Affairs
Washington, DC 20420
Edwin L. Walker
Deputy Assistant Secretary
U.S. Department of Health and Human Services
Administration on Aging
Administration for Community Living
Washington, DC 20001
Kenneth G. Pugh, LCDR, MC
Department of Medicine
National Naval Medical Center
Bethesda, MD 20889
EXECUTIVE SECRETARY
Robin A. Barr, D.Phil
Director, Office of Extramural Activities
National Institute on Aging
Bethesda, MD 20892
