Council Minutes - May 2010

The 110th Meeting
May 25–26, 2010

CONTENTS

1. REVIEW OF APPLICATIONS
2. CALL TO ORDER
3. REPORT: Task Force on Minority Aging Research
4. REPORT: Working Group on Program
5. INITIAL REPORT: Division of Geriatrics and Clinical Gerontology Review
6. PRESENTATION: Cures Acceleration Network
7. PROGRAM HIGHLIGHTS
8. ADJOURNMENT
9. CERTIFICATION

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

The 110th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, May 25, 2010, 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 25, 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 Public Law 92-463.1 The meeting was open to the public on Wednesday, May 26, from 8 a.m. to 1:30 p.m.

Council Participants:
Dr. Lisa Berkman
Dr. Dale Bredesen (May 25 only, by phone)
Dr. Robert Califf
Dr. Peggye Dilworth-Anderson
Dr. Hugh C. Hendrie
Dr. S. Michal Jazwinski
Dr. Sundeep Khosla
Dr. Andrea LaCroix
Dr. Victor Molinari
Dr. Lennart Mucke
Mr. Daniel P. Perry
Dr. Ronald C. Petersen
Ms. Orien Reid
Dr. Arlan G. Richardson
Ms. June Simmons
Dr. James P. Smith
Dr. Terrie F. Wetle

Absent:
Dr. Susan L. Swain

Ex Officio Participants:
Dr. James F. Burris, Department of Veterans Affairs
Dr. Jane Tilly, Administration on Aging

Absent Ex Officio Participants:
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.

In Addition to NIA Staff, Other Federal Staff Present:
Dr. Mary Custer, Center for Scientific Review, NIH
Ms. Devon Drew, Committee Management Office, National Institute of Diabetes and Digestive and Kidney Diseases
Dr. Rene Etcheberrigaray, Center for Scientific Review, NIH
Ms. Ashley Fitzgibbons, Office of Extramural Research, NIH
Ms. Marnie Isabella, Center for Information Technology, NIH (contractor)
Dr. Michelle Washko, Administration on Aging
Mr. Pat White, Office of the Director, NIH

Members of the Public Present:
Ms. Linda Harootyan, Gerontological Society of America
Ms. Erica Froyd, Lewis-Burke Associates
Dr. Thomas Gill, Yale University School of Medicine
Dr. Jaime Grutzendler, Northwestern University
Dr. Leanne Jones, The Salk Institute for Biological Sciences
Dr. Rose M. Li, Rose Li and Associates, Inc.
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Ms. Beth Roy, Social Scientific Systems, Inc.
Dr. Robert Willis, University of Michigan

1. 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 1,263 applications requesting $1,739,717,531 for all years underwent initial review. The Council recommended 818 awards for a total of $1,234,197,965 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.

2. II. CALL TO ORDER

Dr. Hodes welcomed members to the open session of the 110th NACA meeting and called the meeting to order at 8:00 a.m. on Wednesday, May 26, 2010.

1. Director’s Status Report

Dr. Hodes began by providing an update on the NIA budget. He showed how overall NIH purchasing power had peaked in 2003 and that all subsequent adjustments to the budget have been subinflationary, resulting in an erosion in funds available to support research. Although the President’s proposed budget includes an inflationary increase to NIH, there are concerns that this goal might not be achieved. An analysis published in the Congressional Quarterly points out that budget appropriations have not been released on time since 1996 for the 1997 fiscal year, and there is some speculation that the budget will be subject to yet another prolonged continuing resolution at FY2009 levels.

Council members were reminded that the recent health care legislation encouraged NIH, the Agency for Healthcare Research and Quality (AHRQ), and other Federal agencies to implement or augment comparative effectiveness research (CER) programs. The legislation also has established the Patient-Centered Outcomes Research Institute (PCORI), a non-profit organization that will organize, fund, plan, and make recommendations from comparative effectiveness research to inform science application and practice. PCORI is charged with identifying national priorities, research gaps, new clinical evidence, relevance, standards, and economic correlates as it sets a research agenda. It is expected that PCORI will consult with NIH on research, training, and communications and that NIH will continue to conduct and support CER independently. PCORI will be funded initially by direct appropriations, then by a trust fund supported in part by capitation charges on enrollees in the health care system.

Dr. Hodes next discussed the establishment of the Cures Acceleration Network (CAN), which will aim to reduce the barriers between laboratory discoveries and clinical trials, thereby advancing the development of new cures and treatments for debilitating diseases. Situated in the NIH Office of the Director (OD), with an authorized FY2010 budget of $500 million, CAN will provide flexible funding mechanisms such as grant awards, partnership awards that require matching funds, and flexible research awards administered under “Defense Advanced Research Projects Agency (DARPA)-like authority.” Dr. Hodes emphasized that a budget for CAN has been authorized, but not yet appropriated. He further noted that CAN will not be subsumed under the current NIH appropriation.

Dr. Hodes also reminded Council of the Scientific Management Review Board (SMRB), which was established by the NIH Reform Act of 2006 in response to concerns that mechanisms creating new Institutes and Centers (ICs) were irrational and suboptimal. The SMRB, chaired by Norman Augustine a former member of the President’s Council of Advisors on Science and Technology, is comprised of 12 non-Federal members and no more than 9 NIH IC directors (including Dr. Hodes). The NIH Director serves as a nonvoting member. At its inaugural meeting in April 2009, the SMRB heard briefings on the NIH mission, structure, budget, and central services; the National Academies report on organizational change and enhancing the vitality of NIH; and testimony from former NIH Directors with regard to the science and structure of NIH. The Board established three working groups with the following charges:

• Deliberating Organizational Change (DOC) – to draft overarching principles of organization and criteria for contemplating change.
• Substance Use, Abuse, and Addiction (SUAA) – to consider whether changes within NIH could further optimize research into substance use, abuse, and addiction, including the possibility of a merger or formal cooperation between the National Institute on Drug Abuse and the National Institute on Alcoholism and Alcohol Abuse.
• Clinical Center/Intramural Research Program – to consider the challenges of fiscal viability and management for the Intramural Research Program and Clinical Centers, and whether the Clinical Center should be a national resource, rather than a resource restricted to the Intramural Program.

Dr. Hodes concluded his report by discussing The Big Think, a meeting held on May 7 that brought together researchers from outside NIH to identify areas in which the Common Fund might best be used. Meeting participants worked to generate a menu of bold, transformative, and cross-cutting yet specific ideas and to discuss general priorities without an actual vote. The Common Fund is now at about $500 million. Awards from the Common Fund are not intended for open-ended projects but rather to provide incubator space for 5 years, with an absolute maximum of 10 years. Three topics were identified as garnering enthusiastic support:

• High-throughput approaches, including technologies for single-cell biology; protein affinity reagents beyond monoclonal antibodies; generalizable methods for assessing gene function and the effects of allelic series; tissue-specific targeting of small molecules; emerging versus newly diagnosed infections; and more effective measures of environmental exposures.
• Translation, including the need for mouse models beyond knockouts; release and repurposing of “failed compounds” from the private sector; exploration of combination therapy approaches; systematic assessments of known genes and pathways involved in rare diseases; and process engineering to improve success rates of translation.
• The science of health reform, including studies of disease prevention and medical care delivery, assessments of the effects of systematic patient education, centers of excellence on chronic disease management, studies of social networking and health, and randomization of provider incentive models to assess effects on costs and outcomes.

Participants at The Big Think also discussed cross-cutting themes, including ways to encourage investigator independence at an earlier time point, a wish list of ideas scientists would like to pursue if they had the means, and a suggestion for a large, prospective cohort study in the United States, similar to one ongoing in the United Kingdom.

In response to questions from Dr. Wetle about the National Children’s Study, Dr. Hodes acknowledged the importance of life course studies and including children in a large study like the one suggested by Big Think participants. He cautioned, however, that although such a goal is worthwhile, cost remains a concern.

Dr. Molinari noted the large role NIA-supported research could play in health care reform, for example, efforts to reduce the number of inappropriate prescriptions or hospitalizations. Dr. Hodes agreed and highlighted recent scientific initiatives in which NIA has played a leading role, including the Science of Behavior Change initiative and a focus on health economics under the American Recovery and Reinvestment Act (ARRA). However, Dr. Hodes acknowledged that more needs to be done. Drs. Jonathan King and Richard Suzman answered further questions about the two initiatives highlighted by Dr. Hodes.

In response to questions from Dr. Khosla, Dr. Hodes noted that he had not seen any evidence that Dr. Francis Collins, NIH Director, would make any radical moves to discontinue past initiatives. However, Dr. Hodes speculated that the evolution of these initiatives would be influenced by Dr. Collins’ sense of direction, which encompasses highly powered, cutting edge research, biological and behavioral research, and translation of findings to real outcomes. Dr. Hodes further noted that Dr. Collins remains sensitive to the context of the health reform legislation and that he and the Clinical and Translational Science Awards (CTSA) program steering committee are exploring their contribution to the overall national research network. Council members further suggested a role for CTSAs in supporting population studies that will be made possible with the establishment of the electronic medical record. Dr. Wetle also suggested that the adoption of these records across the nation will require a re-examination of the Health Insurance Portability and Accountability Act (HIPAA), which is currently a barrier to researchers across institutions and systems.

After a round of introductions, Dr. Hodes circulated a binder containing media coverage of NIA-supported research.

2. Future Meeting Dates

September 21–22, 2010 (Tuesday and Wednesday)
January 25–26, 2011 (Tuesday and Wednesday)
May 24–25, 2011 (Tuesday and Wednesday)
September 20–21, 2011 (Tuesday and Wednesday)

3. Consideration of Minutes of the Last Meeting

The minutes of the January 2010 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.

3. REPORT: Task Force on Minority Aging Research

Dr. Dilworth-Anderson reported on two presentations heard by the task force:

• Dr. Joan Levy Zlotnik (Director, Social Work Policy Institute, National Association of Social Workers Foundation) and Ms. Angela Sharpe (Deputy Director for Health Policy, Consortium of Social Science Associations) on how organizations can work together to identify standard workforce issues across disciplines. This presentation included overarching recommendations with respect to the recruitment, retention, and mentoring of underrepresented minorities; improving evaluation of diversity program outcomes; and building public support for a diverse scientific workforce. Dr. Levy Zlotnik and Ms. Sharpe also suggested next steps to facilitate development of a common data set. Dr. Dilworth-Anderson noted, for example, that several organizations, faced with the termination of the National Institute of Mental Health Minority Fellowship Program, found ways to standardize their own data to identify minority fellows in science, technology, mathematics, and engineering; enhance recruitment; collect data across organizations; and share best practices. The presentation closed with a detailed list of steps to enhance data standardization.
• Dr. David Weir on building a process and infrastructure for data collection to recruit and retain minority participants in the Health and Retirement Study (HRS). Representation of minority populations remains critical for HRS to support research on the causes, consequences, and trends in racial and ethnic health disparities at older ages. The HRS received ARRA funding to expand its minority sample by adding about 1,200 African- American and Hispanic respondents from the baby boom birth cohorts. Dr. Weir reported no racial or ethnic differences in recruitment into or retention in the study but some differences in cooperation with specific requests. He further reported that well-trained interviewers, and not their race or ethnicity, were the primary determinant of success in reducing disparities in cooperation. Dr. Weir also noted some complications in obtaining biomarker data from minority groups, perhaps related to general distrust among these groups with respect to DNA testing. He pointed out that race-matching appeared to matter more to whites than to blacks, which was surprising. Dr. Dilworth-Anderson informed Council that these findings will appear as part of a special issue to be published by the Gerontological Society of America, and acknowledged the role of the Resource Centers for Minority Aging Research in supporting this work.

Dr. Hendrie described the Indianapolis-Ibadan Dementia Project, a large comprehensive study of 2,500 community-dwelling African Americans in Indianapolis or Yoruba in West Africa. African American ancestry can be traced to the Yoruba. Phase I focused on the epidemiology of Alzheimer’s disease (AD) or dementia, and Phase II integrated a genetic component and focused on the mechanisms of disease. Planning for an integrated investigation of mechanisms in Phase III is under way.

Study results from Phase I indicated that the rates of AD and dementia were twice as high in African Americans as in the Yoruba and that the frequency of vascular risk factors associated with these diseases were all lower in the Yoruba. ApoE4 and education were large risk factors for African Americans but not as much for Yoruba. Individuals who migrated to the American South and had low education status were at highest risk for AD and stroke. Dr. Hendrie also noted that antihypertensives lowered the risk in African Americans and that assessing risk factors in Western populations might be more difficult now because of treatment effects.

Dr. Hendrie also shared some unpublished results from Phase II.

4. REPORT: Working Group on Program

Dr. Jazwinski reported the recommendations of the Working Group on Program:

A second Cognitive Aging Summit will be held in October 2010 as a follow-up to a Summit held in 2007. Coordinated by Dr. Molly Wagster of the Division of Neuroscience, the first Summit led to two requests for applications (RFAs) in 2008, with applications funded in 2009. The second Cognitive Aging Summit will review advances that have occurred in the field since the last meeting. It will feature 36 speakers, as opposed to the approximately 70 speakers who presented at the first Summit, and it will be followed by a meeting of grantees funded under the RFAs issued in 2008. Dr. Wagster reported to Council that NIA has been working with the Foundation for NIH and the McKnight Brain Research Foundation to organize these meetings. She also asked Council members interested in attending to contact her directly, as enthusiasm is overwhelming and slots are quickly filling up.

A motion to approve the Summit was forwarded and seconded by Council members. The motion passed unanimously.

Dr. John Williams, of the Division of Aging Biology (DAB), proposed an RFA concept on Mechanisms Mediating Change in Central Regulation of Bone Mass. This RFA will focus on neuroendocrine function, particularly the central role of brain leptin on bone mass. It will use the R01 mechanism, and DAB anticipates that five or six applications will be funded. During the previous day’s discussion, the working group noted that this is an emerging and somewhat controversial field of research, but that it also is an important one that fits with the NIA mission.

In response to questions he had received the previous day, Dr. Williams described two studies suggesting that selective serotonin reuptake inhibitors (SSRIs) significantly increased the risk for bone fracture. He also discussed results of a PubMed search he had done on the involvement of follicular-stimulating hormone (FSH) in bone turnover. Dr. LaCroix clarified that when she had asked the questions, she had wanted to point out that the epidemiological evidence of a link between SSRIs, and bone fracture is somewhat weak. This observation was not to impugn the studies but to illustrate the still-controversial nature of the field. Dr. Khosla added that this was precisely the context in which RFAs are useful, because the central regulation of bone mass is an important development; and more study is needed by independent groups to address existing controversies.

A motion for the Council to approve the RFA concept was forwarded and seconded. The motion passed unanimously.

The working group also discussed changes at the Center for Scientific Review (CSR) and throughout the NIH with respect to the peer-review process. The group noted that the reviews and summary statements are now a bulleted structure where strengths and weaknesses are listed. This format could be problematic because it encourages reviewers to raise issues without providing documentation or evidence that could help in revisions. The working group also noted that the five criteria could be problematic because reviewers do not understand uniformly what those criteria mean and applicants might be forced to try to “read reviewers’ minds.” These problems, combined with allowing applicants to submit only twice, place investigators in a position of aiming at a moving target. Dr. Mucke added that overall, the new review process is a vast improvement over the old one, but that useful elements of the old process have fallen through the cracks. He suggested a mechanism by which applicants could see a preliminary form of the review and have a short period of time to respond to it. Dr. Mucke concluded that improving peer review should be a continuing process and that his and other suggestions could be raised with CSR in a constructive way.

The working group concluded that the Council should draft a letter explaining its concerns to the CSR Director. A motion to establish a committee to draft a letter to CSR regarding the new format was forwarded and seconded. The motion passed unanimously. Dr. Mucke will lead this effort, which will include Ms. Simmons and Drs. Berkman, LaCroix, Khosla, Wetle, and Jazwinski. Other Council members were asked to submit ideas, suggestions, or other issues. A draft letter will be circulated for review by all Council members, and a final letter is expected to be sent in July 2010.

Council members also suggested that an agenda item be added to a future NACA meeting for appropriate representatives from CSR to present findings from its recent survey and hear the Council’s concerns in person.

During the previous day’s meeting of the working group, Dr. Hodes noted that the critical state of available funds at NIH has translated into a payline at the 8 percentile for research grant awards for NIA, among the lowest of the NIH institutes. Although NIA continues to emphasize supporting the best science, there are concerns that this low payline will influence talented investigators to submit their applications elsewhere and that interest in aging research will thus decline. NIA’s average costs are higher than those for other ICs, but Dr. Hodes emphasized that NIA’s research portfolio reflects scientific planning and priority setting. Other ICs have eliminated certain funding mechanisms, for example, P01 and centers programs, to ensure better paylines. However, NIA continues to see value in these programs. Suggestions from Council members for addressing the low payline included encouraging less-expensive applications over larger ones, setting differential paylines or caps, or simply continuing to support the best science without cost formulas.

Dr. Petersen agreed with a temporary imposition of caps, but expressed concerns that caps might be perceived as NIA pre-judging the value of the science. Dr. Mucke added that most of the working group appreciated the diversity of funding mechanisms and believed that it would be wise to maintain that diversity. Council members also acknowledged the value of having large groups focused on difficult problems, particularly in this age of interdisciplinary research, and the innovation arising from the Transformative R01 and Pioneer Awards. Some members acknowledged the value of large projects but suggested that NIA encourage smaller and shorter projects. Some suggested that NIA try to make the R03 and R21 mechanisms more attractive, as many high-priority projects could be initiated with relatively small amounts of money. Others suggested encouraging smaller and shorter R01s, because younger or newer investigators get a break in priority scores for the R01 mechanism that they do not get for R03s or R21s.

Dr. Jazwinski concluded his report by noting the State of the Science Report on the Prevalence of AD and Cognitive Decline. The report, presented by Dr. Neil Buckholtz, is now online and will be reviewed by Council at the September 2010 meeting.

5. INITIAL REPORT: Division of Geriatrics and Clinical Gerontology Review

Dr. Khosla summarized the findings of the Division of Geriatrics and Clinical Gerontology Review (DGCG) review group, which was positive overall about the Division’s accomplishments, especially in a constrained funding environment. The review group focused on four geriatrics goals, three gerontology goals, clinical trials, interfaces with clinical specialties, translational research, and career development.

• Goal 1: Geriatric disabilities, symptoms, and causes of activity limitation. The review group agreed that this goal was an important and appropriate goal within the purview of DGCG. However, the group expressed concerns that grants in this area might be difficult to fund because it is an emerging field.
• Goal 2: Disease outcomes in older individuals. The Division is examining how to prioritize specific diseases. There were some suggestions about interactions between the Division and relevant specialty societies.
• Goal 3: Multiple morbidities in older persons. The review group recognized that because many older people have more than one disease or condition, NIA and DGCG are unique in the research they support. The review group distinguished comorbidities, in which one disease is dominant, from multimorbidities, in which many diseases are equally dominant. The group noted that clinical trials include few individuals with more than one disease or disability and questioned whether results from these studies are generalizable. Group members also emphasized a need to understand underlying pathophyisology and disease interactions and the potential value of animal models; and they discussed opportunities for DGCG to interact more closely with DAB. In addition, the review group noted the need to educate study sections because of the intrinsic difficulties of performing studies of multimorbidities and comorbidities.
• Goal 4: Unrecognized pathology in older persons. DGCG is studying how to prioritize specific diseases in this regard.
• Goal 5: Physiologic changes across the lifespan. The review group pointed out that not all age-related changes are detrimental; in fact, some might be protective. Review group members noted the need to increase understanding of protective effects, particularly now in an era where there is a general push to treat age-related declines.
• Goal 6: Consequences of early-life events on aging-related changes. The review group acknowledged overall that these types of studies are intrinsically difficult and might be facilitated by more longitudinal studies and better surrogate markers of clinical outcomes. Group members specifically called for a focus on the impact of nutrition.
• Goal 7: Factors contributing to exceptional aging. The review group emphasized a balance between studying exceptional longevity and the rate of aging in the rest of the population. The impact of nutritional factors also was discussed.
• Clinical trials. The DGCG commitment to clinical trials has more than doubled since 2006 and now represents approximately a third of the DGCG budget at $46 million. The review group discussed the impact of this trend on other types of grants and was divided on whether it is appropriate. The group emphasized the need for clear strategic planning on which trials to support and platforms for other research priorities.
• Interfaces with clinical specialties. The review group suggested that DGCG find ways to leverage the resources (expertise, funding) of specialty societies. The Division also could ask a society or professional organization to list the top five research ideas it would like to see NIA pursue, then draw funding ideas from that list.
• Translational research. The review group discussed potential benefits of enhanced interactions with other NIA divisions and the Intramural Program. For example, DGCG could draw expertise from DAB on how to better translate basic studies to clinical studies, and it could tap into the data-sharing resources of the Division of Behavioral and Social Research (DBSR). The review group also called for standardized outcomes for functional studies in older persons.
• Career development. The review group agreed that support for career development is at risk. Group members suggested ancillary studies to clinical trials and leveraging support from professional societies and foundations.

A more detailed report is forthcoming and will be voted on at the September Council meeting.

Dr. Hodes commended the DGCG review group on its effort to look at the entire program and analyze it both by topic and by research gaps or unanswered questions. He reminded the Council that although NIA presents initiatives to Council, it also values ideas and input from the Council and the research community at large.

Dr. Jazwinski also commended the review group and stressed that DGCG is unique in its study of comorbidities and multimorbidities and thus distinguishes NIA from other ICs that focus on specific organs. Dr. Peterson noted the increasing emphasis on collaboration among NIA divisions and suggested that NIA find ways to promote and enhance such collaboration.

6. PRESENTATION: Cures Acceleration Network

Mr. Pat White, Associate Director for Legislative Policy and Analysis in the NIH Office of the Director (OD), began his presentation by discussing the economic and political challenges facing NIH and by acknowledging the work of Senator Arlen Specter on NIH’s behalf. He then summarized the historical and public policy context of the Cures Acceleration Network (CAN).

The idea for CAN was first proposed in 2003 by then-presidential candidate Joseph Lieberman when he called for a $150 billion, 10-year Federal initiative to establish a National Institute of Cures, an entity separate from NIH that would attempt to bridge the “valley of death,” or the translation of basic research discoveries into clinical application. In 2009, Senator Specter, spurred by the disastrous effects of the financial collapse on biotechnology companies and the notion of cures being held back by bureaucratic red tape, introduced legislation for an institute that would:

• Use a different set of reviewers, including patient advocates, venture capitalists, and venture philanthropists.
• Provide authorization for “X prize” funding as a follow-on to ARRA.
• Provide DARPA-like authority.

The language of this legislation changed, following input from the scientific community and was passed as part of health care reform.

CAN will be housed in OD with an authorized budget of $500 million for FY2010. None of the funding for CAN will come from existing IC budgets, and an allowance for “no-year” money will allow CAN to operate without a mandate to spend the money in one particular year. The CAN legislation creates three new award mechanisms to increase flexibility, and it establishes a review board that will advise the NIH Director on barriers to successful translation of scientific discovery and make recommendations about research proposals. In addition, the legislation will facilitate Food and Drug Administration (FDA) review for high-need cures funded by CAN and provide matching non-Federal funds. Support for CAN is wide and varied, coming from patient advocate groups, the pharmaceutical and biotechnology industries, foundations, and philanthropies, as demonstrated by a letter to Congress with over 80 signatories.

Mr. White concluded his presentation by sharing media views on the state of biomedical research and its translation to cures. In an article in the New Yorker, Malcolm Gladwell writes about a small biotechnology company pursuing cancer treatments and shows the difficulty in getting a compound or biologic through the FDA development and approval pipeline. Although the compounds discussed in this article failed testing, Mr. White noted that one of the greatest opportunities for CAN might involve obtaining failed or abandoned compounds, negotiating intellectual property rights, and aiming them at other targets. For example, Pfizer is collaborating with Washington University at St. Louis to provide investigators access to their drug candidates and allowing them to study other effective uses for those candidates. In another article published in Newsweek, Mary Carmichael and Sharon Begley present an indictment of the NIH research enterprise and the culture of academic research. Mr. White pointed out that the article summarizes a prevalent public view of NIH.

Dr. Berkman commented that even with the health care reform legislation, little attention has been paid to prevention, quality of life, health disparities, and the reasons why the United States is behind other developed countries in terms of health. Mr. White responded that CAN is designed to examine pharmaceuticals, compounds, and devices and imagined that an integrative proposal that includes prevention might qualify for CAN funding.

Mr. Daniel Perry remarked that the evolution among advocacy organizations from simply pushing for more funding to the NIH to now focusing on the ability of NIH, FDA, and other organizations to produce something of value to the organizations’ constituents. Mr. Perry noted that the increasing emphasis on faster cures, the establishment of CAN, and the recent establishment of a partnership between NIH and FDA illustrate this evolution. He suggested that NIH continue to identify ways it can be part of this evolution.

The Council also discussed concerns that CAN will be funded at the expense of basic science. Council members agreed on the need for all stakeholders to recognize that basic research is critical and can be exploited by CAN. Mr. White noted ongoing efforts to educate Congress and the public about the value of basic science research and to present CAN as part of a continuum of NIH, rather than as an entity that supplants or usurps NIH.

Dr. Hendrie noted that non-pharmacological interventions, which often work just as well as new drugs, without the negative side effects that sometimes take years to become apparent, are not included in the legislation for CAN. He suggested that they be considered, particularly for older people. Mr. White and Dr. Khosla also discussed the need to manage expectations of what modern science and the pharmaceutical industry can do. Dr. Khosla noted that many in the public have high expectations without understanding the research process, and he expressed concern that the establishment of CAN might set the Federal government up for another indictment like the Newsweek article in the future. Mr. White again emphasized the importance of education and expressed frustration that many in the general public do not know where advances come from or how NIH has played a role in public health benefits now taken for granted. He agreed on the need to guard against overhyping or overpromising CAN.

7. PROGRAM HIGHLIGHTS

   1. Division of Geriatrics and Clinical Gerontology: Functional Trajectories in the Last Year of Life

Despite the importance of daily function among older persons and their families, little is known about the course of disability in key activities of daily living, such as bathing, dressing, and walking at the end of life. Dr. Thomas Gill, of the Yale University School of Medicine, presented the results of a prospective, longitudinal study that aimed to identify distinct patterns of disability in the last year of life and to determine whether and how the distribution of these patterns differs according to the condition leading to death. The study followed 754 community-dwelling individuals, aged 70 years or older, living in New Haven, Connecticut. Dr. Gill and his colleagues conducted monthly telephone interviews and, for the 383 participants who died, evaluated the ability to complete essential activities of daily living (ADLs) during the last year of life.

Dr. Gill and his colleagues identified five distinct trajectories, ranging from no disability to most severe disability. Distribution among these trajectories was fairly even: 17 percent of participants had no disability; 19.8 percent had catastrophic disability, characterized by sudden onset of disability during the last few months of life; 17.5 percent had accelerated disability, characterized by the onset and gradual worsening of disability around 10 months before death; 23.8 percent had progressive disability, characterized by worsening disability during the entire year before death; and 21.9 percent had persistently severe disability throughout the entire last year of life. The most common condition leading to death was frailty, followed by organ failure, advanced dementia, and sudden death. The distribution of disability patterns varied across conditions leading to death, and the burden of disability during the last year of life was largest among participants who died from advanced dementia. A significant number of participants who died from cancer had no disability throughout the last year of life. On the basis of these results, Dr. Gill and colleagues concluded that the need for services to assist with essential ADLs at the end of life is at least as great for older persons dying from organ failure and frailty as it is for persons dying from cancer, but greater for older persons dying from advanced dementia. Dr. Gill noted, however, that for most decedents, there does not appear to be a predictable trajectory of disability based on condition leading to death. Thus allocation of resources for older persons’ care at the end of life remains a challenge.

Most of the Council’s questions focused on the technical aspects of Dr. Gill’s work. However, Dr. Marie Bernard, NIA Deputy Director, asked how Dr. Gill’s research could be translated in the context of health care reform and potential overuse of end-of-life benefits. In response, Dr. Gill emphasized the need to focus more attention and resources on functional disability and to move away from disease-specific criteria.

2. Division of Aging Biology: Aging-related Change to Stem Cells and Stem Cell Niche

Tissue homeostasis depends on stem cells and the correct balance between stem cell self-renewal and differentiation of daughter cells, which is achieved by cues from the stem cell microenvironment, or niche. However, tissue maintenance and repair declines during aging, suggesting that the integrity of stem cells, their niche, or both is compromised.

Dr. Leanne Jones, of The Salk Institute for Biological Studies, presented work using the Drosophila testis as a model system to study how aging affects stem cell behavior. In this model, stem cells surround a cluster of somatic cells called the apical hub, and germline stem cells (GSCs) divide asymmetrically to produce a daughter stem cell and another cell that initiates differentiation to produce a cyst of 16 spermatogonia that ultimately develop into mature sperm. Another population of stem cells, somatic stem cells, produce cyst cells (which surround the developing germ cells and ensure differentiation) and cells that contribute to the hub. The apical hub is a critical component of the stem cell niche in the Drosophila testis. Hub cells secrete the cytokine-like molecule Unpaired (Upd), which activates the JAK-STAT pathway in adjacent stem cells to specify self-renewal and maintenance.

Dr. Jones and her colleagues have found that the average number of male GSCs declines with age, in part because of decreasing expression of upd within hub cells. These data indicate that the hub is not a static structure and suggest the existence of factors to maintain an active stem cell niche. Dr. Jones and colleagues also have identified IGF-II mRNA binding protein (Imp) as one factor that maintains niche function and GSCs over time by stabilizing upd. These studies suggest that genetic programs are in place to regulate maintenance of a functional stem cell niche. Therapeutic strategies devised to activate such pathways to manipulate the size and activity of stem cell niches will thus complement stem cell transplantation in regenerative medicine and the treatment of cancer.

In response to questions from Dr. Khosla, Dr. Jones noted that there is not a good way of measuring senescence in Drosophila and that she and her colleagues have not explored the role senescent cells could play in the stem cell niche. In response to questions from Dr. Hodes, she noted that there are human and mouse homologs of Imp.

3. Division of Behavioral and Social Research: Mental Retirement

Popular opinion suggests that people can stave off cognitive decline through mental exercises such as playing chess or completing crossword puzzles. Although the scholarly literature endorses this idea, the evidence for it is fairly weak. In a review published in 2006, Salthouse called mental-exercise more of an optimistic hope than an empirical reality. He pointed out that causal directions have not been established and that experiments thus far have involved small-scale stimuli and short-term follow-up.

Data from the Health and Retirement Study (HRS), the Survey of Health, Ageing and Retirement (SHARE), and the English Longitudinal Study of Ageing (ELSA) suggest that age-related deficiencies are moderated by age at retirement. In cognitive performance, as measured by immediate and delayed recall of 10 words, recall is lower among men aged 60 to 64 years, relative to the performance of men aged 50 to 54 years, in countries where men retire earlier. In a discussion of these data, Dr. Susann Rohwedder suggested that this evidence could be interpreted as causal because most of the cross-country variation in retirement arises from differences in incentives created by public pension, disability, and tax policies. Retirement policy does appear to influence behavior. In the United States, Sweden, and Japan, workers keep most of the extra income they earn, whereas in Belgium, France, Italy, and the Netherlands, extra income is taxed heavily, providing a disincentive to keep working. Dr. Rohwedder further wrote that these policies were unlikely to have been set in response to observed age-related patterns of cognitive change. Dr. Robert Willis, of the University of Michigan, presented work he and Dr. Rohwedder have done to explore the Mental Retirement Hypothesis, which posits that retirement has a causal effect on the cognitive status of older persons. They considered the theoretical basis for a mental retirement effect in cognitive psychology and human capital theory, and they used policy variation to identify causal effects of retirement on cognitive performance.

Fluid intelligence, or the “thinking part” of ability that includes abstract reasoning, short-term and working memory, and mental processes involved in planning and problem-solving, develops rapidly during childhood and peaks at 20 years, then slowly declines with age. On the other hand, crystallized intelligence, or the “knowing part” of ability that includes the accumulation of influence from education and lifetime experience, continues to accumulate well into an individual’s 30s and remains steady throughout older age. Human capital theory proposes that human capital is the stock of skills and knowledge that is useful in the labor market, health, and other activities. This capital is produced by an investment process that closely resembles the theory of fluid and crystallized intelligence, and incentive to invest is motivated by future returns. The significant negative impact of early retirement on the cognitive ability of men aged 60 to 64 years is consistent with research showing that fluid intelligence is affected by human capital.

Dr. Willis presented two hypotheses that might explain mental retirement. The Disengaged Lifestyle Hypothesis suggests that the work environment is more stimulating than the home environment and that removal of this stimulation by early retirement causes a decline in fluid intelligence. The On-the-Job Retirement Hypothesis suggests that human capital investment is needed to cope with technical changes, work reorganization, and other aspects of the job and that incentives to invest might be low for an individual who expects to work only a few more years, compared with one who might expect to work for much longer. Dr. Willis also noted evidence among Americans of reversal in a century-long trend toward early retirement, which he speculated might be advantageous not only for the fiscal balance of Social Security and Medicare, but also for the cognitive capacity of an aging nation.

Dr. Hendrie expressed concern about how these theories and data would be interpreted by the Federal government in terms of retirement policies, and he wondered whether programs could be implemented to stimulate happily retired individuals. Dr. Willis agreed with the need to keep older people mentally stimulated, and he also suggested that because many people’s social life and happiness come from the workplace, institutional mechanisms should be found to make work transitions less abrupt. Council members also noted the importance of Dr. Willis’ work, particularly at a time when the first of the baby boom generation is reaching the traditional retirement age.

4. Division of Neuroscience: Of Pipes and Vessels—Unclog or Perish

Cognitive decline often follows stroke and cardiac surgery, which affect larger blood vessels. Hypertension and diabetes, which involve microvascular pathology, increase the risk for dementia, suggesting that pathology in small vessels also contributes to cognitive decline. However, little is known about the biology of small vessels. Dr. Jaime Grutzendler, of Northwestern University, presented work exploring the size threshold for neurovascular damage, the effectiveness of hemodynamic forces and endogenous thrombolysis in clearing the microvasculature, the establishment of microvascular blood flow when known mechanisms fail, and the consequences of recanalization failure.

Using microscopy to follow fluorescent emboli injected into the terminal capillaries, Dr. Grutzendler has found that 50 percent of an injected clot is cleared within 2 days by fibrinolysis and blood pressure, but that these clearance mechanisms are inefficient at later time points. Localized hypoxia and a rapid decline in focal spine density are observed with persistent small occlusions; but focal spine density recovers completely after several weeks, suggesting a compensatory mechanism. Surprisingly, any blockage that is not cleared within the first 2 days extravasates within 7 days, regardless of the blockage’s composition. The structure of the blood vessel is retained, and blood flow is completely re-established. To confirm these findings, Dr. Grutzendler and colleagues have performed electron microscopy and time-lapse photography and observed a membrane wrapped around the blockage and an opening in the vessel wall by day 3, with complete expulsion of the clot by day 5. Blood flow is re-established almost synchronously with extravasation. Proteins present in the tight junction are reduced in the area near the clot, whereas matrix metalloproteinases are selectively increased, suggesting that disruption of tight junctions is necessary for extravasation.

Dr. Grutzendler and colleagues have also examined what happens when blood vessels are occluded in aging mice. They have found a marked increase in hypoxia and evidence of permanent synapse damage. In addition, the rate at which extravasation fails is substantial; and the clot ultimately causes cell death, killing the vessel. Thus Dr. Grutzendler and his colleagues have identified a new cellular process, slower than fibrinolysis and blood pressure, that could be important for clearing the microvasculature. Failure to extravasate might represent a new mechanism of neurovascular degeneration, and the ability to clear smaller emboli thus has important implications for recovery following embolic events and stroke. Moreover, aging, AD, hypertension, and diabetes could exert effects on the ability of clots to extravasate.

In response to questions from Council, Dr. Grutzendler remarked that conventional neurobiological techniques would be unable to show the status of the microvasculature. Some studies have quantified the loss of microvasculature, but these studies have yielded conflicting results.

8. ADJOURNMENT

The open session of the 110th meeting of the National Advisory Council on Aging adjourned at 1:30 p.m. on May 26, 2010. The next meeting is scheduled for September 21 and 22, 2010.

9. 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.

1. For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions or (b) in which a conflict of interest may have occurred. This procedure only applied to applications that were discussed individually, not to “en bloc” actions. (Back to text.)
2. For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions or (b) in which a conflict of interest may have occurred. This procedure only applied to applications that were discussed individually, not to “en bloc” actions. (Back to text.)
3. These minutes will be approved formally by Council at the next meeting on September 21-22, 2010, and correction 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)(**Provisional member whose appointment is not yet official)

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

*Lisa F. Berkman, Ph.D. (2012)
Director and Professor
Harvard School of Public Health
Dept of Society, Human Development, and Health, and Dept of Epidemiology
Cambridge, MA

Dale E. Bredesen, M.D. (2011)
Professor, Director & CEO
Buck Institute for Age Research
Novato, CA

Robert M. Califf, M.D. (2013)
Vice Chancellor for Clinical Research, Duke University
Director, Duke Translational Medicine Institute
Durham, NC

Peggye Dilworth-Anderson, Ph.D. (2010)
Professor, Health Policy & Management
Associate Director, Aging and Diversity/ Institute on Aging
University of North Carolina, Chapel Hill
Chapel Hill, NC

Hendrie, Hugh C., MB, ChB, DSC (2013)
Professor, Department of Psychiatry, Indiana University School of Medicine
Research Scientist, Regenstrief Institute, Inc.
Center Scientist, Indiana University Center for Aging Research
Indianapolis, IN

*S. Michal Jazwinski, Ph.D., (2010)
Professor
Department of Medicine
Tulane University Health Sciences Center
New Orleans, LA

*Sundeep Khosla, M.D. (2010)
Professor, Endocrine Research Unit
Division of Endocrinology, Metabolism, & Nutrition
Mayo Clinic College of Medicine
Rochester, MN

Andrea Z. LaCroix, Ph.D., M.P.H. (2012)
Professor
Fred Hutchison Cancer Research Center
Women’s Health Initiative Clinical Coordinating Center
Seattle, WA

Victor Molinari, Ph.D. (2012)
Professor
University of South Florida
Department of Aging and Mental Health
Tampa, FL

*Lennart Mucke, M.D. (2012)
Director and Professor of Neuroscience
Gladstone Institute of Neurological Disease
University of California, San Francisco
San Francisco, CA

Perry, Daniel P. (2013)
President and CEO
Alliance for Aging Research
Washington, DC 20006

Petersen, Ronald C., M.D., Ph.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

Orien Reid (2010)
Chairman, Alzheimer's Disease International
President, Consumer Connection
Laverock, PA

Richardson, Arlan G., Ph.D. (2013)
Director
Barshop Institute for Longevity and Aging Studies
University of Texas Health Science Center
San Antonio, TX

June Simmons (2012)
Chief Executive Officer
Partners in Care Foundation
San Fernando, CA

James P. Smith, Ph.D. (2012)
Senior Economist
RAND Corporation
Department of Labor and Population
Santa Monica, CA

*Susan L. Swain, Ph.D. (2011)
Department of Pathology S2-137
University of Massachusetts Medical School
Worcester, MA 01655

Wetle, Terrie F., Ph.D. (2013)
Associate Dean and Professor
Program in Public Health
Division of Biology and Medicine
Brown University
Providence, RI

EX OFFICIO MEMBERS

Kathleen Sebelius
Secretary
Department of Health and Human Services
Hubert H. Humphrey Building
Washington, DC

Francis S. Collins, M.D., Ph.D.
Director
National Institutes of Health
Public Health Service
Bethesda, MD

James F. Burris, M.D.
Chief Consultant
Geriatrics & Extended Care Strategic Healthcare Group
Department of Veterans Affairs
Washington, DC

John Wren
Deputy Assistant Secretary for Policy and Management
U.S. Department of Health and Human Services
Administration on Aging
Washington, DC

Kenneth G. Pugh, M.D.
Commander, MC, U.S. Navy
U. S. Naval Hospital Rota
PSC 819 Box 18-74