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The 106th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, January 27, 2009, 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, January 27, from 3 p.m. to 5 p.m. for the review, discussion, and evaluation of grant applications and on Wednesday, January 28, from 1:46 to 2:30 p.m. for the review of intramural laboratories and reports 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, January 28, from 8 a.m. to 1:45 p.m.
Council Participants:
Dr. Peggye Dilworth-Anderson (by telephone, January 27 only)
Dr. Lawrence M. Friedman
Dr. Mary Ganguli
Dr. S. Michal Jazwinski
Dr. Sundeep Khosla
Dr. Terry L. Mills
Dr. John C. Morris
Ms. Orien Reid
Dr. Gerald P. Schatten
Dr. Susan L. Swain
Absent:
Dr. Dale E. Bredesen
Dr. Kenneth V. Brummel-Smith
Dr. Carl Eisdorfer
Ex Officio Participants:
Ms. Lori Gerhard, Administration on Aging (AOA), U.S. Department of Health and Human Services (HHS)
Absent Ex Officio Participants:
Dr. James Burris, Department of Veterans Affairs
Dr. Kenneth Pugh, National Naval Medical Center
Ad Hoc Council Participants
Dr. Andrea LaCroix
Dr. Victor Molinari
Dr. Lennart Mucke
Dr. June Simmons
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. Laurent Taupenot, Center for Scientific Review, NIH
Ms. Jane Tilly, Administration on Aging
Members of the Public Present:
Dr. John Cacioppo, University of Chicago (by telephone)
Dr. David Cutler, Harvard University
Dr. Rita Effros, University of California, Los Angeles
Dr. David Felson, Boston University
Dr. Alan Garber, Stanford University (by telephone)
Mr. Rick Hansen, Digicon, Inc.
Ms. Mary Jo Hoeksema, Population Association of America/Association of Population Centers
Dr. Rose Maria Li, Rose Li and Associates, Inc.
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Ms. Amy Pollack, Association for Psychological Science
Ms. Branka Sekis, Social Scientific Systems, Inc.
I. 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 552b(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 953 applications requesting $1,164,240,705 for all years underwent initial review. The Council recommended 508 awards for a total of $822,442,686 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.
II. CALL TO ORDER
Dr. Hodes welcomed members to the open session of the 106th NACA meeting and called the meeting to order at 8:05 a.m. on Wednesday, January 28, 2009.
A. Director’s Status Report
Dr. Hodes reminded the Council that although the NIH budget has remained stable in terms of current dollars since 2003, in constant dollars the budget has experienced a loss of buying power of about 13 percent. This decline has taken place at a time when the number of scientific opportunities and applications has exploded. The NIH is operating under a continuing resolution, which funds the agency at fiscal year (FY)2008 levels until March 6, 2009.
The Omnibus Budget Reconciliation Act of 2009 (OBRA) is trailing behind the Economic Stimulus Package for floor action in Congress. Substantial uncertainty remained particularly concerning the Stimulus Package and its effects on NIH’s budget. As regards the annual appropriation bill, Dr. Hodes noted that although the Senate and House versions differ, it is expected that the NIH will receive a small increase in its budget for FY2009.
Dr. Hodes acknowledged a report given by Ms. Orien Reid the previous day on the rollout of the Research, Condition, and Disease Categories (RCDC) and the new Research Portfolio Online Reporting Tool (RePORT). He reminded the Council that RCDC was developed to improve consistency, transparency, and reproducibility of NIH reports on spending. Selecting a category in RePORT will generate a list of relevant research projects. Overall, the little feedback the NIH has received on RePORT has been positive. The NIH had expected the community to express concern about the potential for nonrelevant projects to be erroneously included in a particular category or the effects of the new system on numbers. However, since the RCDC rollout, there has been little response in this regard. Most categories showed a decrease in spending by 20 to 30 percent, and RCDC appears to capture aspects of projects related to a certain category—for example, aging-associated cell death in AD—without introducing irrelevant items. Dr. Hodes noted the NIH’s expectation that RCDC could one day aid with portfolio analysis and science planning. Ms. Reid indicated the large amount of information provided by RCDC as well as the challenges overcome to launch the new system.
In response to questions from Dr. Gerald Schatten, Dr. Hodes speculated that the National Center for Research Resources (NCRR) would likely receive the $1.5 billion earmarked in the House version of the Stimulus Package for repair, renovation, and instrumentation sharing. NIA leadership is working with staff and constituents to generate a list of needs to provide to NCRR in case this funding is approved. In response to Dr. Schatten’s questions about the additional Stimulus Package funds that may be appropriated for scientific research, Dr. Hodes noted that the turnaround time for this funding would make conventional review of de novo applications difficult. He speculated that the NIH would use the funding toward applications already in hand or toward an expedited program for new applications. In response to a question by Dr. Susan Swain, Dr. Hodes added that bridge funds have also been mentioned in the broader discussion of new spending.
Dr. Terry Mills asked whether RCDC will replace the Computer Retrieval of Information on Scientific Projects (CRISP). Ms. Kathie Reed, of the NIA Office of Planning, Analysis, and Evaluation, responded that CRISP will become an Expenditures and Results extension to the RePORT tool; i.e., RePORTER.
B. Future Meeting Dates
May 19–20, 2009 (Tuesday and Wednesday)
September 22–23, 2009 (Tuesday and Wednesday)
January 26–27, 2010 (Tuesday and Wednesday)
May 25–26, 2010 (Tuesday and Wednesday)
September 21–22, 2010 (Tuesday and Wednesday)
C. Consideration of the Minutes of the Last Meeting
The minutes of the September 2008 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.
D. Introductions
Dr. Hodes introduced new NIA Deputy Director Dr. Marie Bernard and Council members and invited introductions from incoming members Dr. Andrea LaCroix, Dr. Victor Molinari, Dr. Lennart Mucke, and Ms. June Simmons. Dr. Alexander Parsadanian, a new Scientific Review Officer in the Scientific Review Branch, was also introduced.
III. REPORT: Task Force on Minority Aging Research
Dr. Mills highlighted two presentations heard by the Task Force on the previous day. In the first, Dr. Vivian Pinn, Director of the NIH Office of Research on Women’s Health (ORWH), presented an interim report on the NIH Working Group on Women in Biomedical Careers. Co-chaired by Dr. Pinn and Dr. Raynard Kington, Acting NIH Director, the working group includes NIH Deputy Directors, NIH Institute and Center (IC) Directors, dual-career couples, postdoctoral fellows, intramural scientists, and extramural grants administrators. The NIH has launched a Web site, http://womeninscience.nih.gov, which includes information about the working group and links to career development resources within the NIH, professional societies, and other organizations.
Dr. Mills noted the 11 subcommittees of the Working Group and commented specifically on the subcommittee focused on expanding support for research on the efficacy of programs to reduce gender bias. He suggested that the NIA Task Force on Minority Aging Research implement similar efforts to examine the efficacy of NIA programs to reduce bias.
The Working Group called attention to the recommendations from the National Academies Report, Beyond Bias and Barriers: Fulfilling the Potential of Women in Academic Science and Engineering, which was sponsored by ORWH, Eli Lilly and Company, the National Science Foundation, and the Ford Foundation. It also recommended giving attention to the NIH intramural community and the concerns of intramural women scientists and providing special attention to issues of barriers to advancement, minority women scientists, and mentoring.
Dr. Pinn’s presentation also highlighted a number of issues with respect to extramural research, including the availability of detailed information on the involvement of women in extramural research; the doubling of the period of parental leave available to National Research Service Award recipients and a call for institutions to examine their own parental leave policies for all students and postdoctoral fellows; and clarification of Federal cost policies to provide guidance to universities on how to structure indirect cost and fringe benefit arrangements when considering reimbursement for childcare, parental leave, and other factors.
The presentation also highlighted data indicating higher award success rates for experienced males compared to their female counterparts although first-time researchers are equally successful; that males receive larger awards than females do although both sexes receive the same percentage of requests; and that the NIH success rates are lowest for African Americans. A workshop on Mentoring Women in Biomedical Careers has recommended that the NIH develop new requests for applications (RFAs) to study mentoring, include a mentor training requirement on training awards, and incorporate “women of color” as an issue or theme to be addressed in meetings and RFAs. Dr. Mills cautioned, however, that the term “women of color” needs a more specific operational definition.
In the second presentation to the Task Force, Dr. Hinda Zlotnik, Chief of the Minority Biomedical Research Support Branch of the National Institute of General Medical Sciences, provided an update on the Support of Competitive Research (SCORE) Program. This program was designed to increase the competitiveness of faculty at minority-serving institutions. Although SCORE requires that an applicant be a faculty member at a minority-serving institution, it does not require the applicant to be a minority.
The SCORE program includes three categories of awards—SC1, a research advancement award; SC2, a pilot project award; and SC3, a research continuance award. SC1 fosters transition to non-SCORE support, providing $250,000 per year in direct costs and support for 5 years for new investigators or 4 years for previous SCORE awardees. The award is renewable once; thus, investigators could receive up to 9 years in SC1 support. SC2 is a smaller grant, providing up to $100,000 per year (not to exceed $300,000 for the entire award period) for investigators to generate preliminary data. This award could facilitate a transition into SC1 funding and ultimately into R01 funding. Eligible institutions can apply for and hold a maximum of 25 SCORE awards, and eligible faculty can apply for and hold only 1 individual SCORE award. In their applications, principal investigators (PIs) must list developmental goals and describe a plan to accomplish them. If the PI leaves for another institution, the award is not transferable.
Dr. Mills noted that as of FY2008, the program has made a total of 114 awards, including 50 SC1s and 30 SC2s. Twelve other ICs participate in the SCORE program. Forty-one of the SC1 and SC2 awards are co-managed by other ICs, and 12 SC1 and SC2 awards are funded by other ICs.
IV. CONSIDERATION OF THE REPORT ON INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 2008 DATA
Dr. Robin Barr reminded the Council that this report, which is required by law, tracks the inclusion of women and racial and ethnic minorities in intramural and extramural clinical research. He noted the fluctuations in enrollment data that can occur from the entry and exit of large studies. Total NIA numbers fell with the number of protocols between 2007 and 2008. NIA-supported protocols are recruiting African Americans and Latinos/Hispanics in numbers proportional to their representation in the total population. However, all trials are recruiting more women than men. The number of Phase III trials fell from four in 2007 to one in 2008.
A motion to approve the report was forwarded and seconded. The motion passed unanimously.
V. REPORT: Working Group on Program
Dr. John Morris noted three meetings and two RFA concepts presented to the working group during the previous day. The Council also reconsidered the standing Statement of Understanding.
Advisory Meetings
Dr. Felipe Sierra, of the Division of Aging Biology, highlighted recommendations from a September 2008 Summit on the Biology of Aging. The Working Group decided to forward the recommendations to the Council for approval rather than hold them until a planned program review takes place for the Division of Aging Biology. A motion to adopt the recommendations from the Summit report was forwarded and seconded. The motion passed unanimously.
Dr. Dallas Anderson, of the Division of Neuroscience, presented a meeting to be held in March. The meeting, cosponsored by the Alzheimer’s Association, will examine the prevalence of AD, why prevalence estimates vary, and ways to reduce variability. Meeting participants also will discuss key issues in and ways to operationalize criteria for determining AD. A motion to approve the meeting concept was made and seconded. During discussion of the motion, Dr. Mary Ganguli pointed out that the scope and implications of the meeting will go beyond prevalence to the current science underlying criteria, early detection, and biomarkers. The motion passed unanimously.
Dr. Mahadev Murthy, of the Division of Aging Biology, presented a meeting linked to recommendations from the Summit on the Biology of Aging. This meeting will be held to develop consensus criteria for defining normal aging in rodent models. A motion to approve the meeting was forwarded and seconded. The motion passed unanimously.
RFA Concept Clearances
Dr. Suzana Petanceska, of the Division of Neuroscience, presented a proposed program announcement (PA) based on a workshop held in August 2008. The PA will support research into the role of different apolipoprotein E isoforms in brain aging and AD. Dr. Hodes informed the Council that the NIA had received and will consider comments provided by the Working Group the prior day regarding the PA’s focus. A motion to approve the PA was made and seconded. The motion passed unanimously.
Dr. Lisbeth Nielsen and Dr. John Phillips, of the Division of Behavioral and Social Research (DBSR), presented a PA that would support network research resources and infrastructure for emerging behavioral and social research on aging. During her presentation at the Council meeting, Dr. Nielsen added that the requested support builds upon other investments made by the DBSR in centers programs, which traditionally have not been funded at a level to permit cross-institutional activities such as summer institutes. A motion to approve the PA was made and seconded. The motion passed with one abstention.
Statement of Understanding
Dr. Barr reminded the Council that the Statement of Understanding between the NIA and NACA allows the NIA to expedite actions and report on them at later Council meetings. He cited as an example the action the NIA took to support grantees in the aftermath of Hurricane Ike. Dr. Barr also noted that the statement allows the NIA to expedite applications within the 20th percentile although budget constraints have not allowed funding to this level. Dr. Schatten commended the latitude the statement offers the NIA to act expeditiously. A motion to approve the Statement of Understanding was forwarded and seconded. The motion passed unanimously.
VI. REPORT: Council of Councils
Ms. Reid, who represents NACA on the NIH Council of Councils (COC), summarized her remarks to the Working Group on Program from the day before. Full minutes from the COC meeting will be posted when available at https://dpcpsi.nih.gov/council.
VII. REPORT: Division of Behavioral and Social Research Review
Dr. Alan Garber and Dr. John Cacioppo, Co-Chairs of the DBSR review committee, participated by telephone and reported the results of the review, which yielded two sets of documents. The DBSR Review Committee Report contains overarching and specific recommendations as well as a supplemental report primarily for DBSR/NIA staff use that contains more detailed reports in 10 topic areas. The latter reports do not represent consensus recommendations. They are available upon request.
Through a series of conference calls and a face-to-face meeting between May and November, the committee reviewed information obtained from background materials and summaries provided by the DBSR, discussions with selected individuals within the NIA, subcommittee discussions, and written input from several associations. On the basis of this information, the committee determined that the DBSR had been highly responsive to recommendations from its 2004 review. Reviewers were impressed with the Division’s operations and its willingness to take calculated risks in exploring areas of research. The committee noted that the DBSR is a model for interdisciplinary research within the NIH. The Division regularly considers biological measures along with traditional social, behavioral, and economic measures, and its applicants tend to fare better in study sections compared with other NIH applicants. The Committee noted several DBSR accomplishments: Enhanced leadership in the development of new scientific areas through excellent hires, which addresses the primary concern from the 2004 review; continued strong leadership in the development of powerful new datasets and collaborations with other Federal agencies; recruitment of outstanding researchers into behavioral and social research on aging; and improved collaboration with the Division of Neuroscience.
Dr. Garber reported that in a time of difficult budgetary conditions, the Committee recognizes the need to balance multiple agendas but underscored the principle of identifying and supporting work of the highest scientific merit as paramount. Specifically, if tradeoffs are required, the committee recommends an emphasis on research that will change science in a more broadly defined area. Dr. Garber highlighted the Committee’s overarching recommendations and recommendations from several subcommittees:
Continue to emphasize integrative science and multilevel analysis.
Adopt a life course perspective.
Consider establishing a board to advise the DBSR on how to prioritize intervention and translation projects.
Maintain centrality of the micro- and macroeconomy of population aging in DBSR’s portfolio.
Revitalize the social demography, epidemiology, and sociology portfolios, which do not appear to have experienced much recent intellectual or funding growth.
Support disparities research, but direct it more toward theory-based research.
Continue and expand training support, with an emphasis on new models of training.
Develop appropriate datasets and continue to support data availability.
Consider additional staffing in areas of behavioral or health economics, social epidemiology, and interventions.
The Committee generally agreed with the DBSR leadership on the importance of program project grants, and it endorsed actions taken by the NIH to address overburdened review offices and the need for better review mechanisms for interdisciplinary applications. However, Committee members thought it unfortunate that site visits, which can be expensive, were being cut in a time of budgetary constraints. The Committee challenged the DBSR with developing alternative mechanisms to promote interdisciplinary training appropriate for the next generation of aging researchers. In light of the current economic climate, the Committee also challenged the DBSR to develop a strategic plan to address budgetary constraints that will likely continue or worsen in the next few years.
Dr. Sundeep Khosla asked whether the Committee discussed novel technologies that might allow older people to be monitored in their homes, thus promoting the ability to live independently. Dr. Garber and Dr. Cacioppo believe these technologies form a natural area for comparative assessments and for research on interventions and cost effectiveness. Dr. Richard Suzman, DBSR Director, highlighted efforts supported by the Division, including SmartHouse, in which a Roybal Center is working with Intel to develop home monitoring, and studies involving measures of energy expenditure and sleep quality. Ms. Lori Gerhard underscored the AOA’s interest in this line of research.
Dr. Hodes complimented the Co-Chairs for leading a model review. He then addressed the review committee’s concern about site visits. He noted that although in-house site visits are preferable to electronic review mechanisms, the problem is not only expense but also availability of reviewers. The NIA is working to improve the review format. Dr. Hodes also offered to have the NIA provide a progress report within a year on the results of the changes the NIH has already made with respect to peer review.
A motion to accept the Committee’s report was made and seconded. The motion passed unanimously.
VIII. DIVISION HIGHLIGHTS
Due to inclement weather, Dr. Virginia Lee was unable to attend the meeting so did not deliver her presentation on behalf of the Division of Neuroscience on amyotrophic lateral sclerosis and frontotemporal labor degeneration.
Aging Biology: Immune Exhaustion in Aging and AIDS: Parallel Mechanisms, Possible Solutions
Dr. Rita Effros, of the David Geffen School of Medicine at UCLA, began her presentation by summarizing findings from a recent workshop sponsored in part by the NIA. The workshop, which focused on HIV and aging, found that by 2015, half of all HIV-positive patients will be over age 50. Other findings included the older age of newly infected patients, an increased cancer incidence in the HIV-infected population as it ages, and increased prevalence of age-related diseases among this population. In addition, HIV appears to accelerate frailty, and the immune system is involved not only in HIV/AIDS but in many of its associated diseases.
Although many aging studies have used model organisms profitably, certain aspects of immune changes in elderly humans cannot be mimicked in these models. Moreover, all that is known about the immune system is based on cells isolated from blood, but blood cells represent only 2 percent of total lymphocytes in the human body. The majority of immune cells reside in the gut, the population of central memory cells in the gut predicts the rate of HIV disease progression, and immune reconstitution with the initiation of highly active antiretroviral therapy (HAART) occurs more slowly in the gut than in the blood. Yet aside from these observations, almost nothing is known about the effects of aging or HIV infection on the mucosal immune system. A major research gap is the lack of understanding about the effects of age, HIV, or both on gut-associated lymphoid tissue. Despite these gaps, research on the aging immune system has provided new insights into HIV pathogenesis. Likewise, HIV disease has become a model of accelerated aging of the immune system. Whether there are common approaches, and what the synergistic immunological effects are, is unknown.
Dr. Effros’ work has focused on cytotoxic T cells, which recognize and kill cells that have been infected with virus. Because these T cells have unique receptors that recognize specific parts of a virus, presentation of a new viral infection requires a massive expansion of specific cytotoxic T cells. These cells undergo repeated expansions until they reach replicative senescence where they are no longer able to divide or kill virally infected cells. Cells in replicative senescence produce inflammatory factors, are resistant to apoptosis, and have shortened telomeres. They also lose expression of the signaling molecule CD28. The number of CD28-negative cytotoxic T cells increases markedly with age, and cytotoxic T cells isolated from young patients infected with HIV show patterns similar to that seen in much older, HIV-negative individuals. The accumulation of these cells in older people appears to be driven by latent viral infections acquired during youth as cytotoxic T cells are actively involved in keeping those infections latent.
Telomere shortening could be considered as “the canary in the coal mine” for health. CD28-negative cells have short telomeres, and they have been correlated with poor response to influenza vaccine, osteoporotic fractures, and early mortality in the elderly. Shortened telomeres also have been associated with atherosclerosis, premature myocardial infarction, insulin resistance, type 2 diabetes, AD, psychological stress, and microalbuminuria. A study by Cawthon and colleagues associated shortened telomeres with a threefold higher risk of death from heart disease and an eightfold higher risk of death from infection. The level of telomerase, the enzyme that prevents telomere shortening, has been used as a marker of cardiovascular disease risk and the ability to control HIV.
Dr. Effros closed her presentation by presenting data from ongoing studies on the immune effects of enhancing telomerase activity. Council discussion focused on these studies.
Geriatrics and Clinical Gerontology: Recent Findings on Meniscal Tears, Obesity, and Knee Osteoarthritis from NIA-Supported Studies
Osteoarthritis (OA) is the most common form of arthritis. Among the elderly, OA accounts for more mobility disability than does any other disease, and it is the underlying factor in most total knee and hip replacements. In the United States, 27 million people are affected by OA, and this number is expected to increase with the aging population, the obesity epidemic, and increased number of sports-related injuries. Yet there are few preventive strategies and no known treatments that can prevent OA-associated structural joint deterioration. Dr. David Felson, of the Boston University Medical Center, focused his presentation on the knee and specifically the meniscus, which serves as a shock absorber for load. Tears or damage in the meniscus have been associated with knee pain and buckling, and hundreds of thousands of arthroscopic surgeries per year are triggered by meniscal tears. More than half of surgeries removing the meniscus are done in patients aged 45 years or older, and the majority of those surgeries occur in patients aged 60 years and older.
Dr. Felson and his colleagues used the Framingham OA Study to investigate the prevalence of meniscal tears. In this study, 991 participants with mean age of 62 years underwent magnetic resonance imaging (MRI) of their knees. Twenty to twenty-five percent of these participants had had knee pain on most days. The study found that meniscal tears were common even in patients with no knee symptoms, that the prevalence of meniscal tears increased with age, and that meniscal tears were more prevalent in men than in women. Moreover, the study found that meniscal tears were associated with knee pain only because they were related to OA, which causes pain.
The course of meniscal tears without surgical intervention is unknown, and longitudinal studies have been hampered by difficulties in obtaining information on meniscal status in patients who do not have surgery. Another community study, the Multicenter OA Study (MOST), enrolled more than 3,000 people aged 50 to 79 years who had OA or were at high risk for OA. Patients at high risk were overweight or obese and had frequent knee pain or a history of knee injury. Again, study participants underwent knee MRI. MOST found that patients who had meniscal tears but did not receive surgery were at high risk for OA. In light of the high frequency of meniscal tears seen in the Framingham OA Study, knee OA might be a disease more of fibro cartilage than of hyaline cartilage. In addition, more OA might be posttraumatic and mediated by meniscal tear than previously suspected. Thus OA might not be an inevitable disease of aging so much as one of repeated injury.
Dr. Terry Mills noted Dr. Felson’s comments that surgery for meniscal tears also increases the risk for OA and questioned how orthopedists should proceed in light of MOST results. Dr. Felson agreed that the relationship between OA and meniscal tears is complicated. The MOST data might suggest the need to operate on patients who have meniscal tears and symptoms, but more studies are needed to determine what happens with patients who do not experience symptoms.
Ms. Orien Reid noted the higher prevalence of tears in men than in women and asked whether patient histories indicated any lifestyle differences between the two genders. Dr. Felson responded that the presence of meniscal tears did not appear to be related to previous injuries, but he also suggested that the study might not have adequately captured differences in terms of activities. In addition, it is not clear why more men than women have meniscal tears but more women than men have OA.
In response to questions from Dr. Susan Swain about alternative interventions, Dr. Felson noted that the MOST data suggest intriguing opportunities for therapies. Fibro cartilage is partially vascularized, and the rim of the meniscus is often the area where initial degeneration occurs. The finding that OA affects fibro more than hyaline cartilage suggests opportunities for therapy not previously anticipated.
Dr. Sundeep Khosla asked about implications for the pathogenesis of OA and whether meniscal tears induce other factors that might drive OA. Dr. Felson responded that metabolic or genetic abnormalities were not clear, but some orthopedists have reported a rasplike effect on underlying cartilage from degenerative tears.
Ms. Lori Gerhard noted the associations with obesity and asked whether any studies had been done on the role of nutrition and hydration. The prevalence of not only meniscal tears but also dehydration increases with age. Dr. Felson did not know of any such studies.
In response to questions from Dr. Andrea LaCroix about effects of physical activity, Dr. Felson noted that most studies have focused on OA and hyaline cartilage loss and not so much on meniscal tears. In response to a comment from Dr. Mills, Dr. Felson further noted that there are two kinds of meniscal tears: acute tears that occur with sports or walking and incidental tears that occur in older years and do not cause pain. His presentation focused on the latter. Dr. Robin Barr asked whether incidental tears are progressive. Dr. Felson responded that MOST can follow patients over time and that many of the tears seen in the study have a high risk for progression.
Behavioral and Social Research: Measuring the Value of the Medical Sector—Developing a Prototype for National Health Accounts
Dr. David Cutler, of Harvard University, described a new, long-term project to produce a set of National Health Accounts, which can be used to make sound public policy decisions. These accounts will be analogous to National Income and Product Accounts (NIPAs), which provide total gross domestic product (GDP) and its division into major categories such as consumption, investment, Government spending, and net exports. NIPAs play a central organizing role in economic measurement, and because they divide spending increases into prices and quantities, they allow for the calculation of productivity growth.
NIPAs are organized around market activity, but health activities often reside outside the market. Thus, “satellite” accounts have been suggested as a way to measure the costs and benefits of such activities. The satellite health accounts are based on inputs such as medical care, time invested in one’s own health, other consumption such as food and tobacco, and environment and health-related outputs such as length and quality of life and financial externalities, or how changes in a person’s health affect the financial circumstances of others through tax and transfer programs. Constructing a set of national health accounts involves three steps: A global measure of population health, a measure of spending and health at the level of disease or medical condition, and the use of detailed models to link spending and health outcomes at the disease level. Quality-adjusted life expectancy (QALE), or the number of years of quality-adjusted life a person today can expect to live, comprises life expectancy and quality of life. Life expectancy is relatively easy to measure, but quality of life is somewhat complex, relating self-reported quality to symptoms and impairments and tracking how those symptoms and impairments change over time.
Dr. Cutler shared data suggesting that the general population was healthier in 2004 than it was in 1987. About two-thirds of the increase in QALE could be attributed to longer life expectancy. Improved quality of life also was a factor; people experienced fewer impairments in 2004. On the basis of these data, it appears that national health measurement is possible and that disease-based models will help evaluate what has been done and simulate future possibilities.
In response to Dr. Mills’ questions about effects of chronic comorbidities, Dr. Cutler noted that people are living with more chronic diseases but functioning better than they would have years before. He also noted that today people report health comparable to that reported by people 10 years younger in earlier reports. How much of this improvement in quality of life is related to medical care, environment, or social support is not yet clear.
Dr. Hodes commented that NIPAs allow quarterly or annual assessments and could be updated and inform policy. Dr. Cutler noted that the same type of flexibility would be seen with national health accounts although assessments might occur less frequently. He added that GDP is a respected measure because of the scientific rigor involved in assessing it, and he hopes health accounts would be assessed and used in a similar way. In response to questions from Dr. Barr about tying health accounts to national policy goals, Dr. Cutler cited insurance coverage, environmental policies, the physical structure of a community, and nutrition policies as examples of policies that could be informed by national health accounts.
Dr. Lennart Mucke expressed puzzlement regarding the conclusion that the population is healthier, particularly in light of the aging population and the many age-associated diseases. He was concerned that this type of message might signal to the general population and to policymakers that less work on health is needed. Dr. Cutler clarified the conclusion to state that an age-adjusted population is healthier. He added that, at present, the focus is on health spending without looking at other aspects of health. This focus leads to problematic avenues of policy. The construction of national health accounts could provide a better picture and thus improve policy. Dr. Mary Ganguli expressed her understanding that the average 25-year-old is not healthier so much as more optimistic about his or her health. Dr. Cutler responded that more than optimism is involved. For example, impairment appears to be declining.
Ms. Reid noted statistics from America’s Second Harvest, which indicate that 33 million people in the country are hungry or at risk for hunger and that 13 million of those people are children. She expressed concern about their current quality of life and implications for their health in later years. Dr. Cutler responded that health accounts could be broken out for different groups and used to explore which interventions most improve the population’s health. He also suggested ways in which health accounts could be used to track disparities over time.
In response to questions from other Council members, Dr. Cutler further clarified categories of impairment. He also responded to questions from Dr. Richard Suzman by pointing out that national health accounts would not replace the health portion of NIPAs and that the new accounts would be better received by Federal agencies if they first gain academic credibility. Other Council members expressed concern about difficulties in self-assessment for topics like cognition. Such assessments could be affected by age, severity of cognitive decline, and older adults’ fear about changes in their cognition.
IX. INTRAMURAL RESEARCH PROGRAM REPORTS
Laboratory of Cardiovascular Sciences
Dr. Edward Lakatta, Chief of the Laboratory of Cardiovascular Sciences (LCS), focused his presentation on translational and interdisciplinary research conducted by the laboratory. Comprising several units, the Laboratory employs a wide range of experimental models, from molecules to humans, and it interacts with several longitudinal population-based studies such as the Baltimore Longitudinal Study on Aging and the Cardiovascular Health Study. The Laboratory’s process for translational research involves identifying and understanding a need; generating ideas; exploring proofs of concept in molecular, cellular, or animal studies; and promoting human clinical trials. An understanding of regulatory and intellectual property issues is built in from the beginning. Dr. Lakatta pointed out that often the process for translational research is not planned but that LCS facilitates it by being prepared.
LCS has used this process to explore mechanisms and treatment of vascular injury. Using rat and guinea pig models, the laboratory found that taxol could mitigate the angioplasty-associated damaging properties of smooth muscle cells. In collaboration with Boston Scientific, LCS developed a taxol-coated stent and conducted clinical trials that showed a substantial clinical benefit. Taxol-coated stents are now widely used. The intramural program has received royalties from this work, and these royalties are used to fund studies investigating the use of erythropoietin in preventing heart failure.
An exploration of arterial aging is one of the more challenging areas of translational research in which LCS is engaged. Age is a major risk factor for cardiovascular disease, but it has been virtually ignored. The Laboratory thus explores aspects of aging in the absence of clinical disease by studying community populations and classifying them as “successfully” or “unsuccessfully” aging. This classification is based on factors that could contribute to disease. Thus, “unsuccessful aging” does not necessarily mean a participant has a clinical disease. Rather, that person has fallen into the poorest category with respect to a factor associated with disease.
On the basis of its studies, LCS views unsuccessful aging as the manifestation of an interaction between vascular aging and factors involved in vascular disease. In the absence of textbook clinical diseases, aging arteries undergo several major changes that can lead to cardiovascular events. Work by LCS and other groups has shown that at the clinical level, age-associated increases in arterial stiffness predict cardiovascular mortality and lead to increased blood and pulse pressure. Molecular and cellular studies in LCS have shown that intimal-media thickening, another age-associated arterial change, is primarily intimal and arises from vascular smooth muscle cells becoming aggressive and migrating to the intima. This process is related to matrix metalloproteinase 2, which not only breaks down basement membrane but also activates latent growth factors such as transforming growth factor beta. Thus, arterial remodeling arises from the production of proinflammatory mediators by smooth muscle cells. These mechanisms are also apparent in atherosclerosis and hypertension across several animal models. LCS therefore suggests that hypertension and atherosclerosis should be viewed as clinical end points rather than risk factors.
These studies have implications for the development of therapies that will target arterial aging in humans. Lifestyle interventions and pharmacotherapy have proven effective. Exercise conditioning improves endothelial function, pulse pressure, pulse wave velocity, and carotid augmentation index in older persons, and lower sodium diets have been associated with reduced age-associated arterial stiffening. Angiotensin-converting enzyme inhibitors appear to slow vascular aging in rodent models, and drug-diet combinations have been shown to slow or reduce intimal-medial thickening in humans. Dr. Lakatta closed his presentation by showing LCS studies on the use of an investigational drug, which attacks crosslinked proteins, to prevent or reduce arterial stiffness.
Dr. Mucke asked how LCS—and the NIH in general—could provide guidance and share its experiences with academic centers that are struggling with the process of translating research. Dr. Lakatta noted that translational work in LCS could be advertised more, but he also pointed out the many components of NIA infrastructure that help with the translational process. For example, because of LCS’s interactions with the Technology Transfer Branch, it now routinely considers the patentability of its study results.
Dr. Mucke also commented on the many relevant age-related initiatives that do not make it through university business offices because of competing agendas. Dr. Lakatta agreed that age-related issues are often of lower priority. LCS hopes to work with the National Heart, Lung, and Blood Institute, which explores the same issues with a different emphasis, to further promote clinical trials.
Dr. Victor Molinari asked whether LCS’s interest in preventive aging is consistent with the pharmaceutical industry’s push to reduce blood pressure and hypertension at all ages. Dr. Lakatta responded that it is consistent and likened the push to putting fluoride in drinking water because these arterial changes appear to be universal across species. However, proving that reducing blood pressure and cholesterol at younger ages would be beneficial is difficult because of the lack of cardiovascular events, hence the reluctance of pharmaceutical companies to pursue this avenue.
Laboratory of Clinical Investigation
Dr. Josephine Egan, Chief of the Laboratory of Clinical Investigation (LCI), focused her presentation on LCI efforts in diabetes research. The Laboratory studies factors, of which glucose is only one, that regulate insulin secretion. One such factor, GLP-1, is a hormone that is released from the gut when food reaches the small bowel. Upon its release, GLP-1 proceeds through the islets of Langerhans and induces insulin secretion, at which point GLP-1 is quickly broken down. Because it is broken down so quickly, GLP-1 is not an effective pharmacological intervention for inducing insulin secretion. However, extendin 4, an analog that mirrors the action of GLP-1 and maintains insulin secretion after a patient eats, is now a treatment for type 2 diabetes.
With age, the ratio of fat to muscle changes in the human body. This change leads to the metabolic syndrome, characterized by a decrease in insulin sensitivity and a requirement for more insulin. The absence of more insulin leads to increases in blood sugar and blood pressure, decreased glucose tolerance, and changes in lipid profile. Dr. Egan pointed out, however, that there is no one intervention to prevent or delay these changes. However, the LCI is beginning to understand more about the components of the metabolic syndrome. For example, the LCI has found an association between declining production of adiponectin and declines in insulin sensitivity. In addition, the Laboratory has studied nonalcoholic fatty liver disease, in which the insulin receptor becomes dysfunctional, leading to decreased beta oxidation, fatty acid buildup, and steatosis. The National Institute on Alcohol Abuse and Alcoholism (NIAAA), in its work on alcoholic liver disease, has found that alcohol raises the level of endogenous cannabinoids. Work by the LCI has shown that the endogenous cannabinoid system in the pancreas is overactive in the metabolic syndrome. However, a simple blockade of the system is problematic because endogenous cannabinoids are also active in the brain, and blocking them in the brain can lead to depression. The LCI is now working with the NIAAA to develop cannabinoid blockers that do not reach the brain.
Dr. Egan concluded by highlighting other work in the LCI:
The Bioanalytical and Drug Discovery Section is developing a compound that activates the beta-adrenergic receptor. The Section is looking at the use of this compound and its derivatives as treatments for cardiac failure.
The Molecular and Clinical Pharmacology Section is studying calcium channels and the changes that occur with atherosclerosis. The Section has extracted smooth muscle cells from areas both close to and far away from atherosclerotic plaques and found calcium-channel splice variants that stimulate migration of these cells, which worsens atherosclerosis. The Section is now exploring interventions to block those splice variants.
The Magnetic Resonance Imaging and Spectroscopy Section has studied several models for OA and developed and tested a treatment in animal models. The Section is now involved in a collaboration to study this intervention in patients with OA and also is developing several analytical techniques.
X. ADJOURNMENT
The open session of the 106th meeting of the National Advisory Council on Aging was adjourned at 1:46 p.m. on January 28, 2009. The next meeting is scheduled for May 19 and 20, 2009.
XI. REVIEW OF INTRAMURAL RESEARCH PROGRAM
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).
XII. 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 May 19-20, 2009, 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)
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
Kenneth V. Brummel-Smith, M.D. (2009)
Professor and Chair
Department of Geriatrics
Florida State University College of Medicine
Tallahassee, FL
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
Carl Eisdorfer, Ph.D., M.D. (2009)
Knight Professor and Director
Center on Aging
University of Miami
Miami, FL
Lawrence M. Friedman, M.D. (2009)
Independent Consultant
Rockville, MD
*Mary Ganguli, M.D., M.P.H. (2009)
Professor of Psychiatry, Neurology, and Epidemiology
Department of Psychiatry
University of Pittsburgh
Pittsburgh, PA
*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
*John C. Morris, M.D. (2009)
Professor
Washington University School of Medicine
St. Louis, MO
Lennart Mucke, M.D. (2012)
Director and Professor of Neuroscience
Gladstone Institute of Neurological Disease
University of California, San Francisco
San Francisco, CA
Orien Reid (2010)
Chairman, Alzheimer's Disease International
President, Consumer Connection
Laverock, PA
*Gerald P. Schatten, Ph.D. (2009)
Professor, Pittsburgh Development Center
Magee-Womens Research Institute
University of Pittsburgh
Pittsburgh, PA
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)
President and Director
Trudeau Institute
Saranac Lake, NY
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
Lori Gerhard
Director, Office of Planning & Policy Development
U.S. Administration on Aging, DHHS
Washington, DC
Kenneth G. Pugh, M.D.
Commander, MC, U.S. Navy
Department of Medicine
National Naval Medical Center
Bethesda, MD
