Council Minutes - May 2008

The 104th Meeting
May 20–21, 2008

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: Neuroscience and Neuropsychology of Aging Program Review
6. PRESENTATION: Clinical and Translational Science Awards—Clinical Research in a Cost-Effective Environment
7. DIVISION HIGHLIGHTS
8. ADJOURNMENT
9. CERTIFICATION

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

The 104th meeting of the National Advisory Council on Aging was convened on Tuesday, May 20, 2008, at 3 p.m. in Building 31, Conference Room 6, National Institutes of Health (NIH), Bethesda, Maryland. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA), presided.

Council Participants:
Dr. Dale E. Bredesen
Dr. Peggye Dilworth-Anderson
Dr. Lawrence M. Friedman
Dr. Mary Ganguli
Dr. Paul Greengard
Dr. S. Michal Jazwinski
Dr. Sundeep Khosla
Dr. Terry L. Mills
Dr. John C. Morris
Ms. Orien Reid
Dr. Gerald P.Schatten
Dr. Burton H. Singer
Dr. Albert L. Siu
Dr. Susan L. Swain
Dr. Mary E. Tinetti

Absent:
Dr. Kenneth V. Brummel-Smith
Dr. Carl Eisdorfer

Ex-officio Participants:
Dr. James Burris, Department of Veterans Affairs

Absent Ex-officio Participants:
Dr. Kenneth Pugh, National Naval Medical Center
Mr. John Wren, Administration on Aging, U.S. Department of Health and Human Services (HHS)

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. Anthony Hayward, National Center for Research Resources (NCRR), NIH
Ms. Devon Drew, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Ms. Denise Manouelian, NIDDK

Members of the Public Present:
Dr. J. Lee Dockery, Evelyn F. McKnight Brain Research Foundation
Dr. Gina L. Evans, Kellogg Health Scholar, Baylor College of Medicine
Ms. Christy Gilmour, American Academy of Orthopaedic Surgeons
Ms. Linda Harootyan, Gerontological Society of America
Dr. Shevon Harvey, University of Illinois at Urbana-Champaign
Dr. Angelica P. Herrera, Kellogg Health Scholar, University of Texas
Dr. Bradley T. Hyman, Massachusetts General Hospital and Harvard Medical School
Dr. Perry Kirkham, Purdue University
Ms. Pat Kobor, American Psychological Association
Dr. Alan B. Krueger, Princeton University
Dr. Rose Maria Li, Rose Li and Associates, Inc.
Ms. Michelle Rodrigues, SRI
Ms. Besangie Sellars, Kellogg Health Scholar, University of Pittsburgh
Dr. J. Graham Sharp, University of Nebraska Medical Center
Dr. Mindi Spencer, Kellogg Health Scholar, University of Pittsburgh
Dr. Angela Thrasher, Kellogg Health Scholar, University of California, San Francisco and Berkeley
Ms. Julie Wolf-Rodda, Foundation for the National Institutes of Health (FNIH)

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

II. CALL TO ORDER

Dr. Hodes welcomed members to the open session of the 104th National Advisory Council on Aging meeting and called the meeting to order at 8:03 a.m. on Wednesday, May 21, 2008.

A. Announcements

Dr. Hodes announced the renaming of the principal components of the Institute from “programs” to “divisions,” effective April 2008. This change does not reflect any real or substantive reorganization but simply aligns the NIA naming conventions to be consistent with other NIH Institutes. The former and new names are as follows:

• The Biology of Aging Program is now the Division of Aging Biology.
• The Behavioral and Social Research Program is now the Division of Behavioral and Social Research (DBSR).
• The Neuroscience and Neuropsychology of Aging Program is now the Division of Neuroscience (DN).
• The Geriatrics and Clinical Gerontology Program is now the Division of Geriatrics and Clinical Gerontology (DGCG).

Dr. Hodes also announced the appointment of Dr. Marie A. Bernard as the new Deputy Director, beginning October 2008. Dr. Bernard, a former NIA Council member, is Professor and Chair of the Department of Geriatrics at the University of Oklahoma College of Medicine. Prior to this, she had a long, distinguished career at Bryn Mawr College, the University of Pennsylvania, and Temple University. Dr. Hodes acknowledged the able service provided by Dr. Taylor Harden as Acting Deputy Director and prior Deputy Directors Dr. Judy Salerno and Dr. Terrie (Fox) Wetle.

B. Director’s Status Report

Dr. Hodes did not provide an update on the NIA budget situation as there has been no change since the January Council meeting. He reviewed developments related to the NIH Roadmap initiatives and the NIH Research Condition and Disease Categorization (RCDC) effort.

A third cohort of Roadmap initiatives has now been approved publicly and is moving forward. Dr. Hodes focused his remarks on three initiatives being cosponsored by the NIA: (1) The science of behavior change, (2) protein capture technologies, and (3) the connectivity map.
 
The Science of Behavior Change Initiative proposes a pilot study to establish the groundwork for a unified science of behavior change that capitalizes on both the emerging basic science and the progress already made in the design of behavioral interventions in specific disease areas. The relevant science in multiple disciplines is rapidly emerging but is not optimally focused on behavior change. The initiative is potentially transformative because it capitalizes on the coalescence of new disciplines into a new transdisciplinary area and could provide a better understanding of the science behind behavioral decisions (including initiation and maintenance of behavior change) which would have profound implications for a range of science and ultimately for critical public health interventions. The first stages of this initiative involve a series of workshops which may lead to Roadmap requests for applications (RFAs) and an assessment of whether a larger scale Roadmap initiative is warranted 2 or 3 years hence. This initiative was formulated with leadership from Dr. Richard Suzman and Dr. Jonathan King of NIA. When presented in February before the Institutes and Centers (IC) Directors, the topic was met with interest from many ICs and received the most votes among all of the new initiatives proposed. As an example of what already can be accomplished through interventions on behavior and lifestyle and the convergence of behavioral science, neuroscience, and genetics to bring about more informed approaches to behavior change, Dr. Hodes described results from a study showing the effect of lifestyle interventions (weight loss, diet, exercise) by age group (25–44, 45–49, and 60 plus), compared to treatment with metformin (an oral hypoglycemic) and placebo, on diabetes incidence among individuals at high risk of diabetes. With placebo, about 12 percent of individuals in all age groups developed diabetes. The drug metformin had about the same effect as lifestyle interventions for the youngest age group and the least effect for those in the oldest age group. Lifestyle interventions were highly and increasingly effective by age group, with 71 percent less diabetes incidence compared to placebo among those aged 60 and above.

The goal of the Protein Capture Technologies Initiative is to promote the development of new high-throughput technologies for the generation of libraries of diverse small molecules that specifically or selectively recognize, bind, and “capture” human proteins or that distinguish among the natural variants of a single protein. Dr. Hodes explained that this effort will ultimately be capable of providing probes for essentially all of the protein and protein variants in human or other libraries, allowing much more comprehensive analysis, ideally in real time and with fine, spatial discrimination of molecules.

Following the May Council meeting, the format for these Roadmap initiatives was modified:
With the third cohort of Roadmap Initiatives, NIH is transforming the method of soliciting ideas and developing proposals. In addition to input from the scientific community and NIH staff, a committee of senior program staff will work actively to develop and screen proposals.

Two initiatives, the Science of Behavior Change (formulated with leadership from Dr. Richard Suzman and Dr. Jonathan King of NIA) and the Protein Capture Technologies initiative have been given permission to move forward in 2009 as Roadmap Development projects. The Connectivity Map is an initiative that will begin as a pilot project to determine the value of funding a full-scale Roadmap program dedicated to using gene expression profiles to identify disease pathways and discover chemical compounds that perturb the pathways allowing relationships between the pathways to be discerned. Thus, one can deduce some of the connectivity at a molecular level from patterns of change in multiple genes when looking at whole-genome gene expression and studies that respond to various perturbations of those expression patterns.

In reporting on the NIH RCDC, Dr. Hodes noted that fiscal year 2008 data includes approximately 360 categories of research, conditions, and diseases. Applications, grants, intramural projects, and contracts can be coded to one or more of these RCDC categories. The RCDC is to replace what is a very careful but less transparent and less uniform system of coding used currently by NIH ICs. The tentative rollout for public access of the RCDC data is spring 2009. Dr. Hodes reminded Council that the RCDC is the outcome of many imperatives, including a strong request by the Congressional Appropriations Committee and outside advocacy groups for greater transparency to help monitor the research being supported by the NIH. Data based on the old coding system will continue to be presented alongside the new RCDC numbers to permit comparisons during the next year or two of transition. Public communication will be important during the transition period. There will be a Webinar on June 11 to introduce the RCDC to the public. More information is available at rcdcpublicinfo@mail.nih.gov.

Dr. Siu asked how projects map to aging and whether specific text triggers a match. Dr. Hodes elaborated that for a number of conditions (e.g., Alzheimer’s disease [AD]) there are going to be pilot studies to see what happens if one tries to code direct and related topics. He is not certain how interpretable or public the coding algorithms will be and does not expect perfect concordance between the RCDC codings and expert assignments, but the aim will be to provide as much transparency in the process as possible.

Dr. Hodes invited individuals around the table to briefly introduce themselves and invited introductions by NIA staff and other guests in attendance. Dr. Stephen Snyder introduced Dr. Bradley Hyman from Massachusetts General Hospital and Harvard University. Six researchers associated with the Kellogg Health Scholars Program (some of whom also attended the 2007 NIA Summer Institute on Aging Research) introduced themselves from the floor: Dr. Gina Evans, Dr. Shevon Harvey, Dr. Angelica Herrera, Ms. Besangie Sellars, Dr. Mindi Spencer, and Dr. Angela Thrasher. Dr. Sidney Stahl introduced Dr. Rosie Sood, a new research program analyst in the Individual Processes Branch of the DBSR. Ms. Vicky Cahan introduced Ms. Barbara Cire as a new press officer who will lead media activities and serve as editor of the Institute’s new online newsletter.

Dr. Robin Barr shared news about the recent death of Dr. Louise Hsu. Dr. Hsu served for 10 years as Scientific Review Officer for the NIA-Neuroscience study section and was working until almost the day before she died. She was born, raised, and educated in Taiwan and was a friend, mentor, and inspiration to many in her local community, at NIA, and to the broader community in neuroscience and aging.

Dr. Hodes circulated for Council information a compendium of last quarter’s public outreach activities prepared by the Office of Communications and Public Liaison.

C. Future Meeting Dates

September 24–25, 2008 (Wednesday and Thursday)
January 27–28, 2009 (Tuesday and Wednesday)
May 19–20, 2009 (Tuesday and Wednesday)
September 22–23, 2009 (Tuesday and Wednesday)

D. Consideration of the Minutes of the Last Meeting

III. REPORT: Task Force on Minority Aging Research

Dr. Terry Mills began his report by acknowledging the Kellogg Foundation Health Scholars in attendance and encouraging them to consider applying for supplemental awards and dissertation fellowships.

Dr. Mills then reported on a presentation by Dr. Jennifer J. Manly on the genetic epidemiology of AD in African Americans that examined whether African Americans are at higher risk for AD and, if so, whether there are underlying causes that are amenable to alteration or treatment. In investigating these questions, her research team first considered the accuracy of neuropsychological detection of mild cognitive impairment and AD among African Americans and looked for measures that can be used across groups with high sensitivity and specificity. Collection of separate group norms is the most popular approach in the literature, especially among geriatric neuropsychologists, but is not without disadvantages. Separate norms leave ethnic differences unexplained and open for misinterpretation, with the norm for a particular group used as a proxy for assumed educational, socioeconomic, or behavioral differences.

During the prior day’s discussion, Dr. Manly dispelled the notion of culturally neutral tests, pointing to the Wechsler Adult Intelligence Scale visual test and other nonverbal tests as examples of how context or culture can influence interpretation and cognitive test performance. She also demonstrated how certain key variables are not comparable across race/ethnic groups. For example, in deconstructing years of schooling, a typical measure of education, the number of days that constituted a school year was less for the African-American population compared to their White counterparts. Dr. Manly also looked more closely at reading proficiency and student-teacher ratios. When she looked at the effect of race on risk for AD, race by itself was significant; but when she included years of education and also reading proficiency, race became only marginally significant. Instead, reading proficiency, which is known to be based upon the quality of education and might also be related to the context of one’s family experience, was the most significant factor in explaining the risk of AD. Student-teacher ratios are often considered an indicator of education quality, but this ratio is affected by race and geographic region. After controlling for race and sex, Dr. Manly reported that the student-teacher ratio was significant as a predictor of performance on measures of memory, executive function, and language skills. The focus of Dr. Manly’s team is a sample of non-Hispanic Blacks born in the United States who started the study having no or mild cognitive illnesses and who each had at least three of four grandparents born in the United States who self-identified as non-Hispanic Black. In the absence of the APOE-E4 allele, African Americans have a two- to three-fold increase in the risk of both the prevalence and incidence of AD compared to Caucasians. This difference in risk is not explained by differences in years of education but is explained when reading level also is included.

Dr. Mills then turned to a report by Dr. M-D. Kerns on the NIH diversity supplements program (PA 015-05, extended through September 30, 2008) and highlighted the need for more applications particularly at the high school and college levels. Investigators who have R01s and P01s as well as R03s, R15s, and R21s can apply for research supplements to promote diversity in health research. The program offers supplements to participants at a range of education levels, from high school to junior faculty. For this program, diversity is not limited to traditional racial ethnic categories but also includes persons with disabilities or individuals from a low socioeconomic status family background.

IV. REPORT: Working Group on Program

Dr. John Morris reported on several issues discussed during the previous day’s closed session.

A. Advisory Meetings

The September 2007 meeting on Animal Models of Comorbidities in Aging was originally discussed at the January meeting, where it was determined that more time was needed to review its many recommendations. A task force comprising Drs. Jazwinski, Swain, and Siu looked more carefully at the full set of recommendations and concluded that there is consensus only on a subset of them. The Working Group on Program therefore proposed a more focused statement for the full Council’s approval and further proposed that these efforts be supported without set-aside funding:

“We find that there is insufficient consensus on the merits of pursuing further development of the concept at the present time except for selected narrow areas. We move to approve further concept development to support only longitudinal studies on the pathobiology of aging in mice and in some existing disease models; however, we do not support creating new models or combining comorbidities.”

The motion was seconded and passed unanimously.

Dr. Molly Wagster provided an overview of the recommendations from the Cognitive Aging Summit, which was held in October 2007. The summit, made possible in part by the McKnight Brain Research Foundation through a grant to the FNIH, featured two days of scientific presentations followed by a half-day executive session where the recommendations were generated. Dr. Wagster summarized these recommendations into four broad categories: (1) To develop and/or expand methodologies for data analytic approaches for cognitive aging studies, including newer approaches of dynamic modeling; (2) to encourage multidisciplinary programs and multidisciplinary research teams; (3) to characterize behavioral and neural aging in order to create a taxonomy for neural and behavioral profiles of healthy aging; and (4) to accelerate intervention studies for cognitive aging. Dr. Schatten urged that, in the context of a specific recommendation with regard to the use of nonhuman primates for cognitive aging studies, the NIA coordinate with the NCRR, which runs national primate research centers, to make sure that both academic primate facilities that are being used for cognitive aging as well as the NIH-supported national primate centers (NPCs) are leveraged in the most effective way. A motion to approve the recommendations from the Cognitive Aging Summit was made, seconded, and passed unanimously.

A third advisory meeting, the Biology of Aging Summit, is being planned for September 2008 with the purpose of generating a discussion of the current state of the science in aging biology and to make informed predictions about future trends in biogerontology. This will help staff formulate a cohesive and comprehensive development plan for the future and provide direction for their next review, due in May 2009. A motion was made, seconded, and passed unanimously to approve the planned meeting.

B. RFA Concept Clearances

Dr. Morris reported on three proposed RFAs that were presented to the Working Group on Program, all of which were subsequently approved unanimously by the Council.

Since the Cognitive Aging Summit in October 2007, the NIA issued a request for information in late March 2008 seeking comments through April 2008 on the development of two concepts for funding opportunity announcements (FOAs) that stem from the Summit (see above) and are jointly supported by the DBSR and the DN, in collaboration with the McKnight Brain Research Foundation and the FNIH: (1) Neural and behavioral profiles of cognitive aging and (2) interventions to remediate age-related cognitive decline not due to dementia. Dr. Wagster presented on the first proposed FOA, observing that it will help address some practical and pressing issues in the field, such as better differentiation of those individuals who may be developing age-related dementia but are presymptomatic, and rational development of therapeutics. An FOA in this area would help move the field beyond description to probe more deeply into the plasticity of the aging brain and adaptive behaviors and provide a necessary basis against which to design and track therapeutics.

Dr. Jonathan King presented on the second FOA, which seeks to identify new interventions that generate sufficiently large and sustained effect sizes to improve people’s activities of daily living. Possible interventions discussed during the Cognitive Aging Summit included cognitive training, stress management, social engagement, exercise, diet and nutraceuticals, and potential synergistic effects from combinations of interventions (e.g., cognitive training and exercise or diet in an enriched environment). Commercially marketed interventions are not regulated by the Food and Drug Administration (FDA), and their efficacy is not known. Some level of broad comparability of outcomes from pilot studies is needed to provide preliminary data required to assess the merits of full program implementation. An annual investigators’ meeting is envisioned to help develop a cohort of investigators in this field. Dr. Schatten encouraged NIA staff to invite FDA to participate. Dr. King agreed but recognized that the FDA does not necessarily have regulatory capability in this area. Dr. Hodes added that NIA will be meeting shortly with the FDA to explore a more systematic approach for identifying conditions that can, if appropriately defined, become targets for interventions, even in areas where the FDA might have domain through devices and drugs.

Dr. Anna McCormick presented for concept clearance an initiative on trans-Atlantic collaboration on the biology of aging. The initiative is the result of a partnership begun in 2006 with the United Kingdom’s (UK’s) Biotechnology and Biological Sciences Research Council (BBSRC). In meetings with the BBSRC, five areas of high-priority research were identified both as research strengths of the two countries and as areas where collaborative pilot projects would be beneficial to both countries and institutes and address the following high research priorities: Regenerative medicine; epigenetics and epigenomics (which is now one of the NIH Roadmap initiatives); the genetic and molecular basis of aging and longevity; immunobiology and immunosenescence; and cell senescence, particularly its consequences in vivo on the pathology or pathophysiology of aging or age-related diseases. General principles of agreement include joint and comparable support of grants by both the NIA and the UK, and the funding level and period of support would be for pilot-level projects focused on the biology of aging to support collaborative teams. Additional funds are to be budgeted to support travel for collaboration and annual networking grantee workshops to further develop these pilot collaborative teams. The BBSRC has agreed to adhere to the NIH’s review process. This partnership illustrates effective leveraging of research funds and obviates the need for foreign clearance since foreign components will not be paid by the NIH.

C. Other Issues

The January 2008 Council meeting minutes reported a substantial decline in applications received in 2007 (compared to 2006). Dr. Robin Barr explained that two RFAs had 200 applications that suppressed the success rate in 2006, but there were no RFAs for R01s in 2007. As a result, the success rate surged in 2007, and the number of applications dropped. However, NIA has continued to receive large numbers of applications.

V. INITIAL REPORT: Neuroscience and Neuropsychology of Aging Program Review

Dr. Morris reported that the Neuroscience and Neuropsychology of Aging Program (now called Division of Neuroscience [DN]) review has been meeting by teleconference since the January 2008 Council meeting and convened on May 18 with Dr. Hodes and again with other NIA staff on May 19. The review committee comprises five Council members (Drs. Friedman, Ganguli, Greengard, Bredesen, Morris, and Ms. Reid) and other outside experts (Drs. Marilyn Albert, Mony de Leon, Virginia Lee, Denise Park, Carl Cottman, Eli Michaelis, Don Gash, and Ron Peterson). The review is organized around different research topics represented by the DN portfolio: AD Centers (ADC) Program; diagnosis, primarily of AD; clinical trials; normal aging; mechanisms of neurodegeneration; sensory processes and motor function; stress and sleep; population studies and epidemiology; training; translational research; and interactions and collaborations. All of the working groups are expected to submit drafts of their sections of the report to Dr. Morris by June 15, and Dr. Morris will combine them into a full report by July 1, with the goal of completing the report by August and presenting it at the September Council meeting.

VI. PRESENTATION: Clinical and Translational Science Awards—Clinical Research in a Cost-Effective Environment

Dr. Anthony Hayward, Director of the Division for Clinical Research Resources, NCRR, NIH, discussed the Clinical and Translational Science Awards (CTSA) program and how the NIA can benefit by increasing interactions with this program. He stressed that the awards are part of a trans-NIH Roadmap activity developed in response to changing needs of the NIH and the investigators at grantee institutions.

The program’s new approach, proposed by Dr. Zerhouni, combines the program managed by the NCRR with other training programs to create an “academic home” for researchers at awardee sites. The “academic home” will provide for such researchers’ needs. It includes access to advanced informatics; clinical services such as clinic space and nurses; regulatory support; statistical and research design advice; and training. The program also provides for community outreach beyond academic health centers; and interfaces with healthcare providers, industry, and other HHS agencies.

An important component of the CTSA program involves training of individuals to be a part of research teams that cross institutional boundaries in order to implement clinical trials at multiple sites in an efficient and effective way. Attention has focused on improving overall clinical research management by identifying metrics and barriers to implementation and maximizing efficiency of funding from multiple agencies to support similar research activities (such as genotyping or cytofluorometry).

The CTSA program is now more than 2 years old. Twenty-four grantee sites were awarded in 2006 and 2007, and the grantees for 2008 have been notified. Early impact of the program can be measured by the appointment of 18 new KL2 (equivalent to K12) scholars in the Mentored Career Development Program, who are usually physicians postfellowship moving toward assistant professor positions. The CTSA program has created new predoctoral positions designed to encourage entry into clinical research. These programs are starting to include professionals other than physicians, such as nurses, pharmacists, and health services researchers, and with a need for more nurses, dentists, statisticians, and all other types of professions in clinical research.

By the year 2012, Dr. Hayward expects that funding for CTSA will support 60 grantee sites at a cost of about $500 million per year. Funds will come largely from NCRR but will not take money from regular research grants (R01), small research grants (R03), or other basic research awards issued by the many NIH ICs. The NIA is fifth in the list of top ICs in terms of grantees supported by CTSA, preceded by the NIDDK; the National Heart, Lung, and Blood Institute; the NCI, and the National Institute of Allergy and Infectious Diseases. Data from 2007 include 24 NIA awardees with CTSA support ranging from $1 million to a few thousand dollars and the provision of resources from deep freezer space to nurses.

In addition to increasing grantee sites to 60 by 2012, the NIH will seek to improve geographic distribution of CTSA support by targeting the middle of the country with lower population densities (e.g., North Dakota, Nebraska, Kansas), working in concert with NCRR’s Institutional Development Award program to enhance infrastructure in States that currently receive less than 10–15 percent of NIH funding. He added that the CTSA program seeks to support a wide range of research including translational research and links with other disciplines such as primate center research. Many primate centers are supported by NCRR, and where that is the case, the Division of Comparative Medicine has made supplementary awards available to promote collaboration with CTSAs.

To illustrate the structure of a typical CTSA grantee, Dr. Hayward showed how the CTSA award at Emory University in Atlanta, Georgia, is organized with links to healthcare organizations including hospitals, Government agencies (e.g., the Centers for Disease Control and Prevention [CDC]), other collaborative institutions, and health maintenance organizations. He highlighted overlaps with Morehouse School of Medicine, a traditionally minority institution with important outreach capacity to populations experiencing healthcare disparities. These types of linkages assure that CTSA resources are not restricted to the best-endowed centers for research.

Individual grantee sites have created consortia to exchange ideas and resources. Dr. Hayward noted that a number of CTSA grantees on the West Coast and in the Upper Midwest have already organized themselves into alliances that include participation by nonawardee sites. Information about consortium governance and organization is available at http://www.ctsaweb.org/docs/ctsa_governance_manual.pdf.

The CTSA program has adopted an open and flexible form of governance. The Consortium Oversight Committee (COC) comprises one voting principal investigator from each grantee site and half that number of NIH representatives. The committee reports to Dr. Barbara Alving, Director of the NCRR. Dr. Hodes is a member of the NCRR Advisory Board of Directors. In addition, subgroups focus on cross-cutting issues such as clinical research management, ethics, biostatistics, and informatics. At present, 82 individuals serve on steering committees and working groups on topics such as dissemination and translation of clinical research into practice and community engagement. The COC meets in person every 6 months and holds monthly Web meetings with upwards of 1,000 participants, including representatives from the Association of American Medical Colleges, CDC, and the Agency for Healthcare Research and Quality.

Dr. Khosla observed that the CTSAs have essentially absorbed the traditional General Clinical Research Center (GCRC) grants, which were at the heart of translational research in terms of looking at disease mechanisms and physiology and translating findings from animal models into human studies, and asked how the CTSA program can preserve this aspect of human studies. Dr. Hayward replied that he is not aware of any GCRC grant that was cancelled as a result of the creation of the CTSA program. However, in the future, clinical studies may be asked to participate on a cost-sharing basis. CTSAs can provide up to 45 percent additional funding over the GCRC grants to support the additional workload. It also was noted that there is no formal mechanism for NPCs to be integrated into CTSAs. An effort can be made to include NPC directors in CTSA meetings. The NCRR has supplements for animal models for CTSAs.

Dr. Hodes added that the CTSA program is currently addressing the need to establish an index of investigators supported by this program who work in related areas of research. Also, at the September Council meeting one of the CTSA directors is expected to speak about liaisons between the CTSA institutions and various areas.

Dr. Barr asked about investigators who are not at CTSA institutions but could benefit from access to CTSA-supported resources. Dr. Hayward answered that some of this need can be addressed by consortium activities and some through local activities. More outreach is needed to publicize the availability of the CTSA resource.

In response to a question about the training aspect of the CTSA program, Dr. Hayward explained that the awards are institutional career development awards where the grants are made to institutions, not individuals. The institution would select the individual awardees.

Dr. Hayward responded to Dr. Hodes’ request for elaboration on efforts to improve efficiency by giving an example of a request made by Dr. Linda Weiss, Chief of the NCI Cancer Centers Branch, to cancer center directors. She requested that the individual institutions identify and eliminate duplication between CTSA and NCI support. Funds identified need not be returned to the NCI but may be applied to other activities. Dr. Hayward said this would require imaginative thinking, but there is a lot of institutional flexibility to overcome duplication.

VII. DIVISION HIGHLIGHTS

A. Behavioral and Social Research: Well-Being and Aging

Measures of well-being are increasingly viewed in terms of national output with very interesting policy implications and measurement issues. Dr. Alan Krueger, Professor of Economics and Public Affairs at Princeton University, has published widely on well-being, education, terrorism, inequality, social issues, health economics, and the environment. In this presentation, Dr. Krueger described his research linking individuals’ sense of well-being with how they spend their time, which could aid in developing interventions that influence well-being. Experienced well-being, a component of how individuals spend their lives moment to moment, is distinct from more global measures of well-being, such as overall life satisfaction. Measuring experienced well-being is advantageous because it is less prone to the heuristics, social expectations, and selective recall seen with conventional measures of life satisfaction. Measuring experienced well-being also allows one to follow an individual as he or she conducts different activities throughout the day, thus controlling for individual personality differences.

The gold standard for measuring experienced well-being is experience sampling, where study participants receive personal digital assistants and report their feelings and activities at particular points in real time. However, experience sampling is difficult to do and has not been done in a large nationally representative sample. Dr. Krueger and his colleagues have developed an alternate method based on day reconstruction where study participants keep a diary and report on all their activities and feelings associated with those activities for the previous day. Early studies based on samples of women in Texas, Ohio, and France showed these methods almost replicated experience sampling. One of these studies (Kahneman, Science 2004), which focused on tiredness over a 24-hour day, showed a V-shaped pattern in which tiredness declines from the moment of awakening and then increases sharply after a certain point in time. The study also showed an interaction with age. Younger people are more tired when they wake, and the decreasing segment of the V-shaped pattern is steeper than it is for older people.

Dr. Krueger also has examined the correlation between well-being reported on two occasions two weeks apart based on net affect (defined as average positive emotions less average negative emotions). The reported net affect two weeks apart was similar to overall life satisfaction reported two weeks apart. This similarity resulted primarily from personal effects, which might arise from participants’ interpretation of the scale. Dr. Krueger and colleagues thus developed the U-index, which is less dependent on participants’ interpretation. The U-index is the fraction of time someone spends in an unpleasant state, a time when an individuals’ most intense feeling is negative. The U-index is a more robust measure because it involves an ordinal measure of the level of feeling, which can overcome some cultural differences in reporting. The U-index also can provide some information about features in society’s well-being, which could have implications for policies aimed at reducing misery.

In samples of 800 women each in Columbus, Ohio, and Rennes, France, the proportion of women in Ohio reporting satisfaction with their lives is twice that in Rennes. The French appear more reluctant to use the positive or negative extremes of the scale. The U-index for the Columbus sample is 19 percent compared with 16 percent for the French sample. Dr. Krueger noted that this difference was half as large as that between the weekday and a weekend day. Activity rankings are similar between both groups, except for religion and child care. The U-index is high for work and commuting and low for social activity and eating.

Dr. Krueger and colleagues have developed a telephone survey, the Princeton Affect and Time Survey (PATS), to determine whether they can see similar results and to include men. PATS is based on the Bureau of Labor Statistics’ (BLS’s) American Time Use Survey (ATUS) and includes a module that randomly selects three time periods and asks participants about their feelings at those times. PATS results correlate well with those from the day reconstruction method, and some differences are apparent. The U-index is higher for women than men, for Blacks and Hispanics than for Whites, and for people at lower incomes than for those at higher incomes. Dr. Krueger and colleagues also observed a four-point difference between participants aged 25–64 and those aged 65 and older, consistent with other studies showing that negative emotions fade with age. Differences in activity patterns explained 58 percent of the differences in U-index and subjective well-being between older and younger groups. Activity rankings were similar to those seen in the Columbus and Rennes samples, except the U-index was also high for adult care. This result could be important as U.S. society ages.

Dr. Krueger also discussed a study (Krueger and Stone, Lancet 2008) in which he and his colleague found that pain increases with age until 45 years, then plateaus through 75 years. Similar results have been found in work Dr. Krueger has done with the Gallup World Poll, which also found a strong correlation between pain and per capita gross domestic product, particularly at older ages. Krueger and Stone also found that people with low incomes spend more time in pain and more severe pain, consistent with results from a CDC survey showing that individuals with low incomes recall having more pain during the previous month. Dr. Krueger noted that individuals in pain spend more time watching television and less time working, exercising, volunteering, traveling, or engaging in religion. Dr. Krueger closed by noting the potential for these methods. He is now working with the BLS and NIA to add modules to the ATUS based on what he has developed with PATS.

In response to questions from Dr. Jazwinski about the relationship between the U-index and age, Dr. Krueger speculated that with age Americans behave more as the French do—spending less time at work and caring for children, and more time eating. This might explain the lower U-index and higher sense of well-being at older ages. It would be worthwhile to follow the French participants as they age.

Dr. Susan Swain noted that Dr. Krueger’s results suggest that work is a minor activity, and she asked whether Dr. Krueger and his colleagues distinguished between working and retired persons. Dr. Krueger responded that the percentage of time working was similar between the French and American groups but that small differences in time allocation can make a large difference in the aggregate in terms of how cultures are perceived. Dr. Krueger acknowledged that the initial sample of retired persons included some who had said they were retired but in fact were still working. He conceded that it would have been helpful to have information about when individuals retired. Dr. Krueger also discussed other studies examining well-being around the time of retirement.

B. Neuroscience: The Kinetics of Alzheimer Pathology

Dr. Bradley Hyman, the John B. Penney Professor of Neurology at Harvard Medical School and Massachusetts General Hospital, is pursuing research that is yielding critical insights into the progression of AD. Dr. Hyman observed that from a clinical perspective AD can take a decade or longer to progress from its earliest symptoms to severe dementia. This progression suggests slow accretion of both toxic molecules and neurodegeneration. Under the microscope, individual senile plaques are large, about 10 mm in diameter. When the size of plaques is considered in the context of individual molecules, the long time it takes for enough Ab molecules to build a structure is not surprising. Thus, the tempo of Alzheimer pathology is slow and deliberate. On the other hand, in light of the kinetics of precipitation of crystals, state changes of oligomeric molecules, and biological processes of inflammation and glial responses, one might postulate that amyloid deposition could proceed more rapidly. To distinguish these possibilities, Dr. Hyman’s team used multiphoton microscopy and direct in vivo imaging of mice that overexpress amyloid precursor protein (APP) to better understand the kinetics of plaque deposition.

Dr. Hyman’s team also was motivated by a series of “chicken and egg” issues. It is unclear from the literature whether plaques form before inflammatory responses or whether inflammatory cells contribute to plaque formation. Similarly, some have suggested that neuritic dystrophies alter APP trafficking and contribute to the local generation of Ab and plaque formation, while others have suggested that plaques lead to neuritic dystrophies. Moreover, neuronal alterations, with changes in trajectories and spine loss, are observed cross-sectionally near plaques, but which one precedes the other is unknown. Dr. Hyman and colleagues reasoned that observing the formation of individual plaques would allow them to assign a “birth date” to plaques and then determine the tempo and order of these phenomena.

In a series of experiments using separate lines of mice that overexpress APP, secondary markers such as neurons that express yellow fluorescent protein (YFP) or green fluorescent protein (GFP) or microglial cells that express GFP or fluorescently labeled dextran, and fiduciary markers used in angiography, Dr. Hyman and colleagues simultaneously observed neurons, neuronal processes, blood vessels, and microglial cells (Meyer-Luehmann et al., Nature 2008;451:720–4). They observed 40 instances of new plaques being formed. New plaques were a rare event, but they had a dramatic impact on their local environment. Two to 5 days after plaque formation, neuronal trajectories were altered and neuritic dystrophies formed in the vicinity of the plaques, within about 50 microns of the surface. Microglia were recruited and activated and astrocytes were activated about 2 to 3 days after plaque formation. Thus, although plaques form rapidly, within 24 hours, a variety of biologic phenomena play out during the next several days. Interestingly, the plaque size remains stable after the first 24 hours, which suggests that microglial or astrocytes recruitment “walls off” the plaque.

Recent data suggest that oligomeric Ab is critically important for the toxicity of amyloid. Using an oligomeric, Ab-specific monoclonal antibody from Dr. Virginia Lee’s laboratory at the University of Pennsylvania, Dr. Hyman’s group identified a “halo” around amyloid cores. On the basis of these data Dr. Hyman and colleagues concluded that the local microenvironment around a plaque is a region high in oligomeric Ab, which may mediate the downstream effects they observed in the abovementioned studies in transgenic mice.

Dr. Morris appreciated the therapeutic potential of this work and asked about effects of such therapy on the vasculature. Dr. Hyman noted that amyloid also accumulates in the blood vessel walls and appears to be more resistant to clearance following traditional therapies. His laboratory has been able to replicate a side effect of therapy—the T-cell inflammation that can lead to hemorrhage of the blood vessels—and this effect is more a specific T-cell response than an effect of amyloid clearance.

In response to questions from Dr. Khosla regarding amyloid deposition in the eyelid in humans, Dr. Hyman noted that he would not be surprised if similar biology took place in his animal model. He indicated that the specificity of the transgenes spare peripheral tissues but that this question should be explored further.

In response to questions from Dr. Hodes, Dr. Hyman noted that neuronal loss is barely detectable in animals overexpressing APP, although there are some caveats to that. Because neuronal loss cannot be seen in this model, it is not known whether the loss can be prevented. Microtubular structure becomes disrupted in the dystrophic neuritis that is visible, but the structure goes on to form a straight tube, as detected by second harmonic generation. Thus, Dr. Hyman can observe potential morphologic antecedents to plaque formation.

C. Aging Biology: Taking Aging Personally—Individual Paths to Exceptional Longevity

Dr. Jazwinski, Professor of Biochemistry and Medicine and Director of the Tulane Aging Center, discussed a model in which the propensity to age is a function of change and the aging system can be stratified epigenetically at the population, individual, cellular, and molecular levels of aging. Dr. Jazwinski and colleagues have shown that mortality rate increases exponentially with age until the rate for the remaining 10 percent of a population plateaus, and this plateau represents the stratification between rapid and negligible aging. Similar results have been observed in medflies, fruit flies, and worms. Stratification also has been shown with mitochondrial content and gene expression, which also increase rapidly with age in some cells but not in others. Individual change plays a role in aging, and many trajectories of aging can be observed at different levels.

Using yeast as a model system, Dr. Jazwinski and colleagues identified two genes involved in lifespan. One such gene, RAS2, is a yeast homolog of human ras (h-ras), which is important in signal transduction and has been implicated in cancer. The other gene, Longevity Assurance Gene 1 (LAG1), is the yeast homologue of the human LASS1 gene, which is located on chromosome 19p12. LASS1 encodes ceramide synthase, which is involved in the sphingolipid biosynthetic pathway and has been implicated in head and neck squamous cell carcinoma. Disruption of LASS1 results in uncontrolled cell division and lack of apoptosis, and ceramide is a signaling molecule important for nervous system maintenance. Both genes are involved in elaborate signaling networks, including one that senses various stressors and is involved in survival and stress resistance. H-ras is also involved in inflammation and in repressing apoptosis. Circulating lipids increase with age, causing vascular damage, tissue infiltration, and lipotoxicity, which in turn leads to dysfunction and morbidity, creating “garbage” that must be eliminated through apoptosis. Deficiencies in apolipoprotein E (apoE), which clears circulating lipids, lead to a survival stress response involving h-ras, and LASS1 is involved in “garbage disposal.”

Using alu markers (short repeated nuclear sequences spread throughout the genome) to stratify individuals in a Georgia and Louisiana population by geographic region of origin, Dr. Jazwinski and colleagues set out to determine whether h-ras, LASS1, and apoE variants can distinguish population differences in aging. They found that certain haplotypes of the three genes were enriched in centenarians and less so in nonagenarians and that interactions among all three genes determine longevity. These gene-gene interactions displayed an additive effect on longevity through the age of 90, but at later ages the addition of LASS1 to the h-ras X apoE interaction confers an even greater effect. Although these variants of the individual genes appear frequently, the appearance of all three haplotypes together occurs rarely. Dr. Jazwinski and colleagues are learning more about the roles and functions of these genes. Dr. Jazwinski concluded his presentation by noting that this was one of many potential individual paths to longevity. He also noted the low likelihood of finding such interactions in genome-wide association studies and the importance of candidate gene approaches.

Dr. Khosla asked whether Dr. Jazwinski’s hypothesis regarding lipotoxicity could be extended, for example, to patients on statin therapy independent of cardiovascular effects. Specifically, he asked whether effects of biomarkers related to apoptosis or cellular senescence could be shown in surrogate tissues. Dr. Jazwinski responded that his group has studied only blood so far and that sampling some organs of interest is somewhat difficult. He and his colleagues are now validating noninvasive methods for assessing mitochondrial function in skeletal muscle tissue, and they hope to use that to answer some of Dr. Khosla’s questions. Dr. Jazwinski added that biosensors form an important research area, and he envisions the use of biosensors, in the form of a pill, to monitor what happens in a particular organ in real time. Medicine does not currently have the capacity for noninvasive, real-time measurements in multiple locations.

In response to questions about linking the apoE, h-ras, and LASS1 variants with potential function of these proteins, Dr. Jazwinski noted that most of the polymorphisms identified appear in the promoter regions of the genes and that the polymorphisms in apoE affect the level of expression of that gene. How the polymorphisms in the other genes affect expression or function is not known, and where these proteins appear in the relevant signaling pathway remains to be determined.

In response to questions from Dr. Hodes, Dr. Jazwinski noted that data were analyzed separately for the Georgia and Louisiana populations, then results were compared. In this sense, the interactions they identified in one population were replicated in a second.

D. Geriatrics and Clinical Gerontology: Stem Cell Quality Assays—Correlations with Aging/Health

Dr. J. Graham Sharp is Professor of Genetics, Cell Biology, and Anatomy at the University of Nebraska Medical Center. He and his colleagues have used flow cytometric, in vitro, and clonal assays of various stem and progenitor cell populations to test the hypothesis that aging-associated decreases in adult stem cell function compromise tissue repair and regeneration and are thus associated with declines in health and functional status. They have used these assays on bone marrow taken from patients who have undergone elective hip replacement. The primary assay involves side population (SP) cells, which are viable even though they appear to have less than the normal 2N DNA content. SP cells account for 0.01 percent of bone marrow cells and almost all stem cell activity in the bone marrow. Upper SP cells dominate repopulation when bone marrow is transplanted into irradiated mice.

In extracting these cells, Dr. Sharp and colleagues found more fat in the femoral head than red marrow. Further study in cadavers with no history of hip disease revealed primarily red marrow in femoral heads taken from younger patients but more yellow marrow in femoral heads taken from older patients. Dr. Sharp and colleagues also verified that interleukin 6 production increases with age. They further found that the number of SP stem cells declines with age but that the quality of stem cells increases with age. Similar results have been shown by another laboratory in C7B1 mice. Smoking and alcohol use also appear to significantly reduce the number of SP cells. Although this decline is more modest with alcohol use, it is much more significant in mesenchymal stem cells. Ethanol also appears to induce differentiation of mesenchymal cells into adipocytes, which might explain delayed fracture healing or increased osteoporosis in elderly patients who consume alcohol. Exercise intervention doubles the population of SP cells in the circulation in young subjects (aged 19-35 years), however, the amount of exercise needed for benefit in the elderly is not yet clear.

Studies of the maintenance and characteristics of high-quality stem cells in healthy individuals are under way. The status of stem cells in the frail elderly and the effects of exercise should be examined further. Dr. Sharp’s assays also appear to work in blood samples, which could allow the expansion of these studies from hip-replacement patients to the wider community. They intend to share deidentified data with other researchers to aid in analysis.

Ms. Reid noted the increase in the number of dead cells in former smokers and asked why that had occurred. Dr. Sharp responded that he and his colleagues did not know the mechanism and that they had been initially surprised at the result. However, they have seen similar results in animal models.

In response to questions from Dr. Hodes about correlations with hematopoietic competence, Dr. Sharp noted that previous studies have looked at stem cell numbers and found that a minimum of 2 million stem cells is necessary for consistent, long-term reconstitution. However, 10 million cells are necessary for complete immunological reconstitution. At a recent meeting, an investigator presented data showing that fewer stem cells are mobilized in response to cytokine in individuals aged older than 60 years compared with those in younger patients. These results suggest that obtaining a stem cell harvest adequate for transplant might take longer in older patients. Dr. Sharp also reported recent results that showed no significant differences in the quality of stem cells based on the age of the donor when the number of stem cells was kept consistent. However, he cautioned that the sample of donors older than 65 years might not have been large enough to detect a statistically significant effect.

Dr. Khosla mentioned other studies of small embryonic-like stem cells present with similar frequency in the marrow and in the blood, and he asked whether Dr. Sharp had examined the phenotypic characteristics of SP cells. Dr. Sharp responded that although his group knows that the cells are fairly small, they have not yet examined phenotypic markers. They do know that upper SP cells are positive for CD34 and CD133 and that cells closer to the origin, which are more primitive, do not express these proteins.

VIII. ADJOURNMENT

The 104th meeting of the National Advisory Council on Aging was adjourned at 1:20 p.m. on May 21, 2008. The next meeting is scheduled for September 24 and 25, 2008.

IX. 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 the Council at the next meeting on September 24–25, 2008, 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

Dale E. Bredesen, M.D. (2011)
Professor, Director & CEO
Buck Institute for Age Research
8001 Redwood Boulevard
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 & Administration
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

Paul Greengard, Ph.D. (2008)
Vincent Astor Professor
Laboratory of Molecular & Cellular Neuroscience
The Rockefeller University
New York, NY

*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

Mills, Terry L., Ph.D. (2008)
Dean, Division of Humanities & Social Sciences
Morehouse College
Atlanta, GA

*John C. Morris, M.D. (2009)
Professor
Washington University School of Medicine
St. Louis, MO

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

Burton H. Singer, Ph.D. (2011)
Charles and Marie Robertson Professor of Public and International Affairs
Office of Population Research
Princeton University
Princeton, NJ

Albert L. Siu, M.D., M.S.P.H. (2008)
Ellen and Howard C. Katz Professor
Chairman, Brookdale Department of Geriatrics and Adult Development
Mount Sinai School of Medicine
The Mount Sinai Medical Center
(and Director, Geriatric Research, Education, and Clinical Center, Bronx Veterans Administration)
New York, NY

Susan L. Swain, Ph.D. (2011)
President and Director
Trudeau Institute
Saranac Lake, NY

*Mary E. Tinetti, M.D. (2008)
Gladys Phillips Crofoot Professor
Department of Internal Medicine, Epidemiology, and Public Health
Director, Program on Aging
Yale University School of Medicine
New Haven, CT

EX OFFICIO MEMBERS

Michael O. Leavitt
Secretary
Department of Health and Human Services
Hubert H. Humphrey Building
Washington, DC

Elias Zerhouni, M.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 

Kenneth G. Pugh, M.D.
Commander, MC, U.S. Navy
Department of Medicine
National Naval Medical Center
Bethesda, MD

John Wren
Director, Center for Planning & Policy Development
U.S. Administration on Aging, DHHS
Washington, DC