Council Minutes - February 2008

The 103rd Meeting
January 29–30, 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. PROGRAM HIGHLIGHTS
6. PRESENTATION: NIH’s New Research, Condition, and Disease Categorization Process
7. PRESENTATION: NIH-RAID, an NIH Roadmap Program on Rapid Access to Interventional Development
8. INTRAMURAL RESEARCH PROGRAM REPORTS
9. REVIEW OF INTRAMURAL RESEARCH PROGRAM
10. ADJOURNMENT
11. CERTIFICATION

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

The 103rd meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, January 29, 2008, at 3 p.m. in Building 31, Conference Room 10, National Institutes of Health (NIH), Bethesda, MD. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA), presided.

Council Participants:
Dr. Dale E. Bredesen
Dr. Kenneth V. Brummel-Smith
Dr. Peggye Dilworth-Anderson
Dr. Lawrence M. Friedman
Dr. Mary Ganguli
Dr. Paul Greengard
Dr. S. Michal Jazwinski
Dr. Sundeep Khosla
Dr. John C. Morris
Ms. Orien Reid
Dr. Albert L. Siu
Dr. Susan L. Swain
Dr. Mary E. Tinetti

Absent Council Participants:
Dr. Carl Eisdorfer
Dr. Terry L. Mills
Dr. Gerald P.Schatten
Dr. Burton Singer

Ex Officio Participants:
Dr. Kenneth G. Pugh, National Naval Medical Center

Absent Ex Officio Participants:
Dr. James F. Burris, Department of Veterans Affairs
Mr. John Wren, Center for Planning and Policy Development, U.S. Administration on Aging, Department of Health and Human Services

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. David Badman, National Institute of Neurological Disorders and Stroke (NINDS)
Dr. Mary Custer, NIH/Center for Scientific Review (CSR)
Ms. Devon Drew, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Dr. Timothy Hays, NIH/Office of the Director (OD)
Dr. Marc Rigas, NIH/CSR
Dr. Janine Smith, National Eye Institute/Office of Research on Women’s Health
Dr. Pamela Starke-Reed, NIH/Division of Nutrition Research Coordination
Dr. Laura Wilson, National Institute of Allergies and Infectious Diseases (NIAID)

Members of the Public Present:
Dr. Steven N. Blair, University of South Carolina
Ms. Linda Harootyan, Gerontological Society of America
Ms. Amy Iadarola, Rose Li and Associates, Inc.
Dr. Debomoy K. Lahiri, Indiana University School of Medicine
Dr. Rose M. Li, Rose Li and Associates, Inc.
Dr. Stacy Lindau, University of Chicago
Dr. Janko Nikolich-Zugich, Oregon Health & Science University
Ms. Amy Pollick, Association for Psychological Science
Ms. Tina Powell, Social & Scientific Systems, Inc.
Mr. Jim Termaat, Social & Scientific Systems, Inc.
Ms. Alicia Thomas, The Lewin Group

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 103rd NACA meeting and called the meeting to order at 8 a.m. on Wednesday, January 30, 2008.

A. Director’s Status Report

Dr. Hodes opened his presentation by discussing the implications of the Food and Drug Administration (FDA) Amendments Act (P.L. 110-85) in terms of registering NIH-funded clinical trials at ClinicalTrials.gov. The act requires registration of all phase II through IV clinical trials involving FDA-regulated products (drugs and devices). It requires that basic results of these clinical trials be posted within 12 months of trial completion or within 30 days of FDA approval of a new drug or device. It also requires grantees to post updates by completing 12 mandatory data elements. For ongoing trials that involve a serious or life-threatening disease or condition, the deadline for implementing these requirements was December 26, 2007. For ongoing trials that do not involve a serious or life-threatening disease or condition, the deadline is September 27, 2008. Adverse events reporting will not start until March 2009, and expanded registry and results reporting will not be required until September 27, 2010.

Dr. Hodes next reported on the fiscal year (FY) 2008 NIH/NIA appropriations budget. After four Continuing Resolutions, Congress passed an Omnibus Appropriations measure (H.R. 2764), signed into law (P.L. 110-161) on December 26, 2007. The measure designates $29.3 billion for the NIH. This is 1.1 percent above FY 2007 funding and 2.1 percent above the President’s budget request. The measure includes $295 million for the NIH Global AIDS Fund and $111 million for the National Children’s Study. For the NIA, the House provided $1,047.3 million, approximately the same level as provided in FY 2007 after comparable adjustments.

Also included in the 2008 appropriations bill is a provision that requires the NIH to make the results of all studies funded by the NIH available to the public at no cost. Accordingly, the NIH Public Access Policy, which has been voluntary since May 2005, will be implemented as a mandatory policy in 2008. Researchers who receive grants from the NIH will be required to submit a final copy of studies accepted for publication in a scientific journal. The NIH will post the results of the studies in a database available to the public at no cost within 12 months after publication. Council members were provided a two-page fact sheet with more detail on the NIH Public Access policy and were referred to the NIH Public Access Web site (http://publicaccess.nih.gov/), which further explains the policy and describes how to submit journal articles.

Dr. Hodes shared with Council trends in NIA appropriations over the past 5 years, details on FY 2007 spending, and data on research project grant (RPG) success rates. He reported that, in current dollars, the NIA budget has been relatively flat for the past 3 years. However, when adjusted for inflation, constant dollars have actually decreased by 13 percent over the past 5 years. This is a substantial decrease at a time when scientific opportunities and applications for research support have been increasing. Thus, the impact of the era of NIH doubling is eroding.

Research project grants (RPGs) were the mainstay of NIA research support in FY 2007, accounting for 64 percent of the budget. Of NIA-supported RPGs in FY 2007, most (77 percent) were noncompeting or continuation grants, and about one-quarter (23 percent) were competing. Eighty-three (83) percent of support for competing RPGs in FY 2007 came from payline funds; the remaining support came from initiative funds and discretionary funds.

The RPG success rate—i.e., the proportion of applications reviewed that is actually awarded—decreased from FY 2003 through FY 2006 but then increased between FY 2006 and FY 2007. However, this apparent recovery mostly reflects a decrease in the number of applications received rather than an increase in the number of awards or an increase in funding. Investigators most vulnerable during this time include new investigators and investigators who have limited support in their laboratories. To protect the former, the NIA is assuring that the number of new investigators funded will be equal to the average of the previous 5 years. To protect the latter, the NIA is providing bridging funds for 1 year to allow investigators to resubmit their applications if there is a reasonably high likelihood of success. While NIA RPG success rates have been low, they would have been even lower had the NIA not implemented cost management policies. These policies (1) reduced, on average, the level of awards by 18 percent from the recommended study section levels beginning in 2004 and (2) restricted the level of inflation allowed for noncompeting awards beginning in 2006. While necessary, these policies have decreased funding for those investigators with active grants. This compromise represents the Institute’s attempt to temper the potential loss of investigators from the scientific community while still funding current investigators at a viable rate. Dr. Hodes welcomed Council input on this matter.

Dr. Greengard asked whether scientific journals had given permission for articles that were supported through NIH funding to be made available through NIH Public Access. Dr. Barr responded that already 300 journals have agreed to automatically send published articles to the Web site, and the NIH is working to increase that number. However, the NIH cannot force a scientific journal to participate, and the Federal Government is not in a position to negotiate legally with private companies. For journals not among the 300 that have agreed to participate in NIH Public Access, the burden is on the investigator to negotiate for public posting of his/her article. Dr. Hodes added that cases in which a journal refuses to share an article with NIH Public Access will be considered individually. However, the hope is that scientific journals will be encouraged to participate.

Discussion turned next to funding levels and success rates. In response to Council members’ questions, Dr. Hodes clarified that the decrease in funded grant applications applied across the NIH. Dr. Barr added that the decrease was slightly higher at the NIA than other Institutes, and the success rate for NIA grants was slightly above the NIH average last year. For applicants fortunate enough to be funded, it has been necessary to impose an average reduction of 18 percent, so there can be variation (in the size of the reduction) from one grant to the next. There are circumstances in which it would be difficult to cut funding unless there were supplementary funds—for example, in the case of clinical trials. Dr. Hodes surmised that the average duration of grants has likely declined over time due to an increase in the ratio of R21s (which are generally 2-year awards) to R01s (which are usually 4- to 5-year awards).

Dr. Friedman asked if there is a formal cap on the size of a grant that the NIA can fund. Dr. Hodes responded that the only cap that the NIA has imposed is on P01s, and even this cap has exceptions, though infrequent. The NIH requires that grant applications over $500,000 receive prior approval, and the NIA has imposed an additional requirement that awards at or around $2 million be approved by NIA senior and executive staff. There are, however, no additional caps on the size of NIA-funded grants. Another topic that has been considered across Institutes is whether the number of awards or the number of dollars granted to individual investigators should be capped. Again, the NIA does not have a specific policy on this topic but considers these cases individually.

B. Announcements

Dr. Robin Barr announced that Dr. Mary Nekola will be retiring in about a week. Dr. Nekola thanked the Council for their support.

C. Future Meeting Dates

May 20–21, 2008 (Tuesday and Wednesday)
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

The minutes of the September 2007 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.

III. REPORT: Task Force on Minority Aging Research

Dr. Peggye Dilworth-Anderson reported on the task force’s discussion of sex/gender and minority inclusion in NIH clinical research, and new initiatives. She reminded Council of the annual requirement for the task force to report on the inclusion of both genders and all racial and ethnic minority groups in clinical studies. Under Public Law 103-43, women and minorities must be included in research, and they must be included in phase III clinical trials in numbers adequate for valid analysis. As part of its policy, the NIH supports outreach efforts to recruit and retain women and minorities and their subpopulations in clinical studies. Cost is not an acceptable reason for excluding these groups. Principal investigators, review staff, program and grants management staff, the NIH Tracking and Inclusion Committee, Congress, and the public all comply with the NIH inclusion policy.

NIA minority enrollment data for FY 2006 and FY 2007 indicate a slight decrease (0.9 percent) in minority inclusion in FY 2007. One reason for this decrease is that most protocols included the new self-report questionnaire, which separates ethnicity from race. Changes largely due to grant cycling also affected minority inclusion in FY 2007. Larger grants that included large numbers of minorities were either cycling out or were in between funding, resulting in a decrease in the number of minorities in these applications. Dr. Dilworth-Anderson reported that action was taken at the previous day’s NACA meeting to accept the Population Tracking Inclusion Report certifying that the NIA is compliant with guidelines including both genders and all racial and ethnic groups in clinical studies.

Next Dr. Dilworth-Anderson presented data on research supplements to promote diversity. NIH-wide supplements to individuals from underrepresented groups or disadvantaged backgrounds peaked in FY 2004, then decreased in FY 2005 and FY 2006. This pattern was mirrored at the NIA. In FY 2006, the NIA awarded 54 diversity supplements for a total of almost $4 million of support. This is slightly higher than the average of diversity supplement expenditures across all Institutes and Centers (ICs).

Dr. Dilworth-Anderson described a new initiative: the NIA Health Disparities Resource Persons Network. This Web-based resource brings together research professionals in aging, geriatrics, and gerontology who volunteer their services in support of research to address health disparities and improve the health status of racial and ethnic minority older adults. Another objective of the network is to provide technical and capacity-building assistance to the NIA and its research constituency. Also available is a toolkit: Outreach, Recruitment, and Retention of Health Disparity Populations in Aging Research at http://orwh.od.nih.gov/inclusion/outreach.pdf (PDF, 1.4M).

Additional activities planned to facilitate the inclusion of minorities in aging research and to sharpen focus on minority issues include (1) the development of a program announcement titled Promoting Careers in Aging and Health Disparities Research (PAR-08-033), which will expire in 2011; (2) the NIA Summer Institute on Aging Research (July 12 to 18, 2008) that involves a large cadre of minority scholars and strong senior scientists from across the Nation; and (3) the NIH Workshop on Women and Biomedical Research: Best Practices for Sustaining Career Success, which will be held March 4 to 5, 2008 (http://womeninscience.nih.gov).

Dr. Barr emphasized that the diversity supplements are effective for bringing underrepresented young scientists and students into research. An NIA analysis conducted 3 years ago showed that many postdoctoral and junior faculty who received diversity supplements went on to apply successfully for NIH grants independently. Notably, their success rate was the same as the success rate for the general population. While these supplements are clearly successful, there has been a decline in applications. Dr. Barr therefore urged researchers to consider these diversity supplements.

IV. REPORT: Working Group on Program

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

First, the working group had three requests for future Working Group on Program meetings: (1) That specific initiatives be assigned to individual working group members in advance of the meeting so that at least one member has the opportunity to gain an in-depth understanding of the issues, (2) that their agenda include an annotation of the specific recommendations proposed for each new initiative so that members know specifically on what they are voting, and (3) that presentations on new initiatives be strictly time-limited in future working group meetings.

The working group also discussed how resource allocation imperatives should be factored into the approval vote of the Working Group on Program. Members agreed that, while the working group provides advice on the scientific content of the initiatives, the NIA is in the best position to weigh the risks and benefits of allocating specific funds in the context of the Institute’s overall portfolio. The working group also discussed whether it is appropriate for working group members to know the overall fiscal impact of the initiatives they are asked to approve. There was no consensus on this matter.

A. Advisory Meetings

Dr. John Haaga presented to the working group on a Data Review Committee Meeting that convened a distinguished ad hoc committee to review data priorities of the NIA Behavioral and Social Research (BSR) program. The committee examined current data collection, archiving, and dissemination to assess future data and infrastructure needs and to prioritize BSR’s investments in data. The resulting report, issued in November 2007 and available on the NIA Web site, recommended that the BSR collect long-term data at earlier ages to gauge cumulative exposures over the life course. The report also recommended that BSR provide seed funding for data collection in cross-national analyses to (1) harmonize data across national programs; (2) integrate social, psychological, and behavioral models and phenotypes into biological pathways such as gene-environment analyses; and (3) expand research in regard to disparities and disability in cognitive aging. The Working Group on Program approved these recommendations. In the full Council meeting, a motion was made, seconded, and passed unanimously to approve the recommendations of the Data Review Committee Meeting.

Dr. Ying Tian presented to the working group on the Animal Models of Age-Related Comorbidities workshop held in September 2007. The aims of the workshop were to determine (1) what research in studying comorbidities could be supported by animal models, (2) whether existing animal models to support that research are available, and (3) what resources and funding mechanisms should be devoted to expand research in these areas. The Working Group on Program agreed that this is an important topic and discussed how comorbidities might occur as a consequence of aging, the effect of specific comorbid conditions across the lifespan and interactions across multiple organs, and the potential to age an animal model of a specific condition. The working group raised concerns that current animal models of specific conditions of interest are not fully developed or have imperfections and thus do not fully represent those conditions. They agreed that it seems premature to use these models for studies of age-related comorbidities. The working group also agreed that there was insufficient opportunity to digest the workshop report. They therefore recommended that three working group members (Drs. Siu, Swain, and Jazwinski) review the report and the recommendations and report back to the Working Group on Program at the May 2008 NACA meeting. The Working Group on Program thus voted to defer approval of workshop recommendations until May 2008. In the full Council meeting, a motion was made, seconded, and passed unanimously to defer approval of the recommendations of the Animal Models of Age-Related Comorbidities workshop until the May 2008 NACA meeting.

B. RFA Concept Clearances

Dr. Morris presented a proposal from Dr. Sergei Romashkan to issue a request for applications (RFA) to create a consortium for clinical trials on anemia in older persons. The proposal is for 6 years of support, and the National Institute of Diabetes and Digestive Diseases and Kidney Diseases and the National Heart, Lung, and Blood Institute propose to cofund the initiative. A motion was made, seconded, and passed unanimously to approve this RFA concept.

Dr. Morris presented a proposal from Dr. Ronald Kohanski for an RFA on cell lineage for tissue maintenance and repair in the elderly. This is motivated by the need to determine the cellular basis of tissue homeostasis in the elderly and enhance current work in regenerative medicine. Dr. Kohanski proposed a two-step initiative. The first step is to issue an RFA for R21s to develop and characterize systems for cell marking and fate determination and develop the tools to study the decline in adaptive function with age. The second step is to seek applications using the systems developed in this earlier phase to address cell fate decisions and cellular turnover. The Working Group on Program was asked to consider approval of only the first step of this two-step initiative. A motion was made, seconded, and passed unanimously to approve this RFA concept.

Dr. Morris reported on a proposal from Dr. Rebecca Fuldner for an RFA on thymic atrophy with aging. Specifically, the RFA would solicit applications to support basic research to study the biology of age-related thymic involution and decline of T-cell production and function in the elderly. The goal of the RFA is to promote and foster collaborations, and it will encourage awardees to promote multidisciplinary interactions. One working group member was not convinced that now is the appropriate time for this RFA; others disagreed. A motion was made, seconded, and passed with one abstention to approve this RFA concept.

A discussion ensued about the difficulties of voting on this and other RFA concept clearances without sufficient information regarding financial implications. Although Council members are entrusted with other confidential information, they are asked to approve concept clearances with no notion of the level of funding. Dr. Barr explained that NIA is limited in what it can share with Council because the RFA concept clearance process is by law open to the public. Dr. Hodes acknowledged that providing such input without adequate information is a cause of tension and promised to discuss this matter internally to see if it can be addressed to Council’s satisfaction. As an intermediate compromise, NIA agreed to provide Council with a general sense of how much of the budget is directed toward set-asides, on average, per year with the understanding that NIA will stay within that historical framework. NIA also offered to inform Council what the proposed funding would be if all set-asides under consideration for that year were to be approved.

Dr. Morris next reported on a proposal from Dr. Lis Nielsen for an RFA on the social neuroscience of aging. The aim of this initiative is to stimulate interdisciplinary research to examine the genetic and neurobiological basis of social behaviors relevant to aging. The working group agreed that this is a relevant field and needs nourishment that can be provided through an RFA including R01s and R21s. A motion was made, seconded, and passed with one abstention to approve this RFA concept.

The last RFA considered by the Working Group on Program was from Dr. John Phillips for an RFA to develop models that forecast Medicare expenditures. Medicare is facing unprecedented challenges occasioned by the increasing number of older adults and the increasing cost of healthcare. This RFA calls for R01s to conduct basic research that addresses assumptions about Medicare forecasts and to inform Federal research investigations and Federal agencies. A motion was made, seconded, and passed unanimously to approve this RFA concept.

C. Statement of Understanding

The Statement of Understanding between the NACA and Institute staff concerns routine activities and procedures that may be conducted without Council review and clearance. The statement needs to be reconsidered annually at a Council meeting and reapproved or modified via a Council motion in the open session of Council.

Dr. Barr reported that there were no changes to the Statement of Understanding this year. He reminded Council that the statement was modified in May 2007 to remove language stating that applications under $50,000 could be awarded without Council approval. This modification was in response to the 2006 NIH Reform Act, which removed the NIH’s authority to award such applications because there was concern that research that might be deemed controversial was not being subject to the full force of peer review, including the oversight provided by Council. Now, aside from Fellowship applications, all applications must be routed through Council. Dr. Hodes pointed out that this is illustrative of the way in which the role of Council is appreciated. A motion was made, seconded, and passed unanimously to reapprove the current Statement of Understanding.

V. PROGRAM HIGHLIGHTS

A. Geriatrics and Clinical Gerontology: Cardiorespiratory Fitness as a Determinant of Health—Findings From the Aerobics Center Longitudinal Study

Dr. Steven N. Blair (University of South Carolina) presented findings from the Aerobics Center Longitudinal Study (ACLS) showing that cardiorespiratory fitness is a strong determinant of health. He opened his presentation by providing an overview of the ACLS, which follows a cohort of more than 80,000 women and men examined at the Cooper Clinic in Dallas, TX, since 1970. The cohort comprises individuals ranging from 20 to over 90 years of age at baseline who come from middle- to upper-socioeconomic status groups and are predominantly non-Hispanic Whites. The examination takes several hours and provides a wide range of clinical measurements, family and personal medical histories, and lifestyle variables. The study database is large and includes variables not typically found in epidemiological studies, such as measures of body composition and physical fitness. All participants completed a maximal exercise test during the examination, which provides an objective laboratory measure of cardiorespiratory fitness.

While cardiorespiratory fitness has a genetic component, estimated to account for 20 to 45 percent of the variance, it is determined primarily by exercise habits in the weeks before the test. The advantage of using cardiorespiratory fitness as an exposure is that it results in less misclassification of exercise habits than self-report of exercise behavior. Participants are typically categorized into three fitness groups—low, moderate, and high fitness. Low fitness is the least-fit 20 percent in each age and sex group, moderate is the next 40 percent, and high is the most-fit 40 percent. Moderate fitness can be achieved by meeting the consensus public health recommendation for physical activity—accumulating 30 minutes of moderate-intensity activity per day at least 5 days of the week.

Reports from the ACLS show that cardiorespiratory fitness is a strong determinant of chronic disease morbidity and mortality as well as mortality from all causes. Low cardiorespiratory fitness is associated with higher risk of type 2 diabetes, hypertension, cardiovascular disease, coronary heart disease, obesity, and some cancers. All-cause mortality shows a steep inverse gradient across fitness groups. Typically, moderately fit women and men have a 50-percent lower risk of these various health conditions when compared with their low-fit peers. High-fit individuals obtain additional benefit, typically another 10- to 15-percent lower risk of the outcome. Low fitness is one of the strongest predictors of morbidity and mortality of any of the variables in the database. Furthermore, moderate and high fitness provide protection in individuals who are at risk or not at risk for other exposures. For example, obese individuals in the moderate-fitness group have a substantially lower risk of dying than do low-fit persons in the normal weight category. This same pattern of results has been observed in smokers and nonsmokers and individuals with hypercholesterolemia or hypertension compared with those who do not have these conditions. Population-attributable estimates suggest that low fitness accounts for more deaths in the population than other established risk predictors such as hypertension, hypercholesterolemia, diabetes, and cigarette smoking.

The ACLS was funded by the NIA from the early 1980s until 2006. Support from NIA allowed for maintaining morbidity and mortality surveillance in the ACLS cohort and supporting staff who maintained the study and published the research. More than 150 scientific research reports have resulted from this project. Some of these papers have been highly cited and have been influential in helping shape public health recommendations for physical activity that emerged in the mid-1990s. These reports were released by the American College of Sports Medicine (ACSM), Centers for Disease Control and Prevention, NIH Consensus Development Conference, U.S. Surgeon General, American Heart Association, and World Health Association.

Dr. Greengard asked what accounts for the beneficial effects of fitness, if not lower cholesterol levels and lower body mass index. Dr. Blair responded that risk indicators include inflammatory response, fibrinolytic activity, and sympathetic-parasympathetic balance. There are likely other mechanisms that explain the protective effects of fitness—for instance, muscle biologists are investigating whether mitochondria play a role. Activity affects every system in the body, said Dr. Blair, and it seems that most of those effects are beneficial.

Dr. Bredesen asked what recommendations Dr. Blair would make to physicians who are starting their practices and have limited time for each patient. Dr. Blair responded that physicians should refer clients to individuals with expertise in exercise physiology. YMCAs and health clubs often offer such expertise, and the ACSM certifies people to do this work. Another option is for a physician to have an exercise physiologist (preferably one with training in behavioral science) in his/her practice. Dr. Blair added that public health initiatives could help establish such relationships and referral systems. Dr. Blair described his research involving behavioral interventions for physical activity, in which 25 to 30 percent of participants who had been sedentary and unfit were, within 2 years, meeting the consensus public health recommendation for physical activity. This and similar interventions need to be integrated into public health systems and medical practice.

Dr. Brummel-Smith asked how to teach physicians to measure fitness, as opposed to obesity, in an office setting. Dr. Blair responded that the 400-meter corridor walk, which was used in the NIA-funded Lifestyle Interventions for Elders (LIFE) pilot study and the Dynamics of Health, Aging and Body Composition (Health ABC) study, is simple to conduct and is associated with mortality. Arthur Master’s two-step test also provides a reliable measure of fitness, and both tests integrate well in medical practice. Alternately, physicians could refer patients to a YMCA or health club for testing.

Dr. Khosla asked whether randomized control trials have been conducted that show a decrease in mortality, cancers, diabetes, etc., as a result of physical activity. Dr. Blair responded that such trials have not been conducted for physical activity, although evidence of a relationship between fitness and health is already strong.

B. Neuroscience and Neuropsychology of Aging: Alzheimer’s Disease: A Developmental Disorder?

Dr. Debomoy K. Lahiri (Indiana University School of Medicine) described the interaction between genes and the environment in early developmental etiology of Alzheimer’s disease (AD). Advances in human genetics research have significantly increased our understanding of genes involved in various neurodegenerative disorders, such as AD. In addition to genes, environmental factors, including diet, metals, and lifestyle, play an important role in human behavior and the development of disease phenotype. The salient unanswered question in the field today is the nature and timing of such gene-environment interactions.

Dr. Lahiri reported that he and colleagues recently proposed that primary gene sequence variation is often not an immediate operator in neurobiological pathology. Instead, environment acts upon the genetic substrate, producing a “somatic epitype.” Somatic epitypes are a form of epigenotype that arises through environmental influences upon a genome within a single lifetime rather than the more familiar epigenetic inheritance. These somatic epitypes would correspond to physical alterations in gene promoters via (hypo)methylation, chromatin structure, or oxidative damage (as oxo-d8-guanosine). This could be instilled upon the underlying gene sequence by conditions in utero, by maternal behavior, or by maternal nutrition or postnatal environmental effects such as nutrition or transient exposure to heavy metals such as lead (Pb). One such example of a somatic epitype can potentially be found in the SP1 gene.

In studies published in 2007 and 2008, Dr. Lahiri and colleagues demonstrated that the expression of AD-related genes as well as their transcriptional regulator (SP1) is perturbed in a latent early life–associated regulation (LEARn) fashion after transient developmental exposure to Pb in primates. This is consistent with the suggestion that, although the pathological manifestations in AD patients are presumed to result from defects of old age, it is unlikely that the disease process begins late in life without due consideration given to the effects of environment.

Current work with primates and earlier work with rodents, also conducted by Dr. Lahiri and colleagues, validates the proposed LEARn model, which postulates a latent expression of specific genes triggered at the developmental stage. According to the model, environmental agents (e.g., heavy metals), intrinsic factors (e.g., cytokines), and dietary factors (e.g., folate, cholesterol) perturb gene regulation beginning at early developmental stages. However, these perturbations do not have pathological results until significantly later in life. Thus, Dr. Lahiri explained, the LEARn model is not a conventional toxicity model. Furthermore, the key and novel component of the work is that it does not propose conventional acute or chronic Pb toxicity as an etiological mechanism for AD. Instead, it proposes that Pb potentiates an organism to become susceptible to some later trigger that otherwise might not result in AD.

In short, the LEARn model proposes that transitory infancy and early childhood exposure to Pb potentiates greater vulnerability to AD later in life. From an epidemiological standpoint, the current rates of AD, under the LEARn model, would still be increasing as they reflect the levels of increase in Pb in the environment that would have been seen from approximately 1940 to 1950, when the current late-onset AD patient population was in infancy or early childhood. Under the LEARn model, bans enacted in the 1970s and 1980s would not be expected to result in reduced rates of new AD cases until roughly 2035 to 2045. This presumes that these bans effectively removed sufficient Pb from the environment, which may be a questionable conclusion based on the work of M.A Laidlaw and colleagues, which noted that lead levels in children could vary based on Pb levels in soil and whether climate conditions encouraged the soil to become airborne dust. Likewise, the low and subtoxic levels of Pb exposure the LEARn model proposes as inducing a risk factor may also be available through other sources, such as power cords, skin-care products, and other sources with little or no regulation of Pb content, in addition to now endemic Pb found in urban soils from former use in gasoline. Therefore, a long, perhaps decades-long, latency period would occur in the LEARn model between exposure to Pb and any possible development of AD. Application of the LEARn model would suggest potential for predicting, at least to some extent, great vulnerability to earlier insult, and potential therapeutic strategies.

In response to questions from Council members, Dr. Lahiri explained that he chose to focus on Pb in his studies because while other metals (e.g., copper, zinc, iron) also bind to certain regulatory genes, those elements are different and their mechanisms are different from lead. He also stated that cognitive testing was not done on those exposed early or controls to see if there were functional cognitive changes that accompanied the anatomic changes. There was no medical reason for such testing because there was no evidence of plaques in the primates and the cohort was accidentally discovered.

C. Behavioral and Social Research Program: Sexuality and Health Among Older Women and Men in the United States

Dr. Stacy Lindau (University of Chicago) presented on intimate social relationships and health in later life. She opened her presentation by describing the history of the National Social Life, Health, and Aging Project (NSHAP). Dr. Lindau called attention to the taboo nature of the topic of sexuality in later life and argued that understanding sexual relationships of older adults would advance a more humane and holistic understanding of older adulthood and would promote discovery about the biological mechanisms through which social relationships influence health.

Few have studied the health correlates or effects of sexual relationships (beyond the obvious—sexually transmitted disease [STD] transmission, pregnancy, and sexual violence) that are unique among social connections in that they involve both physical contact and close psychosocial interactions. A good deal of evidence supports a positive connection between social relationships and health in later life. Socially connected older adults live longer, are more functionally able, and are less likely to be institutionalized. Spousal relationships are the most critical social connection for older adults, and a broad literature substantiates the protective health effects of marriage, independent of selection into marriage. However, surprisingly little is known about the role of sexuality in explaining the observed health benefits associated with marriage.

The NSHAP collected, for the first time with a very high cooperation rate, detailed data on social life (including social networks, positive and negative aspects of social support, engagement), sexuality (activity, behavior, problems, attitudes), and health (physical function, conditions, medications, behaviors, healthcare utilization) and a broad and unique panel of biological measures. The biological measures obtained for the NSHAP reflect the study’s orientation toward understanding the physiology of intimate and social relationships. Cooperation with the biological measures component of this home-based study exceeded 90 percent for most; vaginal self-swabs were provided by about 68 percent of participants.

Among the main findings of the first NSHAP publication (NEJM, 2007), Dr. Lindau reported that (1) the majority of community-residing adults ages 57 to 85 are sexually active, although the oldest old women were least likely to be sexually active; (2) most older adults value sexuality to some degree, with women more likely than men to rate sex as unimportant; (3) the prevalence of bothersome sexual problems is high among sexually active older adults, and the prevalence of medication use to treat sexual problems is high and almost exclusive to men; (4) communication about sexual matters is poor; people are more likely to have discussed sex with a spouse than with a physician, but only a minority had discussed sex with a physician, and men were more likely to report this than women; (5) overall health was strongly associated with sexual partnership and activity, more so for men than for women, and was more important with regard to many sexual problems than age alone; (6) the majority of older adults had not been HIV tested. Among those who had been tested, women appeared to be slightly more likely than men to obtain their test results, and men were more likely than women to see themselves at risk for HIV infection.

NSHAP investigators worked closely with the Office of Communications to coordinate the publicity of the NEJM paper on sexuality and found media response to be vast, international, ongoing, and overall very positive. Reporters have been particularly interested in STDs among older adults, and several reporters have asked for data particular to understanding the relationship between sexuality and health among same-sex couples. Dr. Lindau explained that because of the sample size, the investigators deliberately excluded most STD testing from the study design. She acknowledged the limitation with regard to same-sex couples and noted the dire need for data pertinent to this population. She also pointed out that the most recent population data on sexuality among younger adults are now 15 years old. Major social, medical, and public health changes in the United States since those data were collected beg for a new longitudinal investment in data collection on human sexuality. Understanding biological mechanisms through which sexual relationships influence health requires a view from earlier life because early-life sexual, health, and social experiences plausibly influence later-life sexuality, relationships, and health outcomes. Finally, although the conceptual framework for the NSHAP involves a dyad-centric view of both health and sexuality, budget limitations precluded enrollment of partners. Enrollment of partners in future studies would present a significant advance in this work.

The NSHAP dataset is publicly available via the National Archive of Computerized Data on Aging (www.icpsr.umich.edu/NACDA). Support for the scholarly community on methods for biological data collection in demographic research is available through the University of Chicago and the National Opinion Research Center, or NORC, Center on Demography and Economics of Aging Core on Biomarkers (http://biomarkers.uchicago.edu), which Dr. Lindau directs.

Dr. Tinetti asked whether the NSHAP sampled in households where there were two partners and, if so, whether both partners were interviewed and their data correlated. Dr. Lindau responded that the sampling frame for the study came from collaboration with the Health and Retirement Study. Due to budget constraints, both partners were not interviewed. Instead, one partner was interviewed and asked questions about the other partner’s health status and sexual function. The study posed detailed questions about marital status but included questions about cohabitation and nonmarital romantic or intimate relationships. Partnership was therefore broadly defined to include individuals who were either married or in a romantic or intimate relationship. The hope is to interview partners in wave 2 of the NSHAP.

Dr. Bredesen asked Dr. Lindau to describe how her research adds to current understanding about sexuality among older adults. Dr. Lindau responded that the biggest advantage of the NSHAP dataset is that it is generalizable to the U.S. population. Earlier studies, in contrast, were either composed of volunteers or, in the case of the Massachusetts Male Aging Study, were limited to men. The broader reach of Dr. Lindau’s work allows people to “locate themselves in these data” and determine whether they are experiencing an inevitable age-related decline or a health challenge that can be reasonably addressed. In addition, the NSHAP adds to the current body of research in that it presents data on sexuality in the context of other social relationships and includes detailed health data.

Dr. Brummel-Smith asked whether the NSHAP examined religious preference and how (or whether) religious preference affected participants’ responses. Dr. Lindau replied that questions about religiosity and religious affiliation are included in the study, and her preliminary findings indicate that these traits are related to sexual risk.

Dr. Ganguli pointed out that many people get tested for HIV infection when they apply for insurance. Dr. Lindau had reported that one-third of NSHAP participants indicated they sought HIV testing for a reason other than those presented, which prompted Dr. Ganguli to ask if this might be the route by which these individuals were tested for HIV. Dr. Lindau regretted not including a close-coded option for HIV testing via insurance carrier. She added that, in addition to testing for HIV, the NSHAP gave participants the opportunity to call in anonymously for their test results. However, few participants did so. This suggests that it is also questionable whether people actually learn their HIV status after being tested through an insurance carrier.

Dr. Tinetti asked whether the NSHAP had looked at other health behaviors (e.g., physical activity, nonsmoking) among sexually active adults to determine if they are confounders. Dr. Lindau responded that a career development award and an R01 that would support research on these issues are in the pipeline. She added that she is collaborating with NIH-funded investigators doing disease-specific work (e.g., cardiovascular disease, diabetes) to incorporate questions about sexuality into their research.

D. Biology of Aging Program: Failures of the Aging Immune System and Their Place in the Integrative Biology of Aging

Dr. Janko Nikolich-Zugich (Oregon Health & Science University) presented on failures of the aging immune system. The immune system has evolved to protect the body against pathogens. Multilayered defenses of the body include intact barriers to invasion, such as skin and mucosal membranes, which are bathed in microbicidal fluids and/or colonized with saprophytic flora. Also among the body’s defenses are a plethora of innate immune mechanisms, which are rapidly deployed but relatively nonspecific, and adaptive immune mechanisms, which are slower but very specific. These mechanisms coordinate to effectively protect the organism against infection. Advanced age is marked by a decline in protective immunity and an increase in morbidity and mortality from infectious diseases. A multitude of defects in the innate and adaptive response to pathogens in aging humans and animals has been described, with those in adaptive immunity appearing more consistent and severe. The challenges in aging and immunity, therefore, are to (1) delineate primary alterations from secondary, compensatory age-related changes; (2) diagnose the level of key immunological impairments in humans by simple screening; and (3) act at the most effective points of intervention to ameliorate and correct immune senescence.

T-cells are strongly affected by aging, and reconstitution of T-cell function often restores immune defense in aged animals. Dr. Nikolich-Zugich proposed that the cause for these defects is threefold. First, accumulation of molecular damage (e.g., DNA damage, oxidative stress, etc.) and decline in renewal and repair affect T cells just as they affect other tissues in the organism, leading to cell-autonomous defects in T-cell production, maintenance, and function. Second, T cells are affected by age-related changes in T-cell environment, including molecules and cells that cooperate with T cells to regulate T-cell development and function; e.g., stromal aging, dendritic cell aging, changes in extracellular matrix, cytokines. Third, repeated rounds of T-cell proliferation in response to pathogens over the lifespan further contribute to T-cell aging. Most of Dr. Nikolich-Zugich’s recent work is focused upon just such changes. He presented data showing that two factors play a decisive role in age-related changes due to excessive use of T cells:

1. T-cell homeostatic mechanisms are in charge of maintaining and/or restoring balance to the T-cell compartment, which constantly undergoes expansion and contraction in response to microbial challenge. In uninfected, specific pathogen–free mice, these forces can exert dramatic influence upon the aging T-cell pool. Dr. Nikolich-Zugich’s recent data in old nonhuman primates demonstrates the impact of these forces upon T-cell homeostasis and aging. In youth, there is robust production of naïve T cells, which defend against new microbial challenges. Soon after birth, this production decreases, and naïve T cells rely on low levels of homeostatic proliferation to sustain their numbers. Dr. Nikolich-Zugich’s laboratory showed that increased homeostatic proliferative expansion and turnover in the naïve T-cell compartment occurs with aging. This turnover was inversely proportional to the remaining naïve T-cell reserve and exhibited a threshold effect, whereby all animals with less than 5 percent of naïve T cells showed dramatic increase in proliferation. Because such cells convert into memory-type T cells with proliferation, Dr. Nikolich-Zugich and his colleagues concluded that proliferative homeostatic expansion operates according to the principles of antagonistic pleiotropy, ensuring renewal of the naïve T-cell pool in youth but eventually precipitating its further loss in advanced age.
   
   
2. In humans, latent herpes virus infections have been linked to accumulation of T cells, some of which show an aging phenotype. Dr. Nikolich-Zugich’s laboratory has shown that T-cell accumulation in response to such viruses is directly linked to the establishment of latency and to subsequent reactivation of the virus; antiviral drugs can prevent this accumulation. This raises possibilities of treating age-related T-cell disorders with T-cell rejuvenation and/or antiviral drugs and stresses the need to perform broad screening to triage the elderly into several different groups for which treatments could be customized based upon the status of their immune system. However, on a broader front, these experiments also underscore the need to thoroughly understand the relationships among the immune and inflammatory systems and microbes that colonize humans for saprophytic or pathogenic purposes. While the Human Microbiome Project by NIAID is in progress, it is limited to bacteria, and the host component is missing. Moreover, little is understood about the impact of disturbances in these interactions due to immunosuppression, aging, and/or concurrent disease(s).

Dr. Swain observed that, in Dr. Nikolich-Zugich’s studies, differences in the CD4 population were small and asked if correlation curves had been performed for this population. Dr. Nikolich-Zugich responded that differences were less striking in CD4 cells than in CD8 cells, possibly because the response to homeostatic cytokines in CD4s is lost earlier. In addition, as CD4s migrate from the thymus, they may not be surviving as well. If CD4 cells are being lost at a higher rate and sooner than CD8s, it might be necessary to look at CD4s earlier in the macaques. Nevertheless, the research does show differences in proliferative population properties between CD4s and CD8s, particularly in aging, where the CD8s are generally doing better.

In response to a question by Dr. Hodes about potential interventions for the proposed model, Dr. Nikolich-Zugich explained that, in terms of homeostatic mechanisms, there will probably be three types of older individuals. First, there will be those who have many naïve T cells and therefore need only standard vaccination regimens. Second, there will be those who have some T-cell loss and age-related slowdown in T-cell production. For these individuals, existing vaccines will need to be modified or immunomodulatory methods used to enhance cytokines and dendritic cells. Third, there will be those older individuals who have lost diversity in their T-cell population and, as a result, do not have a reserve of T cells that can effectively react to pathogens. For these individuals, the approach is to rejuvenate the T-cell system, which means intervening at the level of the thymus. A number of interventions targeting the thymus are currently underway. In addition, Richard Boyd of Monash University has published on thymic regeneration following androgen blockage. Dr. Nikolich-Zugich expressed interest in applying this research in older macaques.

Dr. Khosla asked Dr. Nikolich-Zugich if he had studied menopause in primates or humans and the role that estrogen deficiency may play in age-related changes such as bone loss. Dr. Nikolich-Zugich responded that there is provocative evidence that IL-7 affects the balance between osteoblasts and osteoclasts, but this has not been studied from the perspective of aging. He said he hopes to organize a multidisciplinary study of this type at the University of Arizona Center on Aging.

In terms of interventions to prevent persistent viral infections, Dr. Nikolich-Zugich commented that it is difficult to prevent viral infections. Attempts to develop vaccines for herpes viruses and cytomegalovirus (CMV), for instance, have not been successful, although penciclovir has been somewhat effective with herpes. Modulating reactivation, however, is a more realistic prospect. For example, Dr. Nikolich-Zugich’s studies in macaques with CMV have shown that caloric restriction helps maintain the balance of naïve and memory T cells.

VI. PRESENTATION: NIH’s New Research, Condition, and Disease Categorization Process

Dr. Timothy Hays, Project Director of the Research, Condition, and Disease Categorization (RCDC) Project, described a new process underway to categorize both intramural research and research grants supported by NIH. Currently, NIH reports to Congress and the public on how much it spends and estimates future spending in approximately 250 research and disease categories. Each Institute/Center (IC) provides a central office with data on what they have spent on a particular category. How the category is defined depends on the IC. Although other ICs must agree with this definition, there are no central definitions for the categories on which NIH reports.

In 1998 the National Academies issued a report recommending that NIH improve how it categorizes research. The Academies reiterated this recommendation in a 2003 report. In addition, Congress expressed that it was difficult to understand how NIH generated the numbers it reports, and Congress requested improvements. In 2004 NIH tried a pilot in which bioinformatics tools and text mining were used to categorize research, and at the same time NIH began to rely more heavily on electronic submission vehicles such as Grants.gov. In the NIH 2006 Reform Act, Congress mandated that this process be used to automate coding and categorization.

The RCDC is an electronic system that reports NIH spending across the 27 ICs each fiscal year in approximately 360 research and disease areas. NIH is working with experts to develop central definitions for each category and, at present, is limited to the categories it has reported historically. NIH aims to include project listings based on titles, abstracts, and specific aims; thus, NIH relies on investigators to define their projects accurately. However, the RCDC does offer consistency, as one definition will be used across NIH; transparency, as the RCDC displays every project listed in a category, allowing staff to answer questions more quickly; and efficiency. In addition, the new system provides opportunities for further NIH portfolio analysis.

Dr. Hays presented an example of a typical cross-cutting disease area, which includes a definition, symptoms, and examples of how different ICs apply the area to their research portfolio. In capturing these and applying definitions uniformly, RCDC staff have found examples of IC-supported research that fits into categories that ICs might not have used previously. Therefore, relying on a central definition could prove beneficial.

To categorize a project, the RCDC looks first at the project title, abstract, specific aims, and public health relevance, then runs it against a medical thesaurus with over 300,000 medical concepts. The system determines how often a topic appears in that project and generates a weighted list of concepts that are used in category definitions. The weighted list is compared with other definitions at the NIH, and the project is listed under any category with a sufficient match. For this reason, projects might appear in multiple categories.

Dr. Hays reported that NIH will introduce the RCDC to the public in the summer of 2008 and that the RCDC will launch with FY 2008 projects. FY 2008 data will be reported in February 2009. Reporting for FY 2007 will be redone to allow comparisons.

Dr. Hodes asked Dr. Hays to explain how changes to the definition of a disease category are accommodated by the RCDC. Arriving at a definition for AD, for instance, was an extensive process involving NIA, advocacy groups, and the scientific community, and there is concern that the new definition may not be clearly reflected in the RCDC system. Dr. Hays responded that an RCDC definition is an NIH-wide, agreed-upon definition established by experts identified by the ICs. Alzheimer’s disease, minority health, and clinical research are three categories for which a definition was developed with input from stakeholders and then coded manually by IC staff. Additional analyses will examine the accuracy of the RCDC by category. Dr. Hays also shared that the NIH Office of the Director (OD) will use a variety of tools to help ICs identify emerging concepts. In turn, the ICs will help OD understand whether these concepts should be added to the baseline definition. Every year, there will be changes to definitions within the RCDC because of shifts in the science.

The RCDC currently has the functionality to make available disease-specific funding information by IC. Dr. Friedman asked how NIH will respond to special interest groups concerned by apparent decreases in funding in a specific disease category within the RCDC when that decrease is the result of changes to the system rather than true changes in funding. Dr. Hays responded that there will be a year of crosswalk. For FY 2007, for instance, there will be two numbers for every category: (1) The conventional number as presented by NIH and (2) the number that the new system will generate. This allows NIH to determine which changes are the result of changes to priority setting or changes in an RFA versus changes in methodology.

Dr. Tinetti asked whether 360 is the final number of categories within the RCDC and whether there is a process by which new categories can be added to the system as science evolves. Dr. Hays responded that the number of categories within the RCDC can be expanded. In fact, ICs are already coding new categories unique to them. To do this, they craft a definition within the system and, if other ICs’ projects fall within that definition or if other ICs are known to have an interest in that definition, they are required to work together to arrive at a common, agreed-upon definition. This process will generate additional categories within the RCDC beyond the current 360 categories.

Dr. Khosla asked if there are plans for the RCDC to make available disease-specific funding information by IC. Dr. Hays replied that the RCDC currently has this functionality. He anticipates that people will use the data in a variety of ways to conduct interesting analyses.

Dr. Barr asked if there might be disadvantages to RCDC data being widely available and accessible. Dr. Hays responded that there are some disadvantages. For instance, it is possible that a project will have applicability to 16 categories within the RCDC but will fall into only 4 categories because of the way in which the user has written his/her application. As a result, the RCDC may not represent some projects in some categories. However, the opposite is true as well: projects may appear in categories in which they were not coded previously due to, for instance, an oversight on an IC’s part. There are, therefore, both detriments and benefits to having a publicly accessible system.

As a followup to the previous question, Dr. Barr asked if there is any effort to develop an RCDC system for making publications resulting from NIH grants available. Dr. Hays pointed to an initiative underway that is separate from the RCDC. As part of the NIH Reform Act, the NIH created Computer Retrieval of Information on Scientific Projects, or CRISP, a searchable database of federally funded biomedical research projects that includes publications and patents resulting from those projects. Maintained by the Office of Extramural Research, the database is searchable by keyword and study section, and it will soon begin displaying information by RCDC category as well. A shortcoming is that CRISP draws from PubMed, which does not include all publications by NIH-funded researchers; however, efforts are underway to address this.

VII. PRESENTATION: NIH-RAID, an NIH Roadmap Program on Rapid Access to Interventional Development

Dr. David Badman, Program Director, NIH–Rapid Access to Interventional Development (RAID) Pilot Program, provided an overview of NIH-RAID, which offers assistance with drug development for the academic and nonprofit communities. It is based on a longstanding National Cancer Institute (NCI) program, NCI-RAID, which has been in existence for about 10 years. Other RAID programs include the Type 1 Diabetes–RAID and RAID programs at the NIAID, National Institute on Drug Abuse (NIDA), and NINDS. NIH-RAID is part of the NIH Roadmap, and Roadmap funds pay for half the program. The other half is paid for by ICs interested in particular projects.

NIH-RAID supports one of the Roadmap’s three major themes—reengineering the clinical research enterprise—and its goal is to reduce barriers between laboratory discoveries and clinical trials for new therapies. The program is intended to complement and facilitate private-sector infrastructure rather than replace it. The hope is that venture capital or the biotechnology and pharmaceutical industry will pick up where NIH-RAID leaves off.

The program serves academic discovery laboratories and not-for-profit organizations. However, partnerships with for-profit entities are critical in the development process, and products may be licensed to for-profit partners and still be eligible. Both domestic and foreign institutions are eligible to apply. Eligible projects span the spectrum of human disease and may be supported by multiple Institutes. The current focus of the program is on small molecules and natural products.

To achieve its goal, NIH-RAID provides not grants but resources and services to approved projects through access to a network of contracts maintained by NCI. These services include synthesis of small molecules and oligos and chemical synthesis of small peptides (GMP and non-GMP), scaled-up production to clinical trials, development of analytical methods for bulk substances, isolation and purification of active entities from natural sources, development of pharmacology assays and conduct of pharmacologic studies, investigational new drug (IND)–directed toxicology, and product development planning and advice in IND preparation. In addition, NIH-RAID will now consider (1) requests for manufacture of material for any clinical study and (2) requests for services to support later-stage preclinical development of monoclonal antibodies, recombinant proteins, and gene therapy agents. However, requests for synthesis of monoclonal antibodies, recombinant proteins, and gene therapy agents will not be considered.

NIH-RAID also provides supplementary expertise in regulatory aspects with which investigators may not be familiar. In an independent product-development plan, NIH-RAID helps investigators identify milestones and potential decision points, helps identify additional funding needs and attract resources, and helps clarify the project’s modules and potential costs.

Dr. Badman next described the application process and review criteria. NIH-RAID uses the NIH Resource Access (X01) award mechanism, and applications are received electronically through Grants.gov. There are three receipt dates each year, and applicants are allowed an initial submission and two resubmissions. This year, receipt dates are January 15, May 15, and September 15, 2008. After an administrative assessment, the application goes through CSR peer review and review for IC and NIH Roadmap funding. At that point, a decision is made whether to invite the investigator to present on the status of his/her project. Funding decisions are then made based on the scientific merit of the proposed project, availability of funds, and relevance to program priorities.

Dr. Badman shared with Council an example of a typical project plan and cost assessment. The sample project was funded at a little over $2 million over 3 years and was supported by two ICs as well as the NIH-RAID program. NIH Roadmap funds therefore supported the project at $350,000 per year, and the two ICs each supported the project at $175,000 per year. Because this approach distributes costs among ICs, it is relatively easy to support a number of projects.

NIH-RAID has received 60 proposals over 3 years. Of the first 50 proposals received, the program funded about 25 percent. Reasons that projects did not receive funding included the following: The project was premature, animal data were suspect, or there were intellectual property concerns. Dr. Badman reported that NIH-RAID is actively encouraging investigators to submit proposals as the program has the capacity to support additional projects. For further information on NIH-RAID, Council was encouraged to visit http://nihroadmap.nih.gov/raid or to call the NIH-RAID Pilot Program Office at (301) 594-4660.

Dr. Greengard asked if the Pharmaceutical Manufacturers Association and the Biotechnology Industry Organization were supportive of the NIH-RAID program. Dr. Badman responded that he had talked with these organizations and they are very supportive. He said they do not view NIH-RAID as a competitor and are pleased to have the program doing this work.

Dr. Brummel-Smith asked whether the NIH-RAID program supports development of medical devices. Dr. Badman responded that NIH-RAID supports drug development and pharmaceuticals only. The National Institute on Biomedical Imaging and Bioengineering supports work on medical devices.

Dr. Friedman asked if there are plans to expand the pilot program. Dr. Badman responded that a meeting has been planned to discuss phasing NIH-RAID into a regular program. NIH-RAID will remain a pilot for an additional 4 years, assuming that it is granted an extension. However, if the program is going to continue beyond that point, it must become a regular program funded solely by interested ICs rather than NIH Roadmap funds.

Dr. Swain asked how the success of the NIH-RAID program will be evaluated. Dr. Badman replied that the success of the program cannot be judged by how many drugs are developed because drug development is a lengthy process of 5 to 10 years. However, there are other indicators of success. For instance, one NIH-RAID project resulted in an IND application to the FDA, and another project has been taken over by a pharmaceutical company.

Dr. Tinetti asked how much money was allocated to the NIH-RAID program in FY 2007. She was also interested to know how and where program resources are made available. Dr. Badman responded that the NIH-RAID program was allocated $8 million in NIH Roadmap funds in FY 2007. NIH-RAID has intensified its outreach activities, and the number of applications has increased significantly. In response to Dr. Tinetti’s second question, Dr. Badman said that NIH-RAID resources are provided by NCI contractors located across the country. NCI staff identify the contractors who can best carry out the proposed work, and NCI project officers manage the projects. NIH-RAID staff meet monthly with NCI and funding institute staff to review individual projects, update the status, and decide if additional resources are needed.

Dr. Brummel-Smith said it might appear that taxpayers are supporting the initial phase of research with the NIH-RAID program, thereby permitting pharmaceutical companies to direct their money toward marketing. Dr. Badman replied that pharmaceutical companies are the source of most of the money that brings drugs to the market. The role of NIH-RAID is to help get less-profitable drugs into the health provider community when they otherwise might not.

VIII. INTRAMURAL RESEARCH PROGRAM REPORTS

A. Laboratory of Neurogenetics

Dr. Andrew Singleton, Acting Chief of the Laboratory of Neurogenetics (LNG), opened his presentation by describing the laboratory’s philosophy and focus and by identifying the three core groups within the LNG. The philosophy of the LNG is simple: to use genetics to understand the molecular basis of neurological disorders with the ultimate goal of treating the underlying causes of disease. The laboratory’s primary focus is Parkinson’s disease (PD), although there are programs in AD, stroke, dystonia, ataxia, and amyotrophic lateral sclerosis (ALS) as well. The LNG comprises three core groups: the Molecular Genetics Section, the Cell Biology and Gene Expression Unit, and the Transgenics Unit.

Dr. Singleton next described a traditional strength of the LNG: identification of genetic lesions underlying monogenic forms of neurological disease, including α-synuclein multiplication mutations causing PD, LRRK2 mutations as a cause of PD, ITPR1 deletions causing spinocerebellar ataxia (SCA)-15 (and SCA16), TTBK2 mutations as a cause of SCA11, and PRKRA mutations causing a novel dystonia-Parkinsonism syndrome (DYT16). Dr. Singleton then provided a sampling of the work being undertaken by the integrated research program within the LNG.

LRRK2 (PARK8). Following the LNG’s original identification of LRRK2 mutations as a cause of PD, the laboratory sought to determine the range and frequency of mutations. They showed a wide variety of mutations and one recurring mutation—G2019S. The frequency of G2019S in PD populations has been assessed by the LNG and others in numerous populations (more than 70 publications from 2005 on). These data show a range of frequencies. This mutation underlies approximately 1.5 percent of all Northern European and North American Caucasian apparently sporadic PD cases; 5 percent of all familial cases from the same population; and 11, 23, and 39 percent of all PD cases in Portuguese, Ashkenazi Jewish, and North African Arab PD populations, respectively.

These frequency estimates suggest that the G2019S LRRK2 mutation underlies approximately 10,000 to 20,000 current cases of PD in North America. The characterization of a risk allele, G2385R, by the LNG and others in Asian populations suggests that this risk variant is contributing to 10 percent of all Asian cases of PD. The number of patients with disease driven by a readily identifiable LRRK2 mutation presents unique opportunities to understand the early stages of PD. The aim of current work is to define early (preclinical), accessible markers of disease onset and to gather a cohort for future testing of preventive therapies.

Normal Genetic Variability. Genomewide association studies (GWAS) represent the first wave of reliable and accurate genome-scale technologies. The initial application of this approach to disease has revealed susceptibility loci for several disorders. The LNG has performed a series of pilot experiments to generate publicly available GWAS data for PD, stroke, AD, and ALS. There is a clear need to understand the breadth of normal variation in the human genome and the downstream effects of this variation. The LNG has taken two primary research approaches to address these issues. The first involves genomewide single nucleotide polymorphism (SNP) genotyping in diverse human populations, taken from the Human Genome Diversity Cell Line Panel. The LNG has not only showed the utility of these data for population genetics and as a reference for the extent of normal human genomic variability but also has generated a publicly available resource of genotypes. The second series of experiments involves analysis of the genetic control of expression in the human brain. A first series of experiments coordinating approximately 500,000 SNP loci with the levels of approximately 10,000 transcripts in the human cortex has already been published. However, this work is being extended to other brain regions and to include microRNA expression levels, CpG methylation at more than 20,000 sites, and a survey of histone modifications. These data will serve as a reference to understand the effects of common genetic variability on gene expression, including loci implicated as risk factors for neurological disorders, and also will allow the creation of genomic control networks.

Dr. Greengard asked why mutations in AD but not PD have been modeled with some success in animals. Dr. Singleton suspects this is related to expression of the transgene. He said there is a new driver that seems to work particularly well in dopaminergic neurons.

Dr. Jazwinski asked whether the “in press” study on global genetic diversity was carried out using resequencing. Dr. Singleton responded that the study was done with genomewide SNP arrays, analyzing 550,000 SNPs. Dr. Jazwinski suggested that it would be valuable to examine this variation using resequencing. Dr. Singleton agreed and said methodologies to be released in the next 4 or 5 months will allow isolation out of the axons in the human genome. He also agreed with Dr. Jazwinski’s suggestion that it would be valuable to have a more representative number of genomes sequenced from populations even in the United States. He added that axons are probably only a fraction of the story. For complex diseases, the promoters and the 3’ untranslated regions are probably equally or more important.

B. Laboratory of Neurosciences

Dr. Mark Mattson, Chief of the Laboratory of Neurosciences (LNS), described current and ongoing research of the LNS. The presentation was focused on mechanisms for preserving and enhancing neural plasticity to fend off age-related disease, particularly AD.

Many of the same cellular signaling mechanisms that orchestrate the development of neuronal circuits during development of the nervous system are also critical for the maintenance and adaptive plasticity of those circuits in the adult. The LNS research program seeks to elucidate the cellular and molecular mechanisms that regulate the production (neurogenesis), survival, and structural plasticity of neurons in the context of brain aging and neurodegenerative disorders such as AD. The LNS has identified several particularly important neuroplasticity signaling pathways and has revealed how the aging process (oxidative stress and perturbed ion homeostasis and energy metabolism, for example) interacts with disease-specific abnormalities to cause the dysfunction and degeneration of synapses and the death of neurons in AD. Together with findings from other laboratories, LNS studies of neuroplasticity and animal models of AD have identified three environmental factors that protect the brain against aging and AD pathogenesis: Exercise, dietary energy restriction, and cognitive stimulation. These environmental factors are thought to protect neurons by imposing a mild and transient stress on neurons, which results in the activation of adaptive stress response pathways. This adaptive stress response mechanism, which the LNS has dubbed “neurohormesis,” involves the induction of genes that encode proteins that promote neuronal survival, neurogenesis, and synaptic plasticity.

Because of the hippocampus’s fundamental role in learning and memory, its content of stem cells, and its involvement in AD, the LNS has studied the molecular changes that occur in this region of the brain during normal aging and in AD. In a large-scale analysis of gene expression in different regions of the nervous system and all major organs (the NIA Atlas of Gene Expression in Mouse Aging Project, or AGEMAP), the LNS discovered that many more genes are responsive to aging, dietary energy intake, and gender in the hippocampus compared to other brain regions. Reductions in energy intake by controlled caloric restriction (CR) or intermittent fasting (IF) counteracted age-related molecular alterations in the hippocampus of normal mice and ameliorated learning and memory deficits in a mouse model of AD. Interestingly, CR attenuated the amyloid and tau (neurofibrillary tangle) pathology in the AD mice, whereas IF did not. This suggests that CR suppresses the disease process at an early stage, whereas IF protects neurons despite the presence of amyloid beta-peptide. LNS investigators believe that brain-derived neurotrophic factor (BDNF) mediates the beneficial effects of dietary energy restriction, exercise, and cognitive stimulation on the hippocampus. Because other laboratories have demonstrated that commonly prescribed antidepressants stimulate the production of BDNF, the LNS tested the potential benefit of one such antidepressant, paroxetine, in a mouse AD model. Paroxetine ameliorated cognitive deficits and lessened amyloid and tau pathology in the mice.

In very recent studies (Nature Neuroscience in press, and others), the LNS has investigated the effects of diabetes alone, or in combination with exercise and CR, on hippocampal neuroplasticity. In both insulin-deficient rats and insulin-resistant mice, diabetes impairs hippocampus-dependent memory, perforant path synaptic plasticity, and adult neurogenesis, and the adrenal steroid stress corticosterone contributes to these adverse effects. Rats treated with streptozocin have reduced levels of insulin and exhibit hyperglycemia; increased levels of corticosterone; and impairments in hippocampal neurogenesis, synaptic plasticity, and learning. Similar deficits are observed in db/db mice, which are characterized by insulin resistance, elevated corticosterone levels, and obesity. Changes in hippocampal plasticity and function in both models are reversed when normal physiological levels of corticosterone are maintained, suggesting that cognitive impairment in diabetes may result from glucocorticoid-mediated deficits in neurogenesis and synaptic plasticity. Both CR and exercise counteracted the adverse effects of diabetes on hippocampal plasticity, with CR being more effective than exercise.

More recently, the LNS has collaborated with colleagues in the NIA Diabetes Branch to test the therapeutic potential of the diabetes drug exendin-4 (Byetta) in mouse models of neurodegenerative disorders. Exendin-4 is a stable analog of glucagon-like peptide 1 (GLP-1), which improves glucose regulation by increasing insulin production and cellular insulin sensitivity and by reducing appetite. Previous work at the LNS demonstrated that receptors for GLP-1 are widely expressed in neurons throughout the brain and that GLP-1 protects neurons against oxidative, metabolic, and excitotoxic insults in cell culture and animal models. The LNS has found that exendin-4 treatment slows disease onset and progression and attenuates neuronal dysfunction and degeneration in animal models of Huntington’s disease (HD) and AD. Because exendin-4 has been approved by the FDA for the treatment of diabetes, the LNS is beginning to seek clinical investigators and funding sources for clinical trials in AD and HD patients.

Dr. Mattson presented a final example of the translational research program in the LNS: The “neurohormetic phytochemical” project. Diets rich in vegetables and fruits are associated with reduced risk of several major diseases, including neurodegenerative disorders. Although some beneficial phytochemicals may function solely as antioxidants, LNS investigators and others suspect that many of the beneficial chemicals in vegetables and fruits evolved as toxins (to dissuade insects and other predators) that, at subtoxic doses, activate adaptive cellular stress response pathways in a variety of cells including neurons. In these ways, neurohormetic phytochemicals such as resveratrol, sulforaphanes, and curcumin may protect neurons against injury and disease by stimulating the production of antioxidant enzymes, neurotrophic factors, protein chaperones, and other proteins that help cells withstand stress. To identify novel neurohormetic phytochemicals and move them toward human studies, the LNS is screening candidate phytochemicals for their ability to activate adaptive stress response pathways and protect neurons in cell culture and animal models.

Dr. Mattson closed his presentation by saying that the LNS is identifying novel preventive and therapeutic approaches for AD and other neurological disorders by elucidating the cellular and molecular mechanisms that regulate adaptive neuronal plasticity and promote cell survival and by determining how these mechanisms can be enhanced to counteract aging and disease processes. Further, through collaborations with clinical investigators, the LNS aims to directly test the efficacy of the most promising interventions in human subjects.

In response to a question by Dr. Greengard, Dr. Mattson stated that he did not consider LNS research described here to be “the death of the beta-amyloid hypothesis.” He explained that the LNS has shown that IF is more effective than controlled CR in increasing neurotrophic factor expression. In this model, there is a strong correlation between increased Aβ levels and synaptic dysfunction and cognitive dysfunction. Therefore, one explanation is that IF is protecting the synapses against the adverse effects of Aβ peptide by acting downstream of that peptide.

Dr. Jazwinski described a study in which transient sublethal stress was found to extend lifespan in yeast. Importantly, the yeast was not only able to mount a stress response but also to downregulate it effectively. However, with age, downregulation was a problem. Dr. Jazwinski asked whether any LNS studies in neural systems address this. In response, Dr. Mattson described a recent LNS study of stroke in young, middle-aged, and old animals that had been maintained on IF or controlled diet. The LNS found that, in old animals, IF was not effective in protecting neurons.

IX. 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 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).

X. ADJOURNMENT

The 103rd meeting of the NACA was adjourned at 2:45 p.m. on January 30, 2008. The next meeting is scheduled for May 20 and 21, 2008.

XI. 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 May 20 and 21, 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