Council Minutes - January 2007

The 100th Meeting
January 30–31, 2007

CONTENTS

1. REVIEW OF APPLICATIONS
2. CALL TO ORDER
   
3. REPORT: Task Force on Minority Aging Research
   
4. REPORT: Working Group on Program
   
5. REPORT: Geriatrics and Clinical Gerontology Program Review
   
6. PROGRAM HIGHLIGHTS
   
7. INTRAMURAL RESEARCH PROGRAM REPORTS
   
8. REVIEW OF INTRAMURAL RESEARCH PROGRAM
   
9. ADJOURNMENT
   
10. CERTIFICATION

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

The 100th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, January 30, 2007, at 3 p.m. in Building 31, Conference Room 6, National Institutes of Health (NIH), Bethesda, MD. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA), presided.

In accordance with the provisions of Public Law 92–463, the meeting was closed to the public on Tuesday, January 30, from 3 p.m. to 5 p.m. for the review, discussion, and evaluation of grant applications in accordance with the provisions set forth in Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code and Section 10(d) of Public Law 92–463.1 The meeting was open to the public on Wednesday, January 31, from 8 a.m. to 1:30 p.m.

Council Participants:
Dr. John T. Cacioppo
Dr. Peggye Dilworth-Anderson
Dr. Carl Eisdorfer
Dr. Lawrence M. Friedman
Dr. Mary Ganguli
Dr. Alan M. Garber
Dr. Paul Greengard
Dr. S. Michal Jazwinski
Dr. Sundeep Khosla
Dr. Virginia M.-Y. Lee
Dr. Terry L. Mills
Dr. John C. Morris
Dr. Gary B. Ruvkun
Dr. Gerald P. Schatten
Dr. Albert L. Siu
Dr. Mary E. Tinetti

Absent:
Dr. Kenneth V. Brummel-Smith
Ms. Orien Reid

Ex Officio Participants:
Dr. James F. Burris, Department of Veterans Affairs
Dr. Kenneth Pugh, National Naval Medical Center
Mr. Don Grantt, 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. Francois Boller, Center for Scientific Review, NIH
Ms. Janet Gregory, National Institute of Diabetes and Digestive and Kidney Diseases
Dr. Elisabeth Koss, Center for Scientific Review, NIH
Dr. Nancy Miller, Office of the Director, NIH

Members of the Public Present:
Ms. Loretta Doan, The Endocrine Society
Ms. Christy Gilmour, American Academy of Orthopaedic Surgeons
Ms. Mary Jo Hoeksema, Population Association of America/Association of Population Centers
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Dr. Patricia Kobor, American Psychological Association
Dr. Rose Maria Li, Rose Li and Associates, Inc.
Dr. Katherine Newton, Group Health Center for Health Studies
Dr. George Rebok, Johns Hopkins University
Ms. Michelle Rodrigues, SRI International
Dr. David A. Sinclair, Harvard Medical School

I. REVIEW OF APPLICATIONS

This portion of the meeting was closed to the public, in accordance with the determination that it concerned matters exempt from mandatory disclosure under Sections 552(b)(c)(4) and 552b(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix).2

A total of 957 applications requesting $1,084,049,815 for all years underwent initial review. The Council recommended 479 awards for a total of $681,932,657 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.

II. CALL TO ORDER

Dr. Hodes welcomed members to the open session of the 100th NACA meeting and called the meeting to order at 8:07 a.m. on Wednesday, January 31, 2007.

A. Director’s Status Report

Dr. Hodes reported that the NIH Reform Act of 2006 (Public Law 109-482) was passed by Congress on December 8 and signed into law by the President on January 15, 2007. The Act affirms the vital role of the NIH in advancing biomedical research to improve the health of the Nation and is only the third omnibus reauthorization in the NIH’s history and the first in 14 years.

Specifically, the NIH Reform Act of 2006:

• Establishes the Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI) within the Office of the Director. Dr. Hodes noted that the Act recognizes the NIH Director’s Common Fund. It provides no formula for growth of the Common Fund but requires a review when the Common Fund reaches 5 percent of the NIH budget. In addition, the Act establishes the Council of Councils to advise on research to be funded by the Common Fund and oversee general aspects of planning. The research is expected to be conducted through lead Institutes and Centers (ICs). Thus, specific initiatives supported by the Common Fund would likely require approval by advisory councils to individual ICs.
• Establishes a Scientific Management Review Board to conduct periodic organizational reviews of NIH and to make recommendations on the use of NIH organizational authorities. Dr. Hodes noted that this aspect of the Reform Act involves a large degree of interpretation.
• Authorizes, but does not appropriate, an increase in NIH funding for each of the next 3 years. Dr. Hodes acknowledged previous concerns that this language might indicate a funding “ceiling”; however, in light of the current funding climate and uncertainties about future increases, this language was received warmly.
• Requires a public process for reorganizing NIH programs. Dr. Hodes reminded NACA members that the perceived proliferation of ICs was one impetus for reauthorization.
• Eliminates many reporting requirements or includes them in the new biennial report.

Implementation of the legislation is in progress and is overseen by an ad hoc working group chaired by Dr. Raynard S. Kington, NIH Deputy Director. This working group is charged with completing a careful, detailed analysis of the legislation and proposing plans for its implementation that will aid the NIH in serving the public and the scientific community more effectively. Working group membership includes IC Directors and senior leaders in legislation, policy, management, communications, extramural and intramural activities, budget, and general counsel.

Dr. Hodes then turned to the NIA budget for fiscal year (FY) 2006. The total funding level was $1.036 billion, distributed as follows: 67 percent toward research project grants (RPGs), 8 percent toward centers, 3 percent toward other research, 2 percent toward training, 6 percent toward contracts, 10 percent toward intramural research, and 4 percent toward research management and services. In terms of inflation-adjusted dollars, the budget peaked in 2003 with a steady decline since then, which has compromised the ability of the NIA to support research. The major effect of this decline is a steady decrease in the proportion of applications reviewed that is actually awarded, from 28.6 percent in FY 2003 to 17.4 percent in FY 2006.

At present, the NIH is operating under a continuing resolution at the level of the 2006 appropriation through February 15, 2007. Until a final budget is enacted, the NIH will issue noncompeting research grant awards at a level below that indicated on the most recent Notice of Grant Award (generally up to 80 percent of the previously committed level). A final budget is expected before February 15.

Despite the current budget constraints, the NIH remains committed to buttressing core areas of vulnerability, including maintaining the ability of first-time investigators to compete for support and sustained investment in outstanding established investigators with little or no other significant support. Dr. Hodes stated that R01 applications from new investigators will be considered among NIA’s highest priorities in the use of discretionary funds, and such applications within five percentage points of the payline might be funded out of strict percentile order.

The NIH also is adjusting the number of competing RPG awards, with the goal of stabilizing the yearly variation in the number of awards made. Noncompeting awards will receive no inflationary increase in FY 2007, but Institutes will maintain flexibility to supplement such awards on a case-by-case basis. Such increases will not be considered as part of the base for future budgetary adjustments. Institutes will manage their portfolios by using uncommitted funds and savings from not funding inflationary increases.

Dr. Hodes concluded his report by noting that the House Appropriations Subcommittee has proposed an NIH budget increase of more than $600 million and, further, that the Common Fund become a direct appropriation to the NIH Office of the Director. This proposal could result in an increase in funds available to ICs in FY2007.

In response to questions from Council, Dr. Hodes noted that like other reauthorizations, this authorization will sunset in 3 years and that the general operation of the NIH will not be in jeopardy. He also invited comments from Council regarding the policy to fund applications from new investigators that fall within 5 percentage points of the payline. Although no special action would be needed to maintain this policy, there could be cases when applications beyond the payline would lead the NIA to seek discussion with NACA. Council members noted that this is an appropriate action and further requested that cases where the “5 percentage point rule” has been invoked be highlighted at Council meetings.

One Council member asked whether there should be a moratorium on Method to Extend Research in Time (MERIT) Awards given the severity of the budget situation. Dr. Hodes responded that the NIA has paid careful attention to MERIT Awards in times of stringent funding climates and that these awards have not been allowed to grow unchecked. He suggested that the NIA could provide statistics on active MERIT Awards at the May 2007 Council meeting.

In response to questions about the impact of the current budget situation on large grants, Dr. Hodes noted potential problems with adhering strictly to formulas and the importance of avoiding unintended consequences. He emphasized the need for flexibility across all of NIH and the ability for ICs to seek exceptions.

B. Future Meeting Dates

May 15–16, 2007 (Tuesday and Wednesday)
September 25–26, 2007 (Tuesday and Wednesday)
January 29–30, 2008 (Tuesday and Wednesday)
May 20–21, 2008 (Tuesday and Wednesday)
September 24–25, 2008 (Wednesday and Thursday)

C. Consideration of the Minutes of the Last Meeting

The minutes of the September 2006 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.

III. REPORT: Task Force on Minority Aging Research

Dr. Terry Mills began by acknowledging the past two Chairs, Dr. Spero Manson and Dr. Marie Bernard, for their contributions to the Task Force. He then reminded the 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. The NIH Office of Research on Women’s Health (ORWH) prepares an annual report, which includes a statement by NACA certifying that the Council has reviewed NIA procedures for implementation of the NIH inclusion policy, reviewed the results of that implementation, and determined compliance with the guidelines for inclusion.

Dr. Mills reported that the Task Force reviewed summary data prepared by Dr. Carlos Caban and staff in the Office of Extramural Research. He noted one concern regarding differences in the way racial/ethnic data have been gathered over the years. The old data form, which was implemented in 1977, listed typical racial/ethnic groups. The new form, however, separates Latino/Hispanic into a separate ethnic category and allows individuals to claim more than one race. Thus, the racial classifications for Latino/Hispanic persons must be reconciled between the two forms, and it is not clear what the enrollment numbers reflect when individuals select the “more than one race” category.

NIH-wide minority enrollment in all clinical studies was 39.7 percent in 2006. Minorities comprised 27.4 percent of domestic enrollment and 90.9 percent of foreign enrollment. Thus, a small number of foreign protocols accounted for a significant proportion of minority enrollment in clinical trials. Although the number of minorities enrolling in clinical trials appears to have increased substantially since 1995, the actual percentage of minority participants, relative to total enrollment, has increased only by a little more than 1 percent. Dr. Mills pointed out the need for persistent efforts to engage more minorities in clinical research.

NIA-specific minority enrollment has decreased slightly since 2005. Dr. Mills noted a substantial proportion of minority enrollment in a small set of studies, which can result in a perceived surge one year and a decline the following year.

Dr. Mills reminded Council of discussions regarding an express award submitted by Dr. Taylor Harden to conduct a more comprehensive study of enrollment patterns. He reported that this award is moving forward, and he reminded Task Force members to provide any comments to Dr. Harden by February 10.

Dr. Mills also reminded Council members that NACA has been asked to provide input on the NIA Strategic Plan, particularly on items addressing health disparities. At present, the Strategic Plan articulates NIA efforts to address health disparities, with the following goals:

• Understand health differences and health inequities associated with race, ethnicity, gender, environment, socioeconomic status, geography, and sociocultural factors among older adults.
• Develop strategies to promote active life expectancy and improve the health status of older adults in minority and other underserved populations.
• Use research insights and advances to inform policy on the health, economic status, and quality of life of all older adults.

Integrating these efforts into the overall Strategic Plan has been suggested. Dr. Mills asked the Council to support the current direction, in which health disparities stand alone as a distinct concern.

Dr. Mills closed his presentation by reporting that the NIA, in collaboration with the Fogarty International Center, is sponsoring two international researchers to participate in the Summer Institute on Aging Research, which will take place July 14–20, 2007, at the Aspen Wye River Conference Facility in Queenstown, Maryland. Dr. Harden added that this effort had been led by Dr. Tamara Jones, who will serve as the contact for issues concerning international scientists.

Dr. Alan Garber asked if it is possible to determine whether studies enrolling minorities are meeting their goals of adequate statistical power. Dr. Robin Barr responded that this policy applies specifically to Phase III trials and that the NIA has one such trial enrolling at present. He added that the question of adequate statistical power has been given fair scrutiny NIH-wide and that ICs have received guidance for ensuring it. Dr. Mills noted that during the closed session, some members had questioned to what extent investigators might be informed about the demographics of their area when they made estimates. He pointed out that this question will be addressed by the express award, should it go forward.

Dr. Barr requested approval of the NIA report on population tracking and inclusion for FY 2006. This report separates data into that collected on the old form and that collected on the new form and it separates Phase III trials from most clinical research. In this report, the NIA has provided some explanation for the drop in minority enrollment between 2005 and 2006: primarily, one large study ended during this time. A motion was made, seconded, and passed to approve the 2006 NIA report on population tracking and inclusion.

IV. REPORT: Working Group on Program

Dr. John Morris reported that the closed session on Tuesday, January 30, included a report from the Geriatrics and Clinical Gerontology Program. He also reported that the next Council review of the Neuroscience and Neuropsychology of Aging Program will be delayed until May 2008. This delay will allow the capture of initiatives and decisions from the recent summit on Alzheimer’s disease in addition to those from a summit on cognitive aging planned for the fall.

A. Advisory Meetings

A workshop on animal models for comorbidities has been proposed. This workshop, planned by the Biology of Aging, Geriatrics and Clinical Gerontology, and Neuroscience and Neuropsychology of Aging Programs, will take place in the late spring or early summer and is intended to explore the role of aging in comorbidities and the role of one condition in the development of another. A motion was made, seconded, and passed to approve this workshop.

B. RFA Concept Clearances

Dr. Morris presented a proposal from Drs. Felipe Sierra and Bradley Wise for a request for applications (RFA) on protein homeostasis and aging. Projects supported through this RFA would explore the interconnections among protein misfolding, degradation, and repair and would examine how protein homeostasis drives and is affected by aging. An allocation of $1.5 million has been approved for this RFA, which would promote collaborative efforts through the R21 exploratory/developmental award mechanism. The RFA would be announced in the NIH Guide in May 2007 and the receipt date for applications is planned for August 2007. A motion was made, seconded, and passed to approve this RFA concept.

Dr. Morris also reported on a proposal by Drs. John Phillips and Richard Suzman to develop harmonized instruments to support longitudinal cross-national research. A program announcement would support up to four or five R21 awards for the developmental stages in harmonization. A motion was made, seconded, and passed to approve this program announcement.

The Friends of the NIA has requested a liaison from NACA to their organization. Dr. Morris reported that the Working Group agreed to support this proposal but had requested a description of what was expected of a liaison. This issue will be reexamined at the May 2007 NACA meeting.

Dr. Morris also reported discussions with Ms. Kathie Reed of how the Council can be involved in the development of a new strategic plan for NIA. The Council should review the current Strategic Plan to identify important areas that are missing.

The Working Group on Program has reviewed a report provided by Dr. Barr containing NIA grants activity statistical data. This report provides an overview of what has happened during the past year, by grant mechanism and by program. Dr. Barr added that the Working Group also received the current statistical package, which includes the applications reviewed at this NACA meeting, and that the Council now has four rounds of data. He pointed out that a recent 2-year surge in NIA applications has peaked.

Dr. Gerald Schatten raised questions about previously active, mid-career scientists who might be difficult to track because they have received grants from multiple sources. Dr. Hodes responded that the NIH is attempting to gather these data but that a final assessment has not been completed. He suggested that the NIA could find out what information is available by the May or September NACA meeting.

Dr. Mary Ganguli reminded Council members of previous discussions about pipeline issues and noted the increasing difficulty in encouraging younger people to pursue research careers. In response, Dr. Morris discussed a task force on physician-investigators and its mandate to examine what has been done to increase the number of those investigators, particularly new investigators. He added that questions have been raised regarding the need to expand beyond the initial scope of this task force.

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. Morris reported that the recently passed NIH Reform Act will require some revision to the Statement of Understanding. However, some language in the Act is confusing, and further guidance and clarification is needed. The NIA is proposing no changes at this meeting until further interpretive guidance is received concerning the legislation. A motion was made, seconded, and passed unanimously to reapprove the current Statement of Understanding.

V. REPORT: Geriatrics and Clinical Gerontology Program Review

Dr. Albert Siu noted that the Geriatrics and Clinical Gerontology Program covers a wide range of topics, including those that belong solely to the Program and those that are shared with other programs and Institutes. Because it covers such a broad area, the Geriatrics and Clinical Gerontology Program must balance its activities with its ability to leverage resources from other Institutes. In terms of its specific program goals, reviewers identified the following accomplishments:

• Meaningful progress toward the identification of risk factors and interventions related to geriatric syndromes.
• Appropriate balance in focus and effort on diseases of old age.
• Leadership in examining interactions among various comorbid conditions. The Program is encouraged to expand its leadership role because of the centrality of this issue.
• Highly successful catalyst role in supporting research on changes across the lifespan that influence age-related diseases. Reviewers did, however, debate the appropriateness of long-term epidemiological studies in light of the cost and the state of the science.
• Appropriate emphasis and support on identifying protective factors in exceptional aging.

Overall, Dr. Siu reported that reviewers considered the Program to be headed in the right direction and to have achieved a good balance and made significant progress. Nevertheless, Program staff members were encouraged to increase collaboration with other NIA programs and with other ICs. In addition, the staff members were advised to restrain efforts on initiatives that might be better addressed by other programs or ICs. Dr. Siu added that Program staff had no major disagreements with the recommendations from this review.

VI. PROGRAM HIGHLIGHTS

A. Neuroscience and Neuropsychology of Aging: Lost in Translation: Risk, Epidemiology, and Alzheimer’s Disease

Dr. Mary Ganguli (University of Pittsburgh) discussed the importance of epidemiology in Alzheimer’s research and summarized recent findings. She contended that with increasing emphasis on interdisciplinary collaboration and translation in research, the key concept of risk in epidemiology is becoming “lost in translation.” A clearer understanding of this concept may enhance the translation of epidemiologic findings into basic and interventional research and also the development of a continuous loop of information flow among the various research disciplines.

Dr. Ganguli reviewed Morris’s (1957) list of seven classic uses of epidemiology and focused on two: Completing the clinical picture of disease and community diagnosis. To illustrate the first, Dr. Ganguli pointed to the original case study published by Alois Alzheimer in 1907 of pre-senile dementia characterized by cognitive and behavioral features, in addition to pathological features such as atrophy, plaques, and tangles in the brain. Most striking was the relative youth of the patient, and Alzheimer assumed the disease to be a rare, unusual disease of the middle-aged—an assumption that was to hold for the next half century. In 1964, however, Martin Roth and colleagues conducted a community survey and found senile dementia to be a fairly common disease among the elderly. Thus, epidemiological study by Roth and colleagues completed the clinical picture first described by Alzheimer.

Community diagnosis, which focuses on the occurrence of a disease in the population, is the most familiar use of epidemiology. This aspect of epidemiology focuses on prevalence, the proportion of people affected, and incidence, the rate at which new disease occurs among people who do not have it. Prevalence provides a cross-sectional snapshot of disease burden at a given time, but unlike incidence, it is not an indication of risk. All prevalence studies show that the prevalence of dementia increases dramatically with age, and many but not all studies in developed (industrialized) countries also show higher prevalence of dementia among women. Incidence studies, including NIA-sponsored research by Dr. Ganguli in Monongahela Valley of southwestern Pennsylvania (Neurology 2000;54:1109–1116), show that the incidence rate of dementia increases with age. Up to age 90 years and older, incidence does not differ by sex.

Dr. Ganguli pointed out, however, that because the precision of estimates depends on sample size, estimates of incidence are not as precise in the highest age group as they are in younger groups.

Prevalence is a product of incidence and duration, and in Alzheimer’s disease, duration is equal to survival. Thus, the increase in prevalence with age can result from higher incidence, longer survival, or both. Incidence could be the same between women and men, but prevalence could be higher because of longer survival in women. Data from a study conducted in Cache County, Utah (JAMA 2002;288:2123–2129), revealed similar incidence rates between men and women until the age of 85 to 90 years with higher rates in women beyond that age.

Although longer survival among women might account in part for the increased prevalence of Alzheimer’s disease, mortality is increased among patients with Alzheimer’s disease compared with individuals without dementia, as shown by data in the Monongahela Valley study. This is true for all age groups, although the ratio of mortality rates between those with and without Alzheimer’s disease decreases with age. In younger groups, the mortality among patients with Alzheimer’s patients is three times that without, but in older groups that ratio decreases to twofold. Dr. Ganguli pointed out that the ratio decreases because age itself becomes a competing risk factor for mortality. She also noted that the ratio is statistically significant in women; in men, mortality rates at older ages are so high that the presence of Alzheimer’s disease does not make a difference.

Identification of risk is another classic use of epidemiology. If two groups have different incidence rates for disease, the group with the higher incidence rate is by definition at higher risk for the disease. However, the risk factor apparent in an observational study is merely a signal. The discovery of a risk factor does not mean that investigators have found a cause; instead, it gives investigators a place to look further and helps them to generate hypotheses. A risk factor could represent several different mechanisms: It could be the true cause of a condition, could serve as a mediator, or could be a confounder. In addition, the level of risk could be a function of other phenomena, including the duration of exposure, the timing of exposure, and cohort effects. Dr. Ganguli illustrated these points using several potential risk factors for Alzheimer’s disease that have been identified, including ApoE*4 genotype, vascular factors such as blood pressure and cholesterol, estrogen exposure, and nonsteroidal anti-inflammatory drugs (NSAIDs).

The protective effect of alcohol use against cognitive decline (Neurology 2005;65:1210-1217) is another example of the role of duration and timing in the association between a risk factor and a condition. Compared with nondrinkers, minimal and moderate drinkers exhibited less decline on several tests. Differences were more pronounced when current drinkers were compared with quitters than they were when current drinkers were compared with lifelong abstainers.

Dr. Ganguli concluded her presentation by noting that when different approaches, including laboratory, clinical, and epidemiologic studies, converge on a consistent finding, confidence in that finding is high. When different approaches yield differing results, however, investigators must dig deeper to find the reason for those differences rather than dismiss one group of data. The above factors are not the only risk or protective factors reported from epidemiologic studies of Alzheimer’s disease, but they serve as examples of the complexities and interrelatedness of factors that are not always obvious to casual observers. Collaborative, interdisciplinary studies offer the best hope for disentangling the web of causation.

Dr. Hodes noted the importance of communicating with the public as risk factors are identified and studied in clinical trials. He asked how the scientific community could most responsibly discuss the level of uncertainty and the quality of the evidence with the public. Dr. Ganguli noted that the public tends to look for the “breakthrough of the day” and that it is therefore more important to educate physicians and other care providers, who must answer patients’ questions about what they have heard. She also noted the importance and challenges of developing a relationship with the media.

In response to questions about the quality of data on the incidence of Alzheimer’s disease in other countries, Dr. Ganguli pointed out that Canada, the United Kingdom, Australia, and Scandinavian countries have universal health care and single-payer programs. As a result, these countries are able to carry out long-term prospective studies on representative cohorts because they can recruit individuals from national registries and general practice lists and because the populations are more trusting of researchers and their government. Although the bulk of work on Alzheimer’s disease has been done in North America, Dr. Ganguli remarked that the most rapid aging—and thus the largest number of Alzheimer’s disease cases—is occurring in China, India, and developing countries; some data from these countries are now available.

Dr. Sundeep Khosla mentioned estrogen use and noted parallels with effects on cardiovascular disease. He asked whether investigators studying cardiovascular disease had explored timing and duration of exposure to risk factors and whether these components might affect disparities between observational studies, which showed a protective effect, and intervention studies, which showed no effect. Dr. Ganguli pointed out that trials starting when women reach menopause and following them indefinitely would help to distinguish various effects. She further noted the need for an ingenious combination of trials.

One NIA staff member noted that clinical trials have been held up as a gold standard for communicating findings to the public, but as Dr. Ganguli pointed out, epidemiological studies complete the clinical picture; for example, by showing that treatment must start more than 10 years ahead of time before a positive effect becomes apparent. However, the types of clinical trials that should be done to test epidemiological hypotheses remains a subject of debate, as does the standard to determine when clinical trials are not possible but that enough epidemiological evidence exists to communicate with the public. Dr. Hodes mentioned the possibility of examining surrogate outcomes such as cognitive decline. Dr. Ganguli observed that though these questions remain unresolved they point to the importance of cross-talk among clinicians, epidemiologists, and basic scientists.

B. Geriatrics and Clinical Gerontology: Herbal Alternatives for Menopause Study

Dr. Katherine Newton (Group Health Center for Health Studies and University of Washington) discussed main findings from a randomized, double-blind, placebo-controlled trial testing herbal interventions against menopause symptoms. This trial enrolled 351 peri-postmenopausal women who experienced at least two vasomotor symptoms per day, were age 45 to 55 years in age, had no contraindications to hormone therapy, and had not taken hormone therapy for 3 months or herbal alternatives for 1 month. These women were randomized to receive black cohosh alone, a multibotanical with black cohosh, a multibotanical with soy, hormonal therapy, or placebo.

Dr. Newton pointed out that results from the Women’s Health Initiative (WHI) were released while recruitment was taking place for the herbal alternatives study. Women randomized to the hormone therapy group were unblinded and given a choice to continue in this group or be re-randomized to the herbal or placebo groups. As a result, the number of participants in the hormone therapy group was smaller.

Outcomes were measured at baseline and at 3, 6, and 12 months. Vasomotor symptoms were measured through daily, real-time symptom diaries, where participants recorded symptom frequency and intensity, and through the Wiklund Menopause Symptom Checklist and Vasomotor Symptom Subscale, which provided global measures of menopause symptoms.

Dr. Newton noted that most studies assessing the efficacy of herbal therapies on menopause symptoms use only these checklists and not the real-time symptom diaries. Another strength of the study was the testing of herbal products and approaches commonly used by the naturopathic community in the Pacific Northwest. In addition, herbal quality assurance was independently tested by an outside laboratory. Dr. Newton reported that 12-month retention was good and that drug compliance was high throughout the study. In the multibotanicals with soy group, compliance with the soy diet was high as assessed by a soy food questionnaire and serum measurements.

The mean age among all study groups was 52 years, and mean body mass index (BMI) was between 27 and 28, although women in the hormone therapy and placebo groups tended to be somewhat heavier. Most study participants were White and had more than a high school education. About 40 percent of study participants experienced 7 or more hot flashes per day, about 10 percent had undergone a hysterectomy, and about 40 percent had taken hormone therapy before. Adjusted models were controlled for age, BMI, hysterectomy, menopausal status, and previous hormone therapy.

As reported through the daily symptom diaries, there were no significant differences in vasomotor symptom frequency between herbal approaches and placebo, but as expected, hormone therapy improved these symptoms. The same was true for daytime hot flashes and night sweats. Likewise, none of the herbal approaches improved the self-reported intensity of vasomotor symptoms, while hormone therapy did improve intensity as expected. These results were the same when measured by the Wiklund Menopause Scale and Vasomotor Symptom Subscale. Findings did not differ by menopause status, the number of vasomotor symptoms per day, four- versus five-arm randomization, BMI, or history of hysterectomy. There also were no significant differences with herbal interventions when other outcome measures were assessed. Dr. Newton noted that the duration of the study was too short for investigators to observe severe adverse events. The only adverse events that were observed were menstrual disorders experienced by participants in the hormone therapy group. The study was unable to fully emulate naturopathic practice, and it did not test Remifemin, the most commonly studied black cohosh product.

On the basis of study results, the study team concluded that black cohosh, multibotanicals with black cohosh, or multibotanicals with soy had no impact on vasomotor symptom frequency or intensity, bone mineral density, endometrial safety, or laboratory results. Thus, these products show little potential for playing an important role in relieving vasomotor symptoms.

Dr. Virginia Lee asked whether there are any data on menopausal symptoms for women who consume soy their entire lives. Dr. Newton was not aware of any studies that used soy as an intervention, but she agreed that this is an interesting question because in Asian countries, where soy intake is higher, lower rates of menopausal symptoms have been reported.

Dr. Peggye Dilworth-Anderson asked about the socioeconomic status of the study participants and whether the study included a measure of exercise. Dr. Newton responded that Seattle is a relatively upper middle class area, that most residents are well educated, and that Group Health Center for Health Studies, where the study was conducted, is representative of the community. The study team has yet to assess its measure of exercise.

Dr. Newton and her colleagues are meeting with the NIA to consider next steps. Rates of hormone therapy use plummeted after the WHI results were released, and surveys are underway to assess what is happening with women who participated in the WHI. Pharmaceutical companies are looking at other approaches, and the National Center for Complementary and Alternative Medicine is assessing the effectiveness of other herbal remedies and acupuncture.

Dr. Newton added that these types of studies have received media attention but that investigators must convey a message that vasomotor symptoms usually resolve on their own. Future studies should further assess women who continue to experience these symptoms, as well as those who never experience vasomotor symptoms at all.

Dr. Khosla noted challenges with the public perception of science. He also pointed out that under research conditions, large doses are usually needed for a biologic effect to be observed, but tissue specificity must be considered. Dr. Khosla questioned why selective estrogen receptor modulators had not been employed, but he also acknowledged that many women prefer natural compounds. Dr. Newton noted that the “natural is better” slogan is confusing in light of the origin of many well-known drugs. She added that central or thermoregulatory mechanisms also have not been explored. For example, some selective serotonin reuptake inhibitors are effective against hot flashes, suggesting an unidentified neurological mechanism.

In response to a question about which vascular beds are involved in vasomotor symptoms, Dr. Newton explained that cutaneous vascular beds are involved and that during a hot flash, normal thermoregulatory zones become extremely narrow, compromising the body’s ability to adjust for normal changes. She added that there are no good animal models available to explore menopausal symptoms.

C. Behavioral and Social Research: Advancing Cognitive Training for Older Adults

Dr. George Rebok (Johns Hopkins University) reviewed long-term results of the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial and their implications, summarized major themes from ACTIVE publications, and discussed next steps. Five-year results were published in a lead article in JAMA on December 20, 2006, accompanied by an editorial discussing the promise of behavior-based interventions. The report on the 5-year results enjoyed extensive media coverage, including from National Public Radio, the New York Times, and the Washington Post.

The study design for the ACTIVE trial was prespecified by the NIA and the National Institute of Nursing Research in RFA-AG-096-001. This RFA included three major emphases: Common, multisite intervention protocols; a focus on everyday independence and the cognitive components of functional competence as primary outcome measures; and interventions at the level of basic cognitive abilities rather than directly at the level of the primary outcome measures. The primary aim of the study was to test the efficacy of three cognitive interventions to improve or maintain the cognitively demanding activities of daily living: Memory, reasoning, and speed of processing. These three domains were chosen because all have been related to early age decline and to the ability to carry out everyday activities.

Dr. Rebok noted that the ACTIVE study differed from prior cognitive training research in several ways. It was a multisite, randomized and controlled, single-blind trial with an intent-to-treat analytical approach including all randomized participants rather than only those compliant with the intervention. The study also differed from others in that it included primary outcome measures of everyday functioning and included a more socioeconomically and racially diverse study sample.

Following a multistage recruitment and screening process, participants underwent several baseline measurements and were randomized to one of four treatment conditions. They then underwent several followup tests and a post test after their intervention. At 11 months after the immediate post tests, half of the study participants were randomized to a booster condition, which was given at half the dosage of the original intervention. Study participants then underwent two annual followups and received a second booster at 35 months after the initial training, followed by 3- and 5-year followups. The targeted population included a diverse sample of participants age 65 years or older who were living independently but at risk for loss of independence. Individuals with evidence of substantial cognitive decline or self-reported Alzheimer’s disease; with substantial functional decline or predisposing medical conditions, sensory loss, or communication difficulties; who had undergone similar cognitive training; who did not speak English; or those not likely to be accessible were excluded from the study.

The mean age among the study sample was about 74 years, with a range of 65 to 94 years. About 76 percent of study participants were female and had at least a high school diploma. Twenty-six percent of the study participants were African American, about 36 percent were married, and the mean Mini Mental State Examination (MMSE) score was 27.3. The sample was unusually heterogeneous in terms of representation by minority, low-income, and very old adults. At 5 years, 67 percent of the initial sample had remained with the study. Attrition was higher if participants were male; older; had lower MMSE, reasoning, or memory scores; less education; or more health problems at baseline.

Cognitive training activities had an immediate effect that lasted up to 5 years. Moreover, the specificity of training effects was confirmed. For all three groups (memory, reasoning, speed), effects were significant in terms of size, and they were highly target specific. All trained participants reported less difficulty with instrumental activities of daily living (IADLs) compared to the control group, but this effect was significant only for the reasoning intervention group. Training had no effect on performance-based measures of function, but booster speed training improved performance in everyday speed processing. For reasoning and speed, booster training resulted in better performance on targeted cognitive outcomes, which remained significant at 5 years. For speed training, booster training resulted in better performance on everyday speed of processing at the 5-year followup. These results reinforce findings from several large-scale community studies suggesting that involvement in a wide range of cognitively, socially, and physically engaging activities is associated with reduced risk of incident functional decline.

ACTIVE-based publications have covered several areas, including:

• Short-term and long-term evaluations of training effects and real-world transfer;
• The effects of training on quality of life;
• Predictors of training responsiveness, individual differences in training response, and applications of new methods for the study of longitudinal change;
• Cognitive status and its association with training outcomes and functional changes;
• Race and ethnicity effects on test performance, test bias, and cognitive change;
• Physical factors and morbidity as predictors of cognitive function and change;
• Measurement studies; and
• Mental health and well-being.

Dr. Rebok briefly discussed new challenges for advancing cognitive training. Specifically, are there new ways to train people so that results generalize to multiple areas of daily function? What should be the accepted transfer target(s)? What is the expected time course? What is the best way to extend cognitive training to the cognitively impaired? Can interventions be matched to individual risk profiles?

At the proposed 10-year assessment, almost 50 percent of the cohort will be age 85 years or older. This assessment would be a unique opportunity to prospectively study the long-term and lagged effects of three types of cognitive interventions on functional decline in a well-characterized cohort that, given its advancing age, would be at markedly increased risk for functional loss and dementia. Such an assessment could examine protective effects on cognitive abilities, daily functions, quality of life, safe driving, and health service use. Individual difference factors that moderate responses to intervention, such as low cognitive function, engagement, and ApoE genotype, also could be explored. No additional booster training is planned.

In addition to these next steps for the ACTIVE study, new training approaches will be examined. Such approaches include multifaceted interventions that combine skill-based training and other behavioral and nonbehavioral techniques; hybrid approaches that target cognitive and functional abilities; and high-intensity, high-exposure interventions. Dr. Rebok suggested moving beyond small-group interventions and focusing on public health, cost-effective, population-based interventions that do not require specialized trainers to administer.

In response to questions, Dr. Rebok cautioned that cost-effectiveness analyses has not been done for the ACTIVE study.

Dr. Mills asked about initial improvements in IADLs among ACTIVE participants, followed by an accelerating decline beginning in years 2–3. Dr. Rebok pointed out that the study sample had been carefully screened and excluded people who showed evidence of activities of daily living (ADL) disability. Thus, at baseline, most study participants were at the maximum level of IADL measures, and showing an effect would prove difficult until trajectories separated. Dr. Rebok added that it took 2 to 3 years to see that separation and that participants were reporting more difficulty because of increasing age. The study team wants to continue following this cohort to see whether these difficulties will increase with time. In response to additional questions from Dr. Siu, who noted that many IADLs also have a physical component, Dr. Rebok stated that the study cannot ascertain physical activity levels at various time points.

Communication with the media was raised as an issue. Dr. Rebok explained that the study team is trying to communicate with the media that brief episodes of cognitive training can have long-term effects. The team also is emphasizing that the ACTIVE trial represented a carefully sequenced, structured series of cognitive exercises. However, he agreed that the public and the media often fixate on a perceived quick fix.

Dr. Suzman expressed concern about businesses and groups claiming without empirical validation that their products help improve cognitive abilities. Dr. Rebok reminded the audience that the ACTIVE study included validated training methodologies and he called for better public education about the application of cognitive mental exercise in terms of public health benefits. He also suggested that cognitive exercise should be built into everyday living. Dr. Rebok acknowledged, however, that for broad activity-based regimens, the “active ingredient” is not clear. Therefore, future studies should determine the underlying mechanisms of successful interventions.

Dr. Lawrence Friedman noted that many ADLs rely on combinations of abilities, rather than just memory and speed, and he asked what strategies would allow one to decide upon a training combination to improve function. Dr. Rebok speculated that cross-training strategies targeting multiple abilities, combined with targeting specific everyday activities people want to improve, would be needed. In addition, researchers must examine motivation and compliance rates.

D. Biology of Aging: Genes and Small Molecules that Extend Lifespan

Dr. David Sinclair (Harvard Medical School) noted that the field of molecules that extend lifespan illustrates the value of model organisms and the importance of funding basic science research. He further pointed out that because of studies in these organisms, it has become clear that genes regulate how long organisms live, how well they respond to adversity, and how healthy they are throughout their lifespan. Researchers have looked for conservation among genes regulating processes such as temperature and calorie restriction (CR). Longevity genes may be tightly regulated and influenced by the environment, and if researchers can determine not only what these genes are but also how environmental cues can be circumvented, then they might have found ways to fight infection and inflammation and, ultimately, disease.

The study of longevity genes began with Saccharomyces cerevisiae, or baker’s yeast, in the mid-1990s. As yeast cells age, they develop toxic forms of DNA called extrachromosomal rDNA circles (ERCs). Extra copies of the yeast gene SIR2 (also known as SIRT1 in mice and humans) result in fewer ERCs and a longer lifespan. Moreover, yeast cells and flies lacking this gene do not respond to CR, which has been shown to increase lifespan in several studies. Thus, SIR2 and other members of its family, called sirtuins, might play key roles in mediating the health benefits of CR and are arguably a promising avenue for developing drugs that broadly treat diseases of aging.

Dr. Sinclair’s laboratory has conducted screens for molecules that could activate SIRT1 and found molecules produced by plants in response to stress. Feeding these molecules, called SIRT-activating compounds (STACs), to yeast, worms, and flies extended lifespan, but not without functioning copies of SIR2. STACs are tiny molecules, about the size of a typical drug or smaller. They bind to SIR2 and help it to work more efficiently. Among these molecules is resveratrol, a compound found in red wine.

In experiments done in collaboration with Dr. Rafa de Cabo of the NIA, Dr. Sinclair’s laboratory found that feeding resveratrol to mice on a high-calorie diet pushed them toward a lean physiology and increased lifespan. These mice ran faster, had healthier looking coats, and exhibited improved glucose tolerance. In addition, resveratrol appeared to boost mitochondrial number in liver and muscle. Thus, mice on high-calorie diets and resveratrol looked like mice on a standard diet. Further molecular analysis showed that many biochemical pathways affected by high fat were reversed in response to resveratrol.

Dr. Sinclair’s laboratory is now focused on generating synthetic STACs. Thus far, he and his colleagues have identified several molecules that are 1000-fold more potent than natural STACs.

In response to questions, Dr. Sinclair explained that SIR2 encodes an enzyme, more specifically a deacetylase, which removes acetyl groups from the amino acid lysine. The Sir2 enzyme also appears to regulate proteins involved in inflammation and metabolism. However, its exact function is still not known.

Council members noted that resveratrol is a phytoestrogen and recalled studies of the effects of resveratrol on MCF-7 breast cancer cells. In response to questions about possible feminizing effects, Dr. Sinclair pointed out that the doses used in the cited study were very high and speculated that effects seen in mice would not be observed at the doses humans would ingest.

In response to other questions, Dr. Sinclair noted that his laboratory is still characterizing the eventual cause of death in mice that are fed resveratrol. He speculated that the cause of death might be subtle, as they are with very old patients. He also noted that his laboratory is still working on issues of bioavailability, as most of the work on synthetic STACs thus far has been conducted in vitro or in biochemical assays. Serum levels of these STACs are not yet known.

Dr. Hodes asked about the value of high-throughput screening versus upfront mechanistic approaches. Dr. Sinclair emphasized that his laboratory used the approach he described because it was easier than finding a molecule and struggling to identify its target. He added, however, that both approaches should be used together. Another Council member pointed out that one advantage to screens is the use of results to conduct epistasis analyses to hone in on potential drug targets.

In response to other comments and questions, Dr. Sinclair agreed that most likely there was an endogenous ligand for resveratrol, although the identity of that ligand is not yet known. He also noted that whether resveratrol affects orexogenic or anorexogenic pathways in the brain is not known, although it appears to be protective against Alzheimer’s disease and Huntington’s disease. He further pointed out that resveratrol appears to be hydrophobic, which explains its low bioavailability, and that mice consuming resveratrol with high fat appeared better able to absorb the compound.

Several pharmaceutical companies are pursuing STACs, and several patents are in place.

VII. INTRAMURAL RESEARCH PROGRAM REPORTS

Dr. Dan Longo opened this segment of the meeting by reminding Council that the Intramural Program has a broad program examining the mechanisms underlying the health benefits of caloric restriction (CR). He also reported that the Intramural Program had a challenging year financially but was aided in part by income from a patent.

A. Laboratory of Personality and Cognition

Dr. Paul Costa, Chief of the Laboratory of Personality and Cognition (LPC), highlighted LPC’s broad research agenda which is unified by the objective to understand individual differences in psychological processes and behavioral functioning. Under that unifying theme the LPC investigators address a rich mixture of topics including personality, culture, aging, cognitive competence and decline, and disease risk. The group uses methods that range from self and observer reports of personality to measures of heart rate variability and MRI and PET scans.

Early LPC studies showed that verbal memory undergoes profound longitudinal changes, increasing through a person’s 60s, then leveling off by age 65 and starting to decline at age 70. Dr. Susan Resnick has led research on methodology that can reliably measure brain and cerebrospinal fluid over the years. In a 2003 publication in the Journal of Neuroscience, Dr. Resnick and colleagues presented 4-year data showing losses in gray and white matter and increases in the ventricles. Losses of gray matter, which appeared in particular areas of the brain, seem to be universal and their extent dependent on an individual’s health.

LPC investigators have examined age-specific rates of Alzheimer’s disease in the Baltimore Longitudinal Study of Aging (BLSA). Incident rates in this study are consistent with published rates of other studies based on data from 1985 to 1998. In the BLSA, 155 of 1,236 participants were diagnosed with dementia, and of those, 114 were diagnosed with Alzheimer’s disease. Followup among study participants was an average of 7.5 years. LPC researchers also were among the first to show that visual memory can predict Alzheimer’s disease up to 15 years before diagnosis. Depressive symptoms appear to predict Alzheimer’s disease in men, but not women, although depressive symptoms are more prevalent in women. Hormones also appear to influence cognitive function; free testosterone appears to be associated with a decrease in risk for Alzheimer’s disease.

Another area of LPC focus is the Healthy Aging in Neighborhoods of Diversity across the Lifespan (HANDLS) study. The purpose of this study is to disentangle the association between race, health status, psychosocial factors and cognition in a cohort of African Americans and whites. Such information from this prospective cohort study may help develop effective strategies for the prevention of Alzheimer’s disease.

Dr. Costa also presented work on the Personality Profiles of Cultures project, a multi-faceted investigation of personality across cultures, based on the Five-Factor Theory (FFT). With research collaborations all around the world, this project has garnered a large amount of evidence that largely confirms the universality of essential trait properties across cultures, including factorial structure, sex differences, and developmental trends from adolescence to old age. Other aspects of the project attempt to assess the personality profiles of cultures themselves. The next stages of this research seek to address the origin of personality profiles of cultures, using acculturation studies and to address adolescent personality stability and change in diverse cultures around the world.

Dr. Costa pointed out that adolescent ages and the middle-adult years have been studied more than advanced ages. The LPC has begun Project ACCESS, a study with a population including more than 1,000 Medicare beneficiaries. Study participants have had at least two ADL or three IADL impairments and a prior and significant history of using health care services. Investigators in this study have examined age differences in personality and found that even between the ages of 65 and 100 years, individuals look like others in the United States and across the world in terms of personality. Persons aged 80 to 100 years did tend to score higher in the agreeableness domain, although it is not clear whether that result is an artifact or reflects an actual trend.

In collaboration with Dr. Alexander Weiss in Edinburgh, Dr. Costa has examined personality and all-cause mortality and found that conscientiousness, agreeableness, and neuroticism appeared to be protective against mortality. Dr. Costa also has found that individuals who smoke tend to be emotionally distressed and antagonistic but not very conscientious.

Dr. Costa noted that the Five-Factor Theory has been used to examine mean levels of self-reports and observer ratings, as well as mean perceptions of typical traits or national character stereotypes in cultures. He summarized self-report data; findings included universal age and gender differences, generalizable scores across subgroups, factors related to dimensions of culture, higher variances in Western cultures, and overall similarity between factor structure and the Five-Factor Model structure. These findings tend to agree with observer rating data, and support an interpretation of modest cultural differences in personality. They do not agree with national stereotypes.

Dr. Costa and his colleagues are now including biological measures, using fMRI to link personality variables to neural structures, and obtaining genetic information to examine the heritability of traits. The SardiNIA project, a multidisciplinary genetic study of complex traits and diseases among Sardinians, will likely yield new insights. So far, the SardiNIA Project has shown that personality traits have a heritable component and that the genotypic structure can be recovered for personality scales. Genotyping and genomewide analyses are under way.

In response to comments from Dr. Richard Suzman, Dr. Costa clarified that many of these studies control for education.

B. Laboratory of Genetics

Dr. Minoru Ko provided an overview of the Laboratory of Genetics. This laboratory was established in 1997 with the view that aging events are strongly influenced by genetic factors and biological processes that are active during development. The Laboratory studies development and stem cells with two types of eventual intervention in mind: To help preserve tissues and prevent dysfunction based on knowledge of the needs of a tissue or organ and to regenerate damaged tissues from stem cells. An additional unique feature of the Laboratory is a strong component of technology and resource development, as well as vertical integration of genomic structure, cellular and developmental biology, and physiology and medical genetics.

The Developmental Genomics and Aging Section, headed by Dr. Ko, employs embryogenomics to explore early gene activation in pre-implantation mouse embryos and stem cells. This group has found three waves of gene activation: The first consists of transcripts abundant in the oocyte; the second consists of genes of the zygotic genome, activated for the first time; and the third consists of genes involved in pre-implantation. On the basis of these studies, Dr. Ko’s group has found a gene, DGA1, that is only expressed in pre-implantation embryos and embryonic stem cells. This group also has generated about 50 percent of all mammalian pre-implantation cDNA sequence information in the public database, as well as the NIA Mouse cDNA clone sets and NIA-Agilent 60-mer oligo microarrays used by the scientific community.

The Gene Recovery and Analysis Unit, headed by Dr. Ramaiah Nagaraja, focuses on a mass spectrometry proteomics approach and recombination-mediated target DNA modifications. This unit develops software and methods to optimize protein cohort analyses of the ovary and oocytes. It is also adapting a recombination-mediated target DNA modification strategy, which facilitates efficient gene targeting and promoter analysis in embryonic stem cells and in mice.

The Image Informatics and Computation Biology Unit, headed by Dr. Ilya Goldberg, is focused on genomics in five dimensions, on the development of an open microscopy environment platform, and on pattern recognition for biological image analysis. This unit has the ambitious goal of using technology to automate diagnosis. An open-source software developed by this unit has been widely adopted by microscope vendors and industry groups.

The Chromatin Remodeling and Genomic Instability Section, headed by Dr. Weidong Wang, explores protein complexes involved in diseases and chromatin remodeling. In particular, this group looks at proteins involved in aging syndromes, such as Werner syndrome and Bloom syndrome, as well as those involved in cancer preconditioning. This group has purified the Fanconi Anemia Core complex and identified five new compounds within the complex, thus making a major contribution to the understanding of an important DNA-damage response network consisting of Fanconi anemia and breast cancer proteins.

The Human Genetics Section, headed by Dr. David Schlessinger (also Chief of the Laboratory of Genetics), is focused on three projects: Skin appendage development and ovary development/sex determination, including a study of the molecular pathways involved in X-linked ectodermal dysplasia; a study of the FoxL2 gene, which was identified as one of the genes involved in premature ovarian failure; and the SardiNIA Project, which is conducted in collaboration with a group in Sardinia and the NIA Laboratories of Personality and Cognition and Cardiovascular Science.

Dr. Ko discussed progress on the SardiNIA Project. More than 6,100 participants have enrolled, 98 quantitative traits have been phenotyped, and more than 500,000 single nucleotide polymorphisms have been genotyped. One gene candidate has been identified for each of 90 different traits. The Laboratory of Genetics is continuing to explore candidate genes, but it has included longitudinal outcomes in its followup studies to determine whether these candidate genes are prognostic or serve as points for interventions.

Future prospects for the Laboratory of Genetics include further analysis of developmental systems in relation to age-associated effects on female fertility, cancer, and DNA-repair diseases; integrated studies of the systems biology of stem cells, including analysis of chromatin changes and embryonic stem cells in which transcription factors have been manipulated; and outcome studies of genetic factors in the SardiNIA Project and other populations.

Dr. Ko closed his presentation by announcing that the Laboratory is recruiting a clinical human geneticist/genomicist.

VIII. 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).

IX. ADJOURNMENT

The 100th meeting of the NACA was adjourned at 1:30 p.m. on January 31, 2007. The next meeting is scheduled for May 15 and 16, 2007.

X. 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.

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

Kenneth V. Brummel-Smith, M.D. (2009)
Professor and Chair
Department of Geriatrics
Florida State University College of Medicine
Tallahassee, FL

*John T. Cacioppo, Ph.D. (2007)
Blake Distinguished Service Professor
Department of Psychology
Director, Center for Cognitive and Social Neuroscience
University of Chicago
Chicago, IL

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
11712 Farmland Drive
Rockville, MD

Mary Ganguli, M.D., M.P.H. (2009)
Professor of Psychiatry, Neurology, and Epidemiology
Department of Psychiatry
University of Pittsburgh
Pittsburgh, PA

Alan M. Garber, M.D., Ph.D. (2007)
Director
Center for Primary Care and Outcomes Research
Center for Health Policy
Stanford University
Stanford, CA

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 Biochemistry & Molecular Biology
Louisiana State 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

*Virginia M.-Y. Lee, Ph.D. (2007)
Professor
Dept of Pathology & Laboratory Medicine
Univ of Pennsylvania School of Medicine
Philadelphia, PA

Mills, Terry L., Ph.D. (2008)
Associate Dean for Minority Affairs
and Special Programs
Office for Academic Support & Institutional Services
University of Florida
Gainesville, FL

*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

Gary B. Ruvkun, Ph.D. (2007)
Professor, Molecular Biology
Massachusetts General Hospital
Boston, MA

*Gerald P. Schatten, Ph.D. (2009)
Professor, Pittsburgh Development Center
Magee-Womens Research Institute
University of Pittsburgh
Pittsburgh, PA

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

*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, D.C.

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

Elias Zerhouni, M.D.
Director
National Institutes of Health
Public Health Service
Bethesda, Maryland

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

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

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 15–16, 2007, and corrections or notations will be stated in the minutes of that meeting. (Back to text.)