Council Minutes - September 2001

National Advisory Council on Aging

Summary Minutes: The Eighty-Fourth Meeting

September 24-25, 2001

CONTENTS

1. Review of Applications
2. Call to Order
3. Report: Task Force on Minority Aging Research
4. Report: Clinical Investigators Working Group
5. Program Highlights
6. Report: Working Group on Program
7. Working Lunch Discussion with Center for Scientific Review
8. Comments from Retiring Members
9. Adjournment
10. Certification

Attachment A - Roster of the National Advisory Council on Aging

The 84th meeting of the National Advisory Council on Aging (NACA) was convened on Monday, September 24, 2001, at 3:00 p.m., in Building 1, Wilson Hall, National Institutes of Health (NIH), Bethesda, Maryland. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA), presided.

In accordance with the provisions of Public Law 92-463, The meeting was closed to the public on Monday, September 24, from 3:00 to 5:00 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 Tuesday, September 25, from 8:00 a.m. to 2:00 p.m.

Council Participants:

Dr. John Cambier
Dr. Judith Campisi
Dr. David Espino
Dr. Fred Gage
Dr. Mary Harper
Dr. Lewis Kuller
Ms. Judith Riggs
Dr. Dennis Selkoe
Dr. Ilene Siegler
Dr. James Vaupel
Dr. Jeanne Wei
Dr. Myron Weisfeldt
Dr. David Wise
Dr. Phyllis Wise

Ex-Officio Participants:

Dr. George Fuller
Dr. James Burris, VA

Absent:

Dr. Dennis Ausiello
Dr. Rose Dobrof
Dr. Stanley Prusiner
AoA Representative

The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as Attachment A.

Members of the Public Present:

Linda Harootyan, Gerontological Society of America (GSA)
Andrew Kessler, American Psychological Society
Pam Moore, Capitol Publications
Tim Perrin, American Association of Gerontological Psychiatry
Ase Sewall, Social and Scientific Systems
Raffi Vartian, GSA IAGHE
Jeffrey Halter, the University of Michigan

In addition to NIA Staff, other Federal employees attending were:

Priscilla Chen, CSR/NIH
Ellie Ehrenfeld, CSR/NIH
Michael Martin, CSR/NIH
Don Schneider, CSR/NIH
Janet Gregory, NIDDK/NIH

1. Review of Applications

This portion of the meeting was closed to the public in accordance with the determination that it was concerned with matters exempt from mandatory disclosure under Sections 552b(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). 1

A total of 684 applications requesting $670,431,084 for all years was reviewed. Council recommended 411 for a total of $486,534,379 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.

2. Call to Order

Dr. Hodes called the meeting to order at 8:00 a.m. on Tuesday, September 25, 2001, and welcomed members.

Director's Status Report

Dr. Hodes welcomed Dr. Judy Salerno, recently recruited as NIA's Deputy Director. Dr. Salerno's background includes eight years of experience as the Chief Geriatrician with the Department of Veterans Affairs and four years in the neurosciences laboratory of NIA's intramural program.

Dr. Ruth Kirchstein continues to provide strong leadership as Acting Director of NIH as she has for the last year and nine months. At this time, there is no information on when an NIH Director might be appointed.

Two Institute directors have announced plans to leave NIH—Dr. Enoch Gordis of the National Institute of Alcohol Abuse and Alcoholism (NIAAA) will retire and Dr. Richard Klausner of the National Cancer Institute (NCI) is resigning to go to the Case Foundation of Health Science and Technology.

Ms. Barbara Kellner, a long-time NIA employee, has been selected to head the NIA Office of Planning, Analysis, and Evaluation (OPAE). Dr. Susan Molchan was introduced as a new member of NIA's Neuroscience and Neuropsychology of Aging Program (NNA). Kimberly Howell is a new member of the Office of the Director, Office of Special Populations. Also introduced were Rachel Permuth, Kathy Mann Koepke, and James Scully of the Behavioral and Social Research Program (BSR); and Kate Nagy of OPAE.

Dr. Hodes updated the Council on the Fiscal Year (FY) 2002 budget status. As yet, no appropriations bill has been passed. Until it is passed, NIA anticipates operating conservatively under a continuing resolution.

The President's proposed budget for FY 2002 would modestly increase the percentage of the budget allocated to research project grants (RPG) and maintain other mechanisms consistent with NIA's research goals. A full Director's Status Report, including a report on budget, is appended to these minutes.

Future Meeting Dates

• January 29-30, 2002 (Tuesday-Wednesday)
• May 21-22, 2002 (Tuesday-Wednesday)
• September 24-25, 2002 (Tuesday-Wednesday)
• February 4-5, 2003(Tuesday-Wednesday)
• May 20-21, 2003 (Tuesday-Wednesday)
• September 24-25, 2003 (Wednesday-Thursday)

Consideration of Minutes of Last Meeting

The minutes of the May 22-23, 2001, meeting were approved as submitted.

3. Report: Task Force on Minority Aging Research

Dr. Jeanne Wei, chair of the Task Force on Minority Aging Research provided an overview of the mission of the Task Force and its interest and emphasis on development of future scientists in aging research. As part of the annual report to the Council, Dr. J. Taylor Harden, Assistant to the Director for Special Populations, presented data on the NIH/NIA program, “Research Supplements for Underrepresented Minorities.” The aim of the Research Supplements to Underrepresented Minorities program is to attract and encourage minority individuals to enter and pursue biomedical and behavioral research areers in aging. Most NIA principal investigators, across a range of mechanisms, are eligible to participate in this program that seeks to develop candidates at the high school to junior faculty level. Dr. Harden noted that pay to high school students has been at or about minimum wage and this may be related to the paucity of applications.

The application process for Research Supplements for Underrepresented Minorities is brief with an open receipt date. Guidelines for applying are available on the NIH/NIA website at NIH Guide: RESEARCH SUPPLEMENTS FOR UNDERREPRESENTED MINORITIES .

Dr. Robin Barr, the NIA Training Officer, directs the administrative review committee for this program. The committee meets monthly and includes program administrators from each of the extramural programs. In evaluating applications, emphasis is placed on the research and career development experiences proposed, evidence that adequate mentorship will be provided, and evidence that the planned training experiences and activities are an integral part of the parent grant.

There has been a decline in the number of applications per year from FY 1994 to FY 1999. At the same time average costs of awards have increased. As an application may be submitted more than once for the same individual, if not funded on the first submission, the number of applications submitted is larger than the number of individuals for whom support has been requested.

Data from the FY 1999 trans-NIH report on new minority supplement applications, the latest year for which data are available, ranked NIA in the top six institutes for number of applications received (n=47). NIA had a 64 percent success rate in comparison with other Institutes and Centers with a success rate ranging from 46 to 100 percent. Dr. Harden noted that the inclusion of amended applications that succeed increases the total NIA success rate to 85 percent. It was also noted that Institutes receiving the largest number of applications tended to have a formal and rigorous review process.

Most NIH/NIA minority supplement recipients are African American (52 percent) and Hispanic (39 percent). Most awards from the NIA are made to minority supplement recipients at the postdoctoral, investigator, and pre-doctoral career levels, respectively.

Examples of successful supplement recipients who have become established independent investigators include Dr. Raynard Kington, NIH Associate Director for the Office of Behavioral and Social Research, Dr. Karen Hubbard (R03), Dr. Mike Irizarry (K08 and R01), Dr. Rafael Lantigua (P30), Dr. Tom LaVeist (R01), Dr. Jennifer Manly (R01), Dr. Thomas Obiesesan, (K23), Dr. Robert Taylor (R01), Dr. Robert Vellanoweth (R25, S06), and Dr. Keith Whitfield (R01, R25).

Dr. Wei noted the progress made by this program but underscored the need for more work that needs to be done, especially since it is assumed that minority investigators will make a major impact toward reducing health disparities among ethnically diverse older Americans. In discussion, Council pointed out that it is very important to recruit college or high school students into the program but that salaries for this level of applicant remain fairly low resulting in few applications. A Council member raised the issue of “how to make the match and how to connect people.” He described a program at his institution that surveys investigators and asks if they will take students. The program staff act as a broker to recruit and match students and investigators. As a result of discussion, Council requested that the NIA solicit from Council members the names and addresses of a contact person at each of their universities or organizations who might act as a contact and point of information dissemination about the Supplement program. A listserve might be established that would provide information such as a list of grantees eligible to apply for Research Supplements for Underrepresented Minorities. The grantees might also serve as a referral source. One Council member observed that graduates of minority supplement programs had fared poorly in review on the study section that he had recently served on. He wondered what transitional programs may be available to help these individuals write stronger applications. The same member also observed that some of the most successful programs in recruiting minority students and investigators are themselves focused on the kinds of specific minority-health and health disparity research that is most relevant to the minority groups being recruited. Drs. Hodes and Harden discussed programs that are available to help minority supplement awardees transition to independent grants but agreed that more could be done. They also indicated institutional difficulties in surveying former holders of minority supplements in order to gain an accurate record of who is and is not moving on to independent research support. In closing, another member observed that the U.S. Department of Education has a newsletter that is sent out to science teachers. That may be a useful way to reach science teachers who may inform their high school students about the minority supplement program.

4. Report: Clinical Investigators Working Group

Dr. Weisfeldt reported on the results of the discussion by the Working Group. Drs. Prusiner and Ausiello co-chair this group. Dr. Ausiello did not attend Council. Dr. Prusiner participated in the evening meeting. Dr. Weisfeldt observed that physicians are particularly inclined towards translational research and epidemiological research, and towards clinical trials and remain invaluable to biomedical research for these reasons. However, the numbers of physician-investigators have been declining for some time. The effect is particularly evident in the drop in proportion of R01 grants going to physicians.

Prior reports on this problem cite poor training, inadequate mentoring and burdensome debt as factors in the erosion of physician-driven research. NIH interventions to date include career awards for physicians that are targeted towards patient-oriented research (K23 and K24) and a curriculum award to improve training and qualifications in clinical investigation (K30). Despite these moves, the downward trend in physician-investigators has continued. The most recent intervention (September 2001) is a loan-repayment program targeted towards physicians in the early stages of a research career. It is too early to judge its impact.

The problem appears confounded within the area of geriatrics. Although most clinical specialties provide a two-year training fellowship in which the second year is focused on research, geriatricians have a one-year fellowship in which the focus is clinical. Therefore it appears that the loss of physician-investigators may be most severe in Geriatrics but more data are needed to confirm such a hypothesis.

Dr. Weisfeldt reported and agreed with Dr. Prusiner's comment that combined MD-PhD programs do not address the problem. The length of the training represents a severe disincentive for all but a small percentage of highly capable and committed students.

He endorsed the concept, developed at the Clinical Investigators Working Group meeting, that NIA consider one year support for medical students who wish to take a year off medical school to gain some research training. The experience of the similar Howard Hughes fellowship program has been positive in this regard. Dr. Weisfeldt also expressed the need for a post-MD research training mechanism, perhaps using the K 22 mechanism (the Career Transition award) that could be awarded prior to the individual's appointment to a faculty position.

In discussion, Council members mentioned several innovative programs where geriatric fellowship training is added to training in other specialties and thus allow some research training to occur. They pointed out that 50 percent of geriatricians are women, that many have started families, and, while stressing the value of a training experience in the intramural program or other top research laboratories, indicated that programs based at the home institution may be more practical for many. Council members generally concurred that the model of one year pre-MD followed by three or four years post-MD research training is one that would be attractive to a number of medical students and new MDs. Dr. Hodes indicated that institute staff would develop some model training initiatives for discussion at the next Council meeting in January.

5. Program Highlights

A. Dr. David Snowdon of the University of Kentucky was introduced by Dr. Richard Suzman as presenter for the Behavioral and Social Reasearch Program. Dr. Snowdon presented data on the Nun Study.

In 1991, the National Institute on Aging funded the expansion of the Nun Study to include 678 US members of the School Sisters of Notre Dame religious congregation. At that time, the sisters were 75 to 102 years old and, by the end of 2001, the remaining 250 survivors were 85 to 106 years of age. The Nun Study continues to characterize early, mid, and late life risk factors using medical and personal data from convent archives (Danner D, et al. J Personality and Social Psychology 80(5): 814-813, 2001). The study also annually evaluates the sisters' cognitive, neurologic, and physical function, monitors mortality, and conducts brain autopsies.

This is an opportune time for the expansion of the study given its high public profile and the great enthusiasm of sisters of all ages. An integrated approach will be used to study the brain's relationship to healthy aging—long life with intact cognitive and physical function. Avoiding Alzheimer's disease and stroke are two major ways of maintaining function while extending longevity (Snowdon DA, et al. JAMA 277: 813-817, 1997). For those who live into their 90s and 100s free of Alzheimer's and stroke, Parkinson symptoms and problems with gait, balance, and speed threaten healthy aging by increasing the chances of falling. The study team believes the brain plays a major role in falls, which can severely debilitate an otherwise healthy older adult.

Findings from the Nun Study suggest that Alzheimer's disease is a lifelong disease process. For example, low linguistic ability in the sisters' early life autobiographies is strongly correlated six decades later with both Alzheimer's pathology and symptoms (Snowdon DA, et al. JAMA 275(7): 528-532, 1996). To be effective, interventions need to be initiated before the disease has produced so much neurodegeneration that reversing or slowing the development of symptoms is not feasible.

Risk factors for Alzheimer's disease in the Nun Study, such as its main genetic marker (APOE4), age, and linguistic ability, are strongly associated with memory impairment—but, not with the conversion of memory impairment into full blown Alzheimer's disease. This suggests that the major risk factors for the disease operate very early in the cascade of events leading to the diagnosis of Alzheimer's. The study investigators believe there is a critical time—before the appearance of symptoms—when interventions can have their greatest impact on the prevention of brain diseases and the maintenance of healthy aging.

For these reasons, the team proposes to extend the study of brain diseases and healthy aging by enrolling younger sisters into the Nun Study. They plan to expand the study to include all US School Sisters of Notre Dame, 99.5 percent of whom are 50 years of age and older. They will continue to anchor the study with the 85 to 106 year old survivors, while enrolling approximately a thousand new participants who are 50 to 84 years old. To increase their ability to discover new links in the chain of events leading to healthy aging, the team will add cutting-edge scientific methods and biotechnology. Creative methods of financing also will be needed to take advantage of these new technologies.

Brain tissue, donated by every participant in the study, is a unique resource for identifying the determinants of brain diseases. In the past, the research team has formalin-fixed these brains. In the future, they plan to freeze the cerebrospinal fluid and a hemisphere of each brain within 45 minutes of death. This will provide a richer source of biologic and biochemical material. They also plan to draw blood and image the brain annually. The blood, cerebrospinal fluid, and brain image will then be used to model the neuropathologic features of the brain that would normally be visible only at autopsy.

As an example of the study's high technology approach, Dr. Eugenia Wang from the University of Louisville will use biologic material from the study participants to determine both their genetic makeup and patterns of gene expression. The genes (DNA) and genetic expression (mRNA and proteins) observed in the blood will be used to model genetic expression in the brain tissue. Altering genetic expression has great potential as a preventive and therapeutic method for controlling brain diseases and thereby extending longevity.

Another example of the study's integrative approach is to use annual brain imaging to model the clinical development of cognitive impairment and dementia. Brain imaging also can monitor genetic expression, biochemical parameters, and physiologic processes important in brain diseases and healthy aging. In addition, the images can be used to characterize the pathologic stages of brain diseases such as Alzheimer's. Brain imaging and other innovative methods can be used in the diagnosis and monitoring of brain diseases—which will be important in creating new preventive and therapeutic modalities.

Further information about the Nun Study, including abstracts of all scientific publications, is available on the web ( http://www.nunstudy.org/ ).

In discussion, Council expressed interest in the comparison of the highly educated nuns in the study to other groups of highly educated women in the US population. Dr. Snowdon said that because the average age of the study participants is now 90, it is difficult to find a comparable group. The research team believes this is a unique window of opportunity for study and is focusing on comparing these similar women to each other as opposed to finding a population to compare them to. However, the study population of sisters had been compared in the past with the white population of women when the participants were between the ages of 50 and 84. At that time, the sisters showed a 40 percent reduction in stroke mortality and heart disease mortality, and a slightly higher risk of breast cancer when compared with this control population.

Another Council member asked if there was anything unique about the way this particular congregation structures their community or personal life as compared to other congregations of nuns. Dr. Snowdon said there are real cultural differences among nuns. The existence of these groups offers unique opportunities for research.

B. Dr. Andrew Monjan of the Neuroscience and Neuropsychology of Aging (NNA) Program presented data on Prion Diseases.

Prion diseases are a group of fatal neurodegenerative disorders that occur in humans and animals. Prions are infectious proteins that transform a normal cellular protein (PrP C ) into an abnormal virulent form (PrP Sc ) that accumulates in the central nervous system and produces the fatal neurological disease characterized by sponge-like holes in the brain that result in movement, emotional, and cognitive disturbances. The human forms of these diseases, Kuru, Gerstman-Str@ussler-Scheinker disease (GSS), fatal familial insomnia (FFI), and Creutzfeld-Jakob disease (CJD), are relatively rare. Of recent concern, however, is the epidemic of bovine spongiform encephalopathy (BSE), or “mad cow disease,” that has emerged in Great Britain and parts of Western Europe, and its apparent transmission to humans through consumption of infected meat producing a new variant of CJD (vCJD). Through the end of August 2001, there were 105 human deaths attributable to this disease in Great Britain. On August 23, the Department of Health and Human Services (DHHS) presented an action plan to prevent the introduction of BSE into this country as well as to enhance the surveillance and diagnosis of vCJD and other transmissible spongiform encephalopathies (TSE) in the U.S. It designates to NIH the responsibility for furthering research on TSE.

CJD is relatively rare, with an annual incidence rate of about 1 per million, and occurs late in life with mean age of death about 67 years after an average duration of illness of four months. In contrast, vCJD has been found to be associated with BSE in younger individuals with mean age of death of 30 years after about 14 months of illness. These cases have been following an epidemic pattern over the six years since first identified in Great Britain. BSE also has been found in several countries of Western Europe and recently in Japan. The BSE epidemic was first identified in England in 1986. It appeared to be a consequence of use of waste meat and bone meal from scrapie infected sheep. In 1988, the U.K. banned the further use of these cattle foods and began the slaughter of infected cattle. In 1990, British beef was declared safe for human consumption, and by 1999 over 4.5 million cattle, infected and asymptomatic, had been killed in the UK. The first human vCJD death was in Great Britain in 1995. In the US, the FDA implemented a final rule prohibiting use of most mammalian protein in feeds for ruminant animals. In 1999, the FDA recommended no blood be used from donors who had resided in the UK for a total of six months between 1980 and 1996.

An observation from Dr. Stanley Prusiner's laboratory at the University of California San Francisco led to the finding that low noncytotoxic concentrations of branched polyamines (large molecules with many branches of chains of amino groups) could clear PrP Sc from infected cells (mouse neuroblastoma – ScN2a) in culture (Supattapone S, et al. PNAS USA 96: 14529-14534, 1999). These findings have been repeated and extended (Supattapone S, et al. J Virol 75: 3453-3461, 2001) by showing that PrP Sc from BSE-infected cells were totally cleared beyond detection by low concentrations of branched polyamines, although the scrapie form of prion disease was not affected. It was found that the clearance of PrP Sc occurred within lysosomes (intracellular structures in which proteins are broken down) where PrP Sc has been shown to accumulate. The branched polyamines are the first class of compounds thought to cure an established prion infection in living cells in tissue culture. However, in addition to their selectivity for only BSE, their large size and ionic charge limit their ability to cross the blood-brain barrier and hence they would not be able to gain access to and destroy brain prions in the individual. Nevertheless, they might be useful as disinfecting agents rather than the current use of harsh protein denaturants or prolonged autoclaving.

Another approach to development of drugs to treat the prion diseases comes from using computer-based models of the structure of PrP Sc to determine how best to interfere with the formation of PrP Sc from PrP C (Perrier V, et al. PNAS USA 97: 6073-6078, 2000). Using this structure-based drug design strategy, over 200,000 potential compounds were computer-screened, 80 selected for biological assay in the ScN2a cells, and four were found to be effective in clearing PrP Sc from these cells in tissue culture. The most potent and least toxic was Cp-60 {2-amino-6- [(2-aminophenyl) thio]-4-(2-furyl) pyridine-3, 5-dicarbonitrile}. This small molecule has not yet been tested in animals. However, the approach of using structural biology and computational chemistry has been shown in principle to be productive in identifying therapeutic agents for prion diseases.

Other screening approaches of drugs known to enter the brain resulted in the finding that quinacrine (an anti-malarial drug) and chlorpromazine (an anti-anxiety drug) also caused the clearance of prions from ScN2a cells in tissue culture (Korth C, et al. PNAS USA 98: 9836-9841, 2001). Both drugs are tricyclics, with a side-chain on the central ring at the 9-position being necessary for PrP Sc inhibition. Quinacrine was most effective in curing the infected ScN2a cells at levels of 0.2 to 0.8 µM for six days. Since these compounds were effective at non-toxic concentrations and have been used for many years in humans without major adverse side effects, it is possible to start small clinical trials to test their efficacy in treating persons with CJD who otherwise face certain death.

The potential threat of a larger epidemic of vCJD mandates an increased effort to find therapeutic agents that will cure these prion diseases. Currently, there are concerns that BSE and vCJD may enter the USA. Restrictions on the use of potentially contaminated recycled animal products in cattle feed as well as limitations on blood donations from travelers who have spent several months in Great Britain and parts of Western Europe are in place as preventive measures. These recent papers, while not yet applicable for use in humans, do present some approaches and leads to the treatment and possible prevention of these fatal neurodegenerative disorders.

In discussion, Council members asked about the surveillance and mode of transmission of Creutzfeld-Jakob in the US. Dr. Monjan said surveillance of the disease in the US is done by the Centers for Disease Control (CDC) and that the only cases of transmission have been ionogenic.

In response to further questions, Dr. Monjan indicated that nothing is yet known about how the normal form of the prion protein is converted to the abnormal form nor about the underlying structural characteristics of the compounds that have been shown to clear prion proteins in tissue culture studies.

It was pointed out that Dr. Stanley Prusiner's research group recently published a paper in Nature on antibody clearing of prions in scrapie form in animals. The researchers found certain antibodies to certain epitopes on the prion protein that were very effective in reducing prion titers and reducing infectivity.

C. Dr. David Finkelstein of the Biology of Aging Program summarized recent research performed in the laboratory of Dr. Piero Anversa, an NIA-supported investigator from New York Medical College. Dr. Anversa has been able to show repair of heart damage following an induced myocardial infarction in mice by injecting a population of purified bone marrow cells directly into the heart of the injured mice. By using the technique of confocal microscopy, the research team was able to look at different molecules expressed by individual cells. They were able to demonstrate that the donor cells were being incorporated into the heart. Furthermore, the donor cells were behaving like stem cells, insofar as the research team was able to differentiate into the various cell types found in the heart. (Orlic D, et al. Nature 410: 701-705, 2001)

In a later study, Dr. Anversa and his colleagues attempted to stimulate the proliferation of the stem cells by injection of cytokines before inducing a heart attack in mice. They found that the cytokine-treated animals were better able to survive the heart attack. Once again, using the technique of confocal microscopy these researchers were able to show that the hearts of the treated animals showed less damage. They also were able to show a distinct improvement in heart function by the technique of echo cardiography. (Orlic D, et al. PNAS USA 98: 10344-10349, 2001)

In response to questions, Dr. Finkelstein clarified that many types of cells were differentiated following injection of stem cells and that the cells used were from an enriched population. Council members also described related stem-cell work that helps to extend the significance of the reported findings. Kocher, et al ( Nature Medicine 7: 430-436, 2001), using a mouse model, reported that bone marrow cells from adult humans contain endothelial precursors with characteristics of embryonic hemangioblasts and that these can be used to induce new blood vessel formation following an infarct and also provoke proliferation of existing vasculature. The investigators reported that these changes in the vasculature improved many markers of cardiac function following induced myocardial infarction in mice. Of note was that the bone marrow cells were injected intravenously and found their way to the site of damage. A member also described work that has found increased circulation of endothelial progenitor cells in older adult humans following an infarction. The stem cell intervention may be enhancing a repair process that occurs naturally. Several members then questioned whether there was clear evidence of the particular source of these circulating progenitor cells. There is no clear evidence of the source and some studies were suggested to test whether bone marrow cells could be involved.

D. Dr. Jane Cauley, of the University of Pittsburgh, presented “A Polymorphism in the TGF-ß1 Gene is Associated with Breast Cancer.”

The causes of breast cancer are believed to be highly complex, involving the interaction of many as yet unknown environmental and genetic factors. Thus the search continues not only to better understand the causation of this disease, but to identify more accurate risk factors in women who have greater susceptibility in order to provide better surveillance and/or preventive strategies. Although family history is a known risk factor and two genes--BRCA1 and BRCA2--associated with a striking increase in breast cancer risk have been identified, the mutations in these genes which confer an increased risk are relatively uncommon, accounting for only a small proportion of the breast cancer burden in the population.

Transforming growth factor ß (TGF-ß) is a protein-like growth factor which is produced widely throughout the body and plays a key role in regulating cellular division. Experimental studies using cells in tissue culture systems and with genetically altered mice show that increased TGF-ß levels or activity within the TGF-ß pathway inhibit the growth of mammary cell lines and the development of chemically or virally induced liver, lung, and mammary tumors. Thus it has been hypothesized that mutations in the gene for TGF-ß may play an important role in susceptibility to breast cancer in humans (Blobe GC, et al. N Engl J Med 342[18]: 1350-1358, 2000). To test this hypothesis, a study of the relationship between two different polymorphisms of the TGF-ß gene and the incidence of breast cancer was undertaken in a subset of 3075 women in the Study of Osteoporotic Fractures (SOF) (Ziv E, et al. JAMA 285: 2859-2863, 2001). SOF is an ongoing prospective cohort study of white, community-dwelling women recruited at four US centers who were 65 years or older at baseline (between 1986 and 1988).

After an average follow-up period of 9.3 years, it was observed that the risk of breast cancer was significantly lower in the 458 women lacking the T allele of the gene (i.e., having the C/C genotype) compared to the 2617 women carrying the T allele (having either T/C or T/T genotype). Because a woman can have either a T or C allele on each of the pair of chromosomes containing this gene, the three possible genotypes involving this gene are T/T, CC or T/C. Thus, the protection is dependent on the presence of a C gene on each chromosome in the chromosome pair. In analyses that controlled for confounding factors such as age, age at first menstruation, age at menopause, estrogen use, number of offspring, body mass index, and bone mineral density, women without the T allele (C/C genotype), who comprised only 15 percent of the population, had a 60 percent lower risk of developing breast cancer compared with women with a T genotype.

These findings support the hypothesis that the TGF-ß1 genotype may play an important role as a determinant or predictor of the risk of breast cancer. Further studies are needed to ascertain whether the striking protective effect seen in this population by a relatively uncommon genotype (i.e., the C/C genotype) can be generalized to other populations of differing ages and racial/ethnic composition.

Members' questions included whether family studies had been completed with this polymorphism to discover the full pattern of variations in health among the C/C, C/T and T/T alleles. Dr. Cauley reported that no family studies have been completed although she observed that the sample distribution observed in the SOF study was similar to the distribution in the Japanese study she described, suggesting no striking effects on mortality of the different alleles. Dr. Cauley also described the practical difficulty of trying to find an association with other cancer types in the SOF that has been ongoing for 15 years and for which no records of incident cancers other than breast cancer have been recorded. In response to further questions she indicated that the presumed mechanism of action of TGF-ß is through suppressing cell growth. Dr. Kuller, a council member who also participated in the study, noted that the C/C allele older women show small tumors but enhanced inflammatory responses. It may be that TGF-ß both inhibits cell growth and promotes the inflammatory response. However, it is not yet clear that tumor cells have a TGF-ß 1 receptor on them when dividing.

6. Report: Working Group on Program

Dr. Gage reported on the meeting of the Working Group on Program (WGoP) that took place on Monday, September 24, 2001. He pointed out that one agenda item, training and support of clinical investigators in geriatrics, was reported on by the ad hoc subcommittee so that topic was not addressed in his report.

The first topic discussed was reorganization of some of the Center for Scientific Review (CSR) panels, particularly a report on the meetings of the Boundaries teams for the Muscular, Oral, Skeletal, and Skin (MOSS) and Biology of Development and Aging (BDA) integrated review groups (IRG). NIA staff and the NACA had recommended that a broad range of research be included. The MOSS IRG is one of several organ-based review clusters. The Boundaries group consisted of 37 members and arrived at the meeting with predefined categories. Some concern was expressed about whether NIA's program priorities and new directions will be adequately reviewed by the new study sections.

The BDA meeting had a chair and an aging coordinator. NIA staff were pleased with the range of science represented by team members. The initial set of applications provided to the team consisted of basic but not clinical research applications. NIA staff made additional applications available for the team to consider. On the basis of consideration of the larger set of applications, the BDA team recommended 2-4 groups that include substantial representation from the aging research community. The positive outcome was attributed to the group's Chairperson.

Shortly following the two summer meetings, draft IRG and study section guidelines were posted on the web and are available for comment. Council members were encouraged to send comments to CSR individually and as a group. Dr Jeff Halter, who was aging coordinator for the BDA Boundaries team was invited to join in the discussion. He reiterated the need for Council to comment on the drafts now posted. He felt that NIA would be well advised to monitor progress and to remind CSR that aging research needs to be conceptualized broadly. For example, in response to a question from a member, he said that he expected that many more applications could have been included in the sort that the teams used to develop study section boundaries and scope. Council was reminded to review the statements describing shared interests/referral guidelines between MOSS and BDA review groups and other review groups. It was pointed out that these referral guidelines are important considerations in the application assignment process. Council expressed an interest in being informed before critical decisions are made and in having an opportunity to see comments that CSR receives. Council also agreed to comment on the two IRG (MOSS and BDA) guidelines during their open comment periods to reflect the preceding discussion.

In discussion, Council members reiterated the importance of staff interaction with CSR and of nominating candidates for study section membership who have expertise in aging research.

The review of the Biology of Aging Program (BAP) was discussed. The ad hoc group that reviewed the BAP program was congratulated for its excellent report. This was the first review conducted under the process recently developed by NACA. Council members who took part in the review thought the process worked well, that reviewers received useful information from grantees, and that comments solicited about vision and future directions for the program were helpful.

In the follow-up to Council's earlier focus on review activities at NIH, NIA staff sent review guidelines including policies and procedures to Council members interested in studying the NIA and NIH review processes and procedures. Those Council members reported that the Guidelines looked appropriate although implementation may be challenging. One member observed that the role of review staff is as important as that of program staff and that Council members can help to strengthen the review process. Council was asked to help maintain an outstanding review process and even improve it by identifying candidates for Scientific Review Administrator (SRA) positions and for regular and Special Emphasis Panel (SEP) reviewers. It was agreed that time will be set aside to discuss potential reviewers. It was suggested that former Council members be considered as reviewers.

Three upcoming advisory meetings and conferences had been presented to the Working Group for review and presentation to Council as a whole. The first was a planned meeting on Immunology and Aging. Dr. Cambier said that immunologists and investigators in aging research were brought together about six years ago. Their discussions were broad and did not result in either an expression of interest or an increase in applications from immunologists that focused on aging. The planned conference will be small and will focus on six-seven topics related to immunology of aging. The concept was approved.

A planned meeting on Hutchinson-Guilford Syndrome, a rare childhood disorder, was discussed. This conference is encouraged in legislative language. There is some controversy about whether the syndrome is a premature aging syndrome. It involves metabolism, connective tissue and premature cardiovascular disease, but not cognitive dysfunction, and may be instructive about processes important to aging research. The planned meeting was approved.

A meeting on Racial and Cultural Effects on Measurement and Cognition was considered. There was consensus that this is an important and timely topic. The concept was approved by Council.

Council expressed appreciation to Dr. Gage for his effective leadership of the Working Group on Program. Dr. Hodes announced that Dr. Phyllis Wise will become chair of the Group in January.

7. Working Lunch Discussion with Center for Scientific Review

Drs. Ehrenfeld, Martin, and Schneider of the Center for Scientific Review (CSR) met with Council members during lunch and offered a question-and-answer session focusing on changes that CSR is introducing in the structure and organization of review committees. Two initial review groups (IRG), of substantial relevance to NIA-funded investigators, the Biology of Development and Aging (BDA) and the Musculoskeletal, Oral and Skin Sciences (MOSS) review groups have been proposed, and draft mission statements posted on the web for comment. Council members asked about how and when the process of finalizing the mission and forming the individual review panels would be completed and about further opportunities for Council input.

Dr. Ehrenfeld indicated that the open period for comment on the mission statements of MOSS and BDA extends through October and November and that Council members may comment via the web-site prepared for that purpose. She also indicated that CSR may choose to reconvene the steering committees that prepared the mission statements or seek further outside input, or input at the CSR advisory committee. In some cases, CSR will establish a group without additional consultation. She explained that the process is deliberately slow and allows for comment from the groups affected by the proposed organization. These groups can include steering committees in other areas of scientific review that may have interests that overlap with the proposed missions of the two review groups.

Council members asked how referral decisions will be made to these review groups. Concern was expressed that “aging” can be interpreted narrowly or broadly with strikingly different implications for the number of applications to be assigned to a panel such as BDA. Dr. Ehrenfeld hopes that most referral decisions will be made through self-referral. However, she cautioned that trials in self-referral to date have generated a large error-rate. The implication is that mission statements must be clearly defined with limited overlap in order for self-referral to work well. Dr. Ehrenfeld also cautioned that the steering committees must be allowed to provide independent advice and expressed concern that staff members not lobby particular panel members.

Members also commented on the cross-cutting nature of aging research. It presents a challenge in review assignment as many applications may be assigned either to the discipline of the particular approach or to the panel on aging. The solution of assigning a single reviewer on aging to many different panels leads to insufficient expertise for aging-focused applications on these panels. The concentration of aging applications in one panel can lead to the reverse problem of insufficient expertise in the sub-fields on that panel.

Dr. Ehrenfeld acknowledged the difficulty but made two observations to indicate that the problem is limited. First, though CSR acknowledges some difficulty in review of molecular applications in aging, review of behavioral and social research applications works well even though the same cross-cutting problem exists in these fields. Secondly, when the review outcome of applications from an Institute with very few applications assigned to a panel is compared to the review outcome of applications assigned to an Institute with many applications in a panel, there is little or no difference in the scores obtained. She mentioned that both development and aging share this cross-cutting problem. She indicated that the BDA panel represents an experiment to address the concern that aging and development span many diseases and organ systems by grouping them via their focus on lifespan rather than via disease or organ. It is not completely clear that this arrangement will work, even now.

Dr. Ehrenfeld then described how CSR is evaluating the conduct of review panels. Evaluators participate in review meetings as Special Reviewers but have a light review load. These experts are past members of CSR review groups. If they are recent former reviewers they are not placed on their former panel. Nominations are received from Institute and Review staff as well as professional societies. She indicated that this system of review of review has been highly successful to date.

Dr Hodes thanked Dr. Ehrenfeld and her colleagues for their helpful answers.

8. Comments from Retiring Members

Dr. Fred Gage said he had been impressed with the seriousness of attitude of Council members, their willingness to voice opinions sometimes in contradiction of one another, and their ability to formulate new opinions based on the collective knowledge of the Council. He commended the NIA staff for being unique among the Institutes in their dedication to the Institute's mission and their intelligence and willingness to keep up with the science. He added a special thanks to Dr. Miriam Kelty for her guidance in Council protocol, and to Dr. Richard Hodes for his leadership of the Institute. He recommended that the NIA attempt to send a clearer message to the world outside the Institute—that aging plays a unique and important role in our society and world.

Dr. Mary Harper complimented the Institute on its leadership, the quality and standards of the Instititute's review process, the sense of commitment and dedication of its Council, and the unique features of its Council meetings—the involvement of members on the Working Group on Program and the program highlights presented by all NIA programs at most Council meetings. She recommended that Council members be provided with more information about future NIA meetings, workshops, and conferences, and she suggested that NIA establish more partnerships with foundations and other Federal agencies.

Dr. Dennis Selkoe said he agreed with the points made by Drs. Gage and Harper. He thanked the NNA Program, in particular, for reaching out to him as a young researcher and throughout his career in their commitment to nurturing the science. He believes the level of staff's personal involvement to be more intense at NIA than at other NIH Institutes. He tipped his hat to Dr. Gage for having done a superb job on Council. In closing, he made several suggestions: (1) that everything possible be done to alleviate the workload of staff enough so that they might have time for personal professional development; (2) that we are moving into a clinical realm with the advent of therapies for disease and need to acquire expertise from sources such as, drug companies, biotechnology companies, research organizations, and clinician leaders; and (3) continue to ask current and former Council members for recommendations of individuals who can serve on review panels.

Dr. Hodes proposed that the Institute send out rosters to Council members in advance of the next meeting and establish an agenda item on Council recommendations for reviewers.

Dr. James Vaupel spoke of the value and rewards of evaluation and review if done in a constructive way. And, he reiterated that the three most important criteria for an organization like NIA are intelligence, openness, and dedication—and that he had been extremely impressed by these characteristics throughout the total NIA organization.

Dr. Jeanne Wei thanked Dr. Hodes and the members of Council for the tremendous honor and privilege of serving with them and learning so much.

9. Adjournment

The 84th meeting of the National Advisory Council on Aging was adjourned at 2:30 p.m. on September 25, 2001. The next meeting is scheduled for January 29-30, 2002.

Attachments:
A. Roster of Council Members
B. Director's Status Report to the NACA

10. Certification

I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete. 2

______________________________________
Richard J. Hodes, M.D.
Chairman, National Advisory Council on Aging
Director, National Institute on Aging

Prepared by Miriam F. Kelty, Ph.D.

Attachment A

MEMBERSHIP ROSTER
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING
(All terms end December 31)

Chairperson
Richard J. Hodes, M.D.
Director
National Institute on Aging
National Institutes of Health
Bethesda, Maryland 20892

Ausiello, Dennis A., M.D. (2003)
Chief, Medical Services
Massachusetts General Hospital
Boston, Massachusetts

Cambier, John C., Ph.D. (2003)
Ida and Cecil Green Professor and
Chairman, Integrated Dept. of Immunology
University of Colorado Health Sciences Center
and National Jewish Medical & Research Center
Denver, Colorado

Campisi, Judith, Ph.D. (2002)
Senior Scientist
Division of Cell and Molecular biology
Lawrence Berkeley Laboratory
University of California
Berkeley, California

Dobrof, Rose W., DSW (2002)
Brookdale Professor of Gerontology
Brookdale Center on Aging
Hunter College of the City of New York
New York, New York

Espino, David V., M.D. (2004)
Professor
Department of Family & Community Medicine
Division of Community Geriatrics
University of Texas Health Science Center
San Antonio, Texas

Gage, Fred H., Ph.D. (2001)
Professor
Laboratory of Genetics
The Salk Institute
La Jolla, California

Harper, Mary S., Ph.D. (2001)
Geropsychiatric Research Consultant
and Distinguished Adjunct Professor
The University of Alabama
Tuscaloosa, Alabama

Kuller, Lewis H., M.D., DrPH, MPH (2004)
Professor and Chairman
Department of Epidemiology
Graduate School of Public Health
University of Pittsburgh
Pittsburgh, Pennsylvania

Prusiner, Stanley B., M.D. (2004)
Director and Professor
Institute for Neurodegenerative Diseases
School of Medicine
University of California
San Francisco, California

Riggs, Judith A., M.A. (2004)
Director of Public Policy
Alzheimer's Association
Washington, D.C.

Selkoe, Dennis J., M.D. (2001)
Professor of Neurology and Neuroscience
Center for Neurologic Diseases
Brigham and Women's Hospital
Boston, Massachusetts

Siegler, Ilene C., Ph.D., MPH (2003)
Professor of Medical Psychology
Dept of Psychiatry & Behavioral Sciences
Duke University Medical School
Durham, North Carolina

Vaupel, James W., Ph.D. (2001)
Director and Professor
Max Planck Institute for Demographic Research
Rostock, Germany

Wei, Jeanne Y., M.D., Ph.D. (2001)
Senior Physician
Division of Gerontology
Beth Israel Deaconess Medical Center
Boston, Massachusetts

Weisfeldt, Myron L., M.D. (2002)
Chairman Department and Professor
Department of Medicine
Columbia University
New York, New York

Wise, David A., Ph.D. (2002)
Professor
National Bureau of Economic
Research Cambridge, Massachusetts

Wise, Phyllis M., Ph.D. (2003)
Professor and Chair
Department of Physiology
College of Medicine
University of Kentucky
Lexington, Kentucky

Ex Officio Members

Tommy G. Thompson
Secretary
Department of Health and Human Services
Washington, D.C.

Ruth L. Kirschstein, M.D.
Acting Director
National Institutes of Health
Public Health Service
Bethesda, Maryland

LTC George F. Fuller, M.D.
White House Physician
Washington, D.C.

(Vacant)
Department of Veterans Affairs
Washington, D.C.

(Vacant)
Administration on Aging, DHHS
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.

2 These minutes will be approved formally by the Council at the next meeting on January 29-30, 2002, and corrections or notations will be stated in the minutes of that meeting.