The 95th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, May 24, 2005, at 3 p.m. in Building 31, Conference Room 6, National Institutes of Health (NIH), Bethesda, Maryland. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA), presided.
In accordance with the provisions of Public Law 92–463, the meeting was closed to the public on Tuesday, May 24, 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, May 25, from 8 a.m. to 2 p.m.
The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as Attachment A.
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 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).2
A total of 1024 applications requesting $876,470,422 for all years underwent initial review. The Council recommended 587 awards for a total of $582,588,201 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. Richard Hodes called the meeting to order at 8:20 a.m. on Wednesday, May 25, 2005, and welcomed members to the open session of the National Advisory Council on Aging.
Director’s Status Report
Dr. Hodes summarized some of the issues identified at a recent NIH leadership retreat of Institute directors to address challenges associated with the current budgetary climate at NIH. A number of ad hoc committees were formed to address issues related to research investments and opportunities across NIH. The functions of one such ad hoc committee are to define the proposed NIH Office of Portfolio Analysis and Strategic Initiatives (OPASI), which is co-chaired by
Dr. Hodes and Dr. Kington, Deputy Director, NIH, to address the need for better methods and better information for managing large and complex scientific portfolios, to coordinate trans-NIH scientific initiatives, and to develop better tools and information for informed decision-making. Currently, the planning process for each of the 27 Institutes and Centers (ICs) is distinct. Although there are areas that involve collaboration across ICs, there is no formal or centralized process to coordinate or assess such efforts. OPASI would generate the analyses necessary to implement the infrastructure for a number of initiatives that might not easily be addressed by individual ICs, for example Roadmap-like plans and other trans-NIH initiatives. In addition to providing NIH with transparent decision-making related to trans-NIH and IC-specific strategic planning, priority setting, and portfolio management, the OPASI is intended to improve NIH’s ability to integrate and balance public health needs and burden of illness with scientific opportunities. Measuring burden of illness or public health need is challenging. Nevertheless, this is an opportune time to implement a process using the available information for planning purposes.
One model of OPASI would include: (1) Strategic Analysis to develop and use analytic tools—such as knowledge management to assess current research portfolio investments with respect to public health need or burden of illness; (2) evaluation of the outcomes of research investments, such as the Government Performance Results Act (GPRA) and Program Assessment Rating Tool (PART) evaluations; and (3) strategic coordination to develop common processes and formats for NIH-wide planning. Whether the NIH can or wants to develop a common process and format for NIH-wide planning, and how and in what ways this central office would work with the Institutes as they develop their own plans, are issues that have received intensive discussion. The charge to the committee is to move toward establishing this office within the NIH/OD during the next year. The critical question is how this will inform budget allocations.
Dr. Hodes discussed the Neuroscience Blueprint, an ongoing collaboration among 15 Institutes. Of these, the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Mental Health (NIMH), and the NIA have the greatest investment in neuroscience. The collaboration began when Dr. Elias Zerhouni suggested that coordinating research interests in neuroscience might help IC planning and might help NIH highlight the expanding collaboration and cooperation across Institutes with interest in neuroscience. A first step was to inventory major neuroscience efforts. Individuals representing broad fields of neurosciences across institutes met to discuss priorities, priority-setting, general strategies, and organizational structure. Working committees have focused on identifying available scientific tools and resources and determining how to expand and disseminate them. Improving understanding across ICs, reducing duplication of effort, and producing efficiencies of scale across ICs echo the OPASI theme of coordination and synergy.
In FY 2005, 0.15 percent of the neuroscience research budgets of each of the participating Institutes will commit to a common pool and this amount is expected to increase by 0.15 percent of the budget annually until FY 2008, when each participating IC is expected to contribute 0.60 percent of its neuroscience research budget. Approximately $100 million over 5 years contributed by the 15 ICs is expected to be supplemented in the proposed President’s budget in FY 2006 by $12 million from the OD. The fraction of the total NIH budget that is invested in the Neuroscience Blueprint and in the Roadmap Initiative, the two largest trans-NIH initiatives, adds up to 0.02 percent and 0.83 percent, respectively. In FY 2006, the percentages are expected to increase to 0.09 percent and 1.16 percent. Although the amount invested is modest, strategic investments in these areas should permit a number of research initiatives.
In addition to the global inventory of neuroscience tools, the Neuroscience Blueprint initiatives for FY2005 include the Neurobiology of Disease Training Initiative, Microarray Consortium Expansion, and Pediatric MRI of Normal Development Expansion. Possible initiatives for FY2006 include Neuromouse; training initiatives in neuroimaging, computational neuroscience, and translational research; core facilities for neuroscience research; and behavior and neural health initiatives. These latter initiatives had their origins with strong leadership from NIA, NINDS, and NIMH in the “healthy brain” initiative, and they are now a high priority for future Blueprint initiatives. The behavior and neural health initiative will assess cognitive, affective, and behavioral endpoints along with neuroimaging or other biologic parameters. With that as a baseline, the intent is to construct candidate metrics, including questionnaires, biomeasures, surrogate markers, and imaging of cognitive and mood domains. These would be validated in multiple centers and would result in behavioral outcomes that correlate with neurocircuitry and biological markers to serve research across broad domains.
The initiative on core facilities for neuroscience research would focus core activities that might serve neuroscience investments and provide a common infrastructure. There are, for example, institutions with an Alzheimer’s research center, a Udall or Parkinson’s Center, and a number of other centers. Core resources could serve more broadly and more comprehensively if they were coordinated. Training initiatives would address neuroscience areas where training is most needed across multiple ICs.
The Neuroscience Blueprint has generated constructive dialog. It is not clear whether it will be a template for other initiatives or whether the proposed OPASI structure would help others to coordinate or coalesce. For example, the obesity initiative is often cited as an example of an initiative that might have been anticipated in terms of a public health need and could have benefited from an earlier, more coordinated approach. NIA is likely to participate in many of these types of initiatives because many NIA issues and priorities span interdisciplinary and inter-institute areas of interest. Dr. Hodes noted that these types of trans-NIH initiatives require a commitment of effort and compete for staff time but are important and promise to be productive.
During the question period, Dr. Hodes addressed speculation that NIH may reduce the number of Institutes to try to optimize its structure. Dr. Hodes recalled that the former NIH Director, Dr. Harold Varmus, formulated a proposal that was published in Science and widely disseminated, suggesting groupings of Institutes. The issue has resurfaced in the context of NIH’s legislative re-authorization. Although the NIH functions under general authorization that does not require specific authorizing bills, reauthorization provides an opportunity for the authorizers to make recommendations, including authorizing funds for specific areas of research or disease, and commenting on such things as NIH structure. Dr. Hodes stated that there are strong advocates for each of the ICs, and the suggestion that they be clustered, dissolved, or altered would be a complex public and political, as well as scientific, issue.
In response to a question about the strategic coordination arm of OPASI, Dr. Hodes stated that NIH’s ability to assess the scientific portfolio it supports must be improved. For example, NIH should know what it supports on a particular subject matter and the areas of emphasis, gaps, and duplication. In addition to the knowledge management of a scientific portfolio, the measurement of public health need, burden of illness, and other challenges involve difficult but essential judgments, such as how to prioritize research support and how to translate an understanding of public health needs to better inform allocation and stewardship of scientific resources.
The formation of OPASI could change the dynamics among stakeholders. By making the planning process within NIH more transparent, some advocacy groups may be reassured that their concerns are being addressed in a coordinated way.
A Council member noted a natural conflict between allocating funds based on disease burden in the general population and the advocacy of dedicated groups representing a rare disease.
Dr. Hodes agreed, but cautioned that even with a quantitative metric of burden of illness or public health need, it is not clear how this would translate into priorities. Some would argue that the rare disease may be important not just for those who are afflicted but because of its potential for informing the science that underlies more common diseases.
A composite book of NIA media coverage was circulated for review. Some materials were provided to Council members, such as the Journal of Gerontology issue on Environmental Effects in Genetic Studies of Aging, a monograph on Aging Health Public Policy: Demographic and Economic Perspectives, and the NIA exercise video.
Dr. Hodes next reported on staff transitions. Ms. Lynn Hellinger has joined the NIA as Associate Director for Management. Ms. Vicky Cahan was appointed as the head of the Office of Communications and Public Liaison (OCPL). Dr. Ronald Kohanski, formerly Associate Professor of Pediatrics at the Johns Hopkins University, joined the Biology of Aging Program (BAP) as Program Director for the Cardiovascular Biology Program. Dr. Lisbeth Nielsen joined the Behavioral and Social Research (BSR) Program from Stanford University. She will manage BSR’s Psychological Development and Integrative Science portfolio.
Dr. Huber Warner, Associate Director for BAP, will return to the University of Minnesota where he was previously a full Professor to become Associate Dean for Research in the College of Biological Sciences. Dr. Hodes remarked that while Dr. Warner assumed the administrative leadership of his office, he remained a scientist at heart, in practice, and in attitude.
Future Meeting Dates
- September 27–28, 2005 (Tuesday–Wednesday)
- January 31–February 1, 2006 (Tuesday–Wednesday)
- May 23–24, 2006 (Tuesday–Wednesday)
- September 26–27, 2006 (Tuesday–Wednesday)
Consideration of Minutes of Last Meeting
The minutes of the February 2005 meeting were considered. A motion was made, seconded, and passed to approve the minutes.
III. Report: Task Force on Minority Aging Research
Dr. Marie Bernard, Chair of the Task Force on Minority Aging Research, reported on the following: (1) The group’s lively discussion of an article on racial and ethnic differences in human genetic linkage maps which described the relative locations of genetic markers on chromosomes (Jorgenson E et al. Am J Hum Genet. 2005;76:276-290), (2) the racial and ethnic composition of NIA grantees, (3) minority investigator career development, and (4) preliminary recommendations from the review of minority aging programs within NIA.
Several individuals in addition to Task Force members served as discussants on the Jorgenson et al. and other related papers, including Dr. Jennifer Harris from NIA’s Behavioral and Social Research (BSR) Program and the Department of Genes and Environment, Institute of Public Health in Norway; Dr. Keith Whitfield, an NIA-funded researcher from Pennsylvania State University; and Dr. Marilyn Miller from the Neuroscience and Neuropsychology of Aging (NNA) Program. The Task Force encouraged NIA to continue its interdisciplinary approach toward the definition and meaning of race. To provide a balanced perspective, environment, phenotype, and genotype should be considered and revisited periodically.
Dr. Bernard turned next to a report provided by Dr. Robin Barr in response to the Task Force’s request for information about the composition of NIA grantees by race and ethnicity, as reported by investigators on the PHS 398 form. Dr. Barr cautioned that only 85 percent of investigators complete the voluntary form. The numbers of underrepresented minorities (African Americans, Hispanics/Latinos, Native Americans, Alaska Natives, and Pacific Islanders) have increased somewhat during the period 2002 through 2004. NIH-wide, significantly more K awards are going to underrepresented minority candidates, in part due to five Institutes that have K award programs targeted to underrepresented minorities. For regular research (R) awards, these groups remain underrepresented in biomedical research.
The Task Force members were apprised of minority investigator career development synergies between the Resource Centers for Minority Aging Research (RCMAR) and other institutes. Trainees from the six funded RCMARs have grants and support from at least 12 other institutes and Federal agencies, generating significant multiplier effects as a result of this training initiative.
Dr. Harden presented a preliminary report on progress on eight recommendations from the review of NIA minority aging research that was completed in 2000. These recommendations included (1) eliminating health disparities; (2) defining race, culture, ethnicity, and socioeconomic status; (3) implementing longitudinal and life course studies; (4) integrating biology, genomics, and genetics; (5) refining methods and strategies for research in minority populations; (6) improving recruitment and retention of minorities in research; (7) strengthening and clarifying policies on inclusion of minorities; and (8) building capacity and enhancing training and information dissemination. The preliminary report was based on data from the NIA intramural, BAP, and BSR programs. The group expects to review the remaining programs in September, with data analyses and some recommendations prepared for the February 2006 meeting.
Dr. Miller was invited to share data on the Alzheimer’s disease (AD) Genetics Initiative and Studies in Diverse Populations from the NNA Program. The National Alzheimer’s Coordinating Center (NACC) was established in the late 1990s to provide an infrastructure that facilitates collaborative research among the AD Centers (ADCs) funded by the NIA since 1984. One of the mandates is to maintain a database of patient and control information collected by the ADCs. Between 2000 and 2005, nearly 24,000 new subjects enrolled, with 8 percent Hispanic or Latino, 0.7 percent American Indian or Alaska Native, 2 percent Asian (no Pacific Islanders or Native Hawaiians), 12 percent African American, and 79 percent White. The strong representation of minority populations (now 21 percent compared to 4 percent in the early 1990s) is partly due to the inclusion of 23 satellite centers which were funded to reach out to rural and minority areas that have no ADC.
The AD Genetics Initiative develops resources to find additional risk factor genes for late-onset AD (LOAD), specifically to identify new pathways to understand AD, identify target interventions, and identify people at high genetic risk for AD. The objective is to recruit 1,000 families with 3 living members who can donate blood samples, 2 of whom developed AD after age 60, and to complete the recruitment by the end of 2006. Eighteen ADCs have participated actively in contributing genetics data as part of this initiative, as well as individual NIA-funded investigators and other scientists studying the genetics of AD.
Dr. Miller then discussed scientific issues of interest. The presence of an APOE-ε4 allele is a determinant of AD risk in whites, but the association between APOE-ε4 and AD in African Americans remains unclear. Differences in study designs, or other as yet unidentified genetic variants, or environmental or behavioral risk factors may contribute to disease risk and to APOE variability among African Americans. However, among Caribbean Hispanics, familial late onset AD (LOAD), in contrast to sporadic AD, is strongly associated with APOE-ε4. Two areas of interest are now apparent in the human genome. The first is on chromosome 12—the Caribbean-Hispanic population showed an increased frequency of AD as compared to non-Latino whites. Linkage was found to a region of the short arm of chromosome 12 in Caribbean Hispanics with familial LOAD (Mayeux R et al. Am J Hum Genet. 2002;70:237). The second is on chromosome 18—linkage to LOAD was found on the long arm of chromosome 18 (18q). Three hundred forty markers were studied in 490 family members of 96 families (Lee et al. Mol Psychiatry. 2004; 9: 1042). In one study of early onset AD among Caribbean Hispanics, a new mutation in the PS1 gene was found in 18 unrelated Hispanic families with early onset familial AD. This same mutation was found in a separate group of 319 unrelated individuals in New York City (Athan et al. JAMA. 2001; 286: 2257).
In African Americans, presenilin-1 again appears as a problem. An African American family show an unusual autosomal dominant mutation and rapidly progressive dementia with unusual psychosis. An NIA intramural group has identified a presenilin-1 point mutation only in the individuals with the disease (Rippon et al. Arch Neurol. 2003; 60: 884).
NNA and NIA have emphasized minority recruitment at ADCs and in epidemiology research. NIA supports several genetic epidemiologists interested in studying minority populations. Future work likely will include study of the variation within the alleles to see where the founder populations are. It would be relevant to understand, for example, whether some Hispanic populations have substantial genetic proximity to what are being identified as African American populations. Given the great diversity within racial/ethnic subgroups, it is very difficult to look at regions in the genome using race/ethnicity as a parameter. A more promising approach might be to focus on a unique and more homogenous population to reveal insights about the general population.
IV. Report: Working Group on Program
Dr. Leon Thal reported on the deliberations of the Working Group on Program (WGOP), which met on May 24, 2005.
A. Advisory Meetings
NIH State-of-the-Science Conference on Management of Menopause-Related Symptoms
The NIH State-of-the-Science Conference on Management of Menopause-Related Symptoms, held in March 2005, was cosponsored by the NIA, Office of Research on Women’s Health (ORWH), the National Center for Complementary and Alternative Medicine (NCCAM), and the Office of Medical Applications of Research, as well as 11 other ICs and Federal agencies.
Dr. Sherry Sherman reported that the conference was motivated in part by the Women’s Health Initiative (WHI) finding of increases in cardiovascular disease, stroke, pulmonary embolism, and breast cancer among women using estrogen/progesterone for disease prevention; the resulting confusion over the place of menopausal hormone therapy in the management of menopausal symptoms; and interest in alternative strategies for symptom management. The conference was focused on the characteristics of menopausal symptoms and the factors that influence them, on evidence concerning the benefits and costs of commonly used interventions for relief of menopause-related symptoms, and on future research directions for strategies to ameliorate symptoms.
The dearth of long-term postmenopausal data from prospective cohort studies makes it difficult to characterize the onset, severity, and duration of specific menopausal symptoms adequately. It is clear, however, that rates of menopausal symptoms and the nature of symptoms appear to vary by race/ethnicity, also symptoms are experienced by women who have had surgery (hysterectomy and/or oophorectomy), chemotherapy, or radiation. Therapies are particularly needed for women on estrogen with or without progestin therapy and for women who have had premature ovarian failure.
Estrogen opposed or unopposed is the most consistently effective therapy for vasomotor symptoms and vaginal dryness. Low-dose estrogen therapy appears to be effective for hot flashes in many women. The role of estrogens in ameliorating problems with sleep, mood and depression, and sexual function, as well as decreased quality of life is not clear. Estrogen, with or without progesterone, is associated with significant risks. Progestins have inconsistent effects on vasomotor symptoms. Among androgens, testosterone (with estrogen) may have positive effects on libido, particularly in ovariectomized women, but there are results only from small short-term studies. Dehydroepiandrosterone (DHEA) has mixed effects on vasomotor symptoms and libido. Androgens are associated with significant side effects, such as acne and hirsutism. Another approach, Tibulone, a selective estrogen response modulator, may have beneficial effects on vasomotor symptoms, sleep disturbances; osteoporosis, and potentially libido. It has not been approved in the US, but is undergoing testing.
Other promising agents for relief of menopausal symptoms include antidepressants, such as Fluoxetine and venlafaxine paroxetine, and other drugs (e.g., Gabapentin, Clonidine, Bellergal). However, the long-term effects of these agents are unknown. In complementary and alternative medicine approaches (CAM), phytoestrogens (i.e., dietary soy, flax, soy extracts, isoflavone preparations), other botanicals (e.g., red clover leaf, black cohosh, other herbs), and behavioral interventions (e.g., exercise, paced respiration, biofeedback) have been evaluated.
NIH is strongly encouraged to promote the development and use of standard definitions, measures, outcomes, and statistical methods so that findings from studies using different strategies can be compared. Analyses of data from cohort studies on the onset, timing, and duration of symptoms should be expedited; characteristics of women who have no or minimal symptoms should be identified; and research should focus on symptoms in women with premature, surgically induced, and chemotherapy- or radiation-induced menopause. With respect to therapeutic interventions, optimally effective doses, combination regimens, durations of use, and the timing of therapy need to be identified. Most importantly, long-term risks of adverse effects have to be clarified in adequately powered randomized clinical trials. It also would be very useful to evaluate approaches to identify appropriate candidates for specific therapies.
NIA is exploring next steps with the ORWH in a trans-NIH menopause working group. The group is considering examining the methodological issues, particularly definitions of the menopause transition that are nonstandard and have plagued the comparison of findings from study to study. NCCAM, NIA, and other ICs cosponsored a request for applications (RFA) using the Small Business Innovation Research (SBIR) mechanism to develop strategies for objectively assessing hot flashes. Also discussed by the working group were standardizing data collection instruments and capitalizing on existing databases, particularly the WHI, in secondary data analysis to determine the risks for subgroups with symptoms.
Exercise: A Guide from the NIA
The Office of Communications and Public Liaison (OCPL), working with the Geriatrics and Clinical Gerontology Program, is convening an advisory expert panel to help update the very popular Exercise: A Guide from the NIA. The first panel was convened in 1996, and the guide was issued in 1998. It is timely now to reassess, reevaluate, and update the guide. The panel will begin work in June to assess the current guide, review research findings and other information, and update as needed. There is considerable interest in looking at behavioral motivational issues with respect to initiating and maintaining exercise now that the benefits of exercise have been demonstrated. The guide encourages people to exercise and provides information on how to exercise safely, especially for people with arthritis or other limitations.
B. RFA Concept Clearance
Three requests for RFA concept clearances were presented, all of which were recommended for approval by the Working Group on Program, and approved by Council voice vote.
Dr. Carrington described an RFA to investigate the fatty infiltration and replacement of musculoskeletal tissues that occurs with aging. In addition to fatty infiltration, a change in the character of some of the musculoskeletal tissue cells can occur so that an adipocyte-like phenotype is adopted. It is important to understand the causes and mechanisms of this change with age, particularly because adipose is a powerful endocrine organ and may be secreting factors both locally and into the circulatory system that can affect musculoskeletal and other tissues.
Dr. Wagster presented a proposal from the Neuroscience Blueprint for concept clearance. These proposals are produced through project teams with representatives from the participating 15 Blueprint ICs. NIA is leading the development of the proposed initiative to foster neuroepidemiological research in large cohort studies. Through formal and informal assessments of the research community and a number of participating ICs, it was determined that the most useful and immediately needed research resource is a set of measures or an assessment tool that is reliable and valid and could briefly but comprehensively assess multiple indicators of neural and behavioral health, such as cognitive, emotional, sensory and motor function. This would maximize yield from large cohort studies and clinical trials with minimal increase in subject burden and cost. It would be used across studies, designs, and diverse populations, allowing for comparison of data across studies and the ability to combine datasets. This proposal has been supported by the Blueprint coordinating committee as well as by the directors of the neuroscience institutes.
Ms. Hahn presented the third concept clearance request for an RFA to encourage small businesses via the SBIR (R43/R44) and Small Business Technology Transfer (STTR) (R41/R42) mechanisms to develop survey technology and archiving methods for behavioral and social surveys of older people. BSR has supported at least a dozen longitudinal surveys, which have become increasingly complex and multidimensional, collecting biological samples as well as administering performance tests. As a result of many advisory meetings, including those convened by the National Academy of Sciences, and consultations with individual Principal Investigators, BSR has identified two areas for development: (1) Archiving of already collected data to facilitate secondary data analyses and (2) improving survey technology with a particular emphasis on biological indicators to increase the portability, speed, ease, unobtrusiveness, and cost-effectiveness of data collection for population-based household surveys and behavioral interventions.
C. Biology of Aging (BAP) Review
Dr. Thal reported that BAP will be undergoing a Council review. The committee has been charged with this task and had their first meeting on May 24. Dr. Judith Campisi has agreed to chair the committee. A report is expected by the next council meeting.
D. Other Issues
Dr. Bernard has agreed to organize a small geriatrics research workforce to begin to address the issue of support needs for aging research. The discussion will continue at the next Working Group on Program meeting.
V. Report: Finding Synergy: Advancing the Development of Physician–Investigators in Aging and Geriatrics—Update
Dr. Salerno explained that in 2001, Council expressed concern about the lack of physician investigators in aging research. Not only are fewer physician–investigators entering biomedical research, fewer are staying once they do enter. Council members joined NIA staff in planning a meeting, held in November 2002, that brought together professional organizations, academia, foundations, and advocacy groups in aging to consider ways to further the development of physician–investigators in aging. A number of recommendations were formulated, and some advances have been made. In particular, the NIH has addressed the issue of salary support by allowing R01 funding to be used for salary support for career awardees.
NIA also has developed a partnership with a number of foundations to support physician-researchers. The Beeson Career Development Award program, is now in its second review cycle, as a public-private partnership which develops clinically trained researchers in aging. Foundation co-funding has made it possible to support a continuing mentorship program, an annual meeting to promote scientific exchange, and an advisory group. Every Beeson scholar has a Beeson advisor in addition to the advisor or mentor at his or her local institution. Nearly all of the scholars from the past 10 years of the program (including prior to NIA’s partnering with the foundations) have been retained in aging research or in related fields. The NIA is committed to continuing this program. This year, in addition, there is a cosponsored program supported through a T35 training mechanism whereby medical students at institutions across the country are introduced to aging research through a summer experience. A joint solicitation reflecting support by both foundations and NIA elicited an overwhelming response. Each training site will be able to support a number of medical students.
Discussion ensued about the need for protected time for investigators in the very early stages of faculty development prior to the time that they receive their first career award. There is no program at NIH today that provides “bridging” support for new faculty, and it is rare for a new applicant to compete successfully for a career award given without at least one, if not two, application revisions. Given budget limitations, it is difficult to develop broad-ranging new mechanisms, but one partial solution being discussed is to continue support through an investigator’s transition from postdoctoral fellow to new faculty.
VI. Presentation: Transdisciplinary Science and OBSSR—Lessons From Tobacco Research and Visions for the Future
Dr. David Abrams, Director of the Office of Behavioral and Social Sciences Research (OBSSR), NIH, shared his vision for transdisciplinary science and OBSSR, and ways in which the NIA can play a role in that vision. He began by presenting an overview of the OBSSR, followed by his vision for the future of BSSR, drawing on lessons learned in tobacco research to illustrate his points.
Overview of the Office of Behavioral and Social Sciences Research
The OBSSR is a trans-NIH office that works with the extramural and intramural research communities and seeks synergisms across all 27 Institutes and Centers (ICs). Its mission has four components: (1) Increase scope of, and support for, BSSR; (2) inform NIH leadership and NIH community about BSSR; (3) represent NIH to outside BSSR community; and (4) disseminate BSSR information to NIH and the public. The OBSSR does not fund grants directly but provides supplemental funds and seed monies to relevant trans-NIH and IC-specific activities. One of the initiatives that OBSSR spearheads is an analysis of behavioral and social science core measures that might contribute to the understanding of gene environment interactions over the lifespan. Attention will be paid to transdisciplinary research, including critical basic science as well as “dissemination research” (i.e., from bench to bedside to community). Advances in measurement tools, statistical and sampling methods, and data sharing capabilities will help to address questions that combine biology with behavioral, social and population sciences.
Dr. Abrams defined “transdisciplinary” research as characterized by more than “multi-disciplinarity” (researchers in different disciplines working on a problem area independently, each from their own perspective), and “trans-disciplinarity” (working jointly from a shared conceptual framework, drawing together discipline-specific theories and concepts, and developing new synthesis, measures, and methods (cf. Rosenfield P.L. Soc. Sci. Med. 1992; 35 (11): 1343-1357). Transdisciplinarity influences how one conceptualizes problems and asks questions, leading to more comprehensive theories and research designs, new methodologies and better measures of underlying constructs. Expected outcomes are higher explanatory power, and greater likelihood of translating research into interventions that work. An investment in transdisciplinary research also changes how the next generation of researchers is trained.
Dr. Abrams called for more explicit thinking about life span development and sensitive periods (e.g., in utero, adolescence), as well as particular attention to intra-individual variation interacting within nested contexts over time. More longitudinal research with at least four or more data points will facilitate the study of transitions and trajectories. In discussing biopsychosocial interactions, Dr. Abrams described behavior as the leading edge of a gene environment interaction. The identification of behavioral phenotypes is particularly challenging. It therefore is not surprising that the genes for alcoholism, drug addiction, and so forth, are so hard to find. Behavioral expression can be seen as a lifetime history of gene environment interaction.
Biobehavioral Model of Nicotine Addiction and Tobacco-Related Cancers
Dr. Abrams presented trends in cigarette smoking among 12th graders, by racial/ethnic group in the United States for the period 1977-1998, based on cross-sectional data from the Monitoring the Future youth behavior biennial surveys. The cigarette consumption trend among adults over the last century shows a pattern of steadily rising adult per capita cigarette consumption until a decline beginning in the mid-1960s. This decline in smoking, which has been associated with the accumulation of interventions and public health messages, was followed 20-30 years later by a reversal of increasing cancer rates, especially among men. One might argue that discoveries of epidemiology, social and behavioral sciences linking smoking with premature disease and death have resulted in interventions at every level, from economic and tax incentives, policies, and behavioral treatments, to underlying genetic vulnerabilities in lung cancer exposure. All of this has combined to create a dramatic public health success story of the past century.
Nevertheless, more than 440,000 deaths in the U.S. each year are attributable to cigarette smoking. In addition, it is not clear whether the female age-adjusted lung cancer death rate has leveled off. Globally, the picture is bleaker. Cigarette consumption is increasing exponentially in China, particularly among women.
A generic biobehavioral model of nicotine addiction has been applied to cancer. Psychosocial, psychological, and behavioral and biologic factors interact to produce the addiction and the lifetime exposures that will eventually lead to cancer and premature death. Dr. Abrams presented findings from his multi-generational study of nicotine dependence phenotypes. His study had an embedded genetic sibling pair and family linkage design to examine factors such as the transmission of nicotine dependence across generations and to determine how that might interact with co-morbidities such as depression, other substance abuse, and other mental health issues that often are associated with smoking. This study relied on following a subset of 7,000 pregnant women from the National Collaborative Perinatal Project in the New England area between 1959 and 1964 along with their children. Biomarkers were available from stored cord blood. By tracking the epigenetic pathway from pregnancy and in utero exposure through adolescence,
Dr. Abrams sought to examine the modifications in the trajectories as a result of the gene-environment interaction.
Dr. Abrams further explained that by constructing a two-generational model, it is possible to relate mothers’ smoking patterns during pregnancy and early childhood environmental factors to adult cohorts’ current nicotine dependence profiles as well as mood, psychiatric and attentional factors. Approximately 48 percent of the mothers smoked during pregnancy, as verified by serum cotinine levels in the cord blood, and in utero exposure was classified as none, moderate, and heavy (Beuka, Shenassa and Niaura, Am J. Psychiatry, Dec 2003). Observed patterns were consistent with the expectation that experimentation in youth is not related to the genes for nicotine addiction but is more likely related to attention-seeking, sensation-seeking, attention deficit hyperactivity disorder (ADHD), or shyness or a propensity toward depression which might make youths vulnerable to peer pressure to try to smoke. Some of the relationships emerge more clearly when one observes the progression from ever-smoking to regular smoking, from ever-smoking to nicotine dependence, and from regular smoking to nicotine dependence. Youths whose mothers smoked in utero were about twice as likely to become nicotine dependent after starting to smoke as youths whose mothers did not smoke in utero. When new measures from a more recent study are introduced, an even stronger relationship is observed.
Dr. Abrams discussed the Chicago Neighborhood Study, where researchers measured the proximal neighborhood environment across roughly 80 neighborhoods in Chicago where the subject children live, following the children as they progressed to adolescence. Also included were factors associated with the family, work, school, and neighborhood environments (e.g., density of the neighborhood’s smoking outlets and enforcement of youth tobacco laws that prevent the sale of cigarettes to youth). Controlling for poverty and social cohesion, and some other confounders, there is a strong relationship between tobacco uptake and progression to daily smoking among the youths living in these neighborhoods as a function of outlet density. Thus, some of the uptake trajectories appear to be clearly related to the environment and the neighborhood smoking density, which may not be genetically driven.
Mapping full phenotypes requires characterizing environmental exposure and individual susceptibility over the lifespan. For some of the behavioral issues of interest, the challenge of the future is to understand the gene-environment interaction. A rapid uptake curve could be associated with a strong environment, such as outlet density that is driving most of smoking, or with genetic susceptibility, or both. Only with a two-type design applied across the lifespan can one begin to tease these apart.
Dr. Abrams described next the Functional Magnetic Resonance Imaging (fMRI) study. Beginning to understand this interaction requires multiple measures and multiple disciplines. Another critical issue to be considered is that nicotine crosses the blood-brain barrier approximately seven seconds after inhaling it. Thus, it is not surprising that nicotine is an insidious addiction given its stimulation of the dopaminergic reward pathway of the brain. In developing pharmacogenomic treatments, it is important to consider the endophenotypic expression of underlying nicotine susceptibility through stress studies and exposure to nicotine or cues to nicotine. Ways to look at individual nicotine susceptibility use individual reactions to particular cues, such as higher craving and higher physiologic stress reactivity on the sight and smell of cigarettes after a period of deprivation.
In summing up, Dr. Abrams noted that transdisciplinary research offers the potential to reduce the population prevalence of smoking through interventions arising from the multi-level, interactive character of the approach. His hope for the next decade is to advance cross-disciplinary work, whether it be in the study of pre-disease pathways, basic science areas, health communities, population health, health disparities, interventions or development of new measures and methodology. There is a need to strengthen the infrastructure within universities and the NIH to support and enrich a transdisciplinary team science approach, ensuring also that junior investigators can be rewarded for pursuing team science.
In response to one Council member’s inquiry about the accuracy of retrospective reports of cigarette smoking, Dr. Abrams stated that respondents’ memories generally are adequate if there is sufficient sample size and power. There are, however, ways to elicit reliable answers by anchoring to memorable events. Progress is needed on efficient markers of the measures so that they can be tested in a laboratory in a relatively short timeframe, and serve as the basis for validation of self-reports. (This is also one of the goals of the Neuroscience Blueprint initiative.) According to Dr. Leon Thal, a similar exercise was conducted by the MacArthur Foundation about twelve years ago in a study related to child language development. A series of communicative disorder inventories were completed by parents and their responses were validated against measures taken from laboratory observations of children. It was found that between certain ages, parents were quite accurate in their reports.
An exciting opportunity is exemplified by methodologies like item response theory that can map each item’s sensitivity on a questionnaire to the outcome of interest, rapidly identifying the two or three items that can proxy for a 20- or 30-item questionnaire. With web-based and computer-assisted technologies, quick branching algorithms can be developed with skip patterns and follow-on questions that make it possible to increase the usable information collected within survey time constraints.
Dr. Molly Wagster, a co-architect of the Neuroscience Blueprint initiative, commented that a trans-NIH solicitation is being planned that serves to underscore interest in standardized measures and instrument development, incorporating item response theory and its applications. The larger goal is to develop brief batteries that can be administered to large numbers of individuals and in diverse populations.
VII. Program Highlights
Neuroscience and Neuropsychology of Aging: Regulation of Beta-Amyloid Formation
Professor Paul Greengard, a member of Council, presented current studies conducted by his research group in the area of regulation of β amyloid (Aβ) formation and Aβ toxicity.
He began by providing a historical review of the important discoveries between 1907 and 2005 in the area of Aβ peptide, the major pathological determinant of AD. He then turned to studies on the regulation of intracellular β amyloid precursor protein (βAPP) trafficking and how this regulation determines the levels of Aβ production, the major constituent of cerebral vascular amyloid plaques, versus the production of the soluble form of APP (sAPPα), a protein that plays a beneficial role in brain function. Professor Greengard’s research group demonstrated that the increased incidence of AD in postmenopausal women could be explained by the discovery that estrogen increases the translocation of APP from the trans-Golgi network to the plasma membrane, thereby preventing the production of Aβ. Similarly, the increased incidence of Alzheimer’s disease in patients suffering diabetes mellitus could be accounted for by the discovery that insulin increases the secretion of Aβ from an intracellular to an extracellular location. Professor Greengard reported recent data demonstrating that phospholipase D1, essential for the budding of vesicles from the trans-Golgi network and secretion from the plasma membrane, interacts with presenilin-1 (PS1), a multitransmembrane–spanning protein predominantly found in the endoplasmic reticulum and early Golgi. This interaction results in increased trafficking of βAPP to the cell surface, which inhibits PS1–mediated production of Aβ.
Professor Greengard further described studies demonstrating the development of a cell-free system, reconstituted from mouse neuroblastoma cells that had been doubly transfected with human amyloid precursor protein (βAPP695) and human wild-type PS1 transgene. The results showed that APP could be converted to Aβand that this process required the presence of adenosine triphosphate (ATP). In the absence of ATP, βCTF, the C-terminal fragment of γ-secretase action on APP, accumulates, and Aβ formation is prevented. These results demonstrate that γ-secretase, which degrades βCTF to Aβ is an ATP-dependent enzyme. Moreover, the addition of Gleevec, an anticancer agent utilized in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors, by virtue of its ability to inhibit the tyrosine kinase Abl, also inhibits γ-secretase activity leading to an accumulation of βCTF and a reduction of Aβ. Of particular interest, Gleevec inhibits βCTF cleavage (thereby reducing Aβ, but not Notch-1 protein cleavage. (Notch-1 is required for neuronal and glial differentiation in the cerebellum.) Moreover, Gleevec is able to rescue long-term potentiation (LTP), commonly regarded as the cellular basis of memory, in an AD/Down’s Syndrome mouse model. These results suggest the possibility that using Gleevec derivatives to inhibit the production of Aβ by affecting the action of ATP may prove useful for the treatment of AD.
Professor Greengard concluded by discussing recent studies on the mechanism by which Aβ disrupts glutamatergic (excitatory) neurotransmission, inhibits synaptic plasticity, and reduces LTP. Dr. Greengard and his collaborators have demonstrated that this toxic action involves activation by Aβ of the α7 nicotinic receptor, leading to an increase in intracellular calcium. This is followed by the sequential activation of the protein phosphatases, PP2B and STEP, and dephosphorylation of tyrosine 1472 of the NMDA receptor (a receptor that plays a critical role in synaptic plasticity mechanisms and thus is necessary for several types of learning and memory), leading to its endocytosis and disruption of glutamatergic transmission. These findings have elucidated an important signaling pathway by which it may be possible to reduce or prevent Aβ toxicity. Two approaches are currently being investigated by Dr. Greengard’s research group in this regard: (1) Inhibition of the formation of Aβ through the modification of APP trafficking and (2) inhibition of Aβ toxicity through the elucidation of the molecular mechanism by which Aβ disrupts synaptic transmission.
Biology of Aging: Impact of Aging on Stem Cell Repair in Atherosclerosis
Dr. Pascal Goldschmidt-Clermont, Chief of Cardiology, Duke University Medical Center, spoke on cell-therapy solutions for arterial disorders.
Atherosclerosis is an accumulation of fatty plaques in arterial walls. The plaques form at sites of microscopic injuries, and can lead to narrowing of arteries; severe narrowing of coronary or cerebral arteries are causes of heart attacks and strokes which are major health problems in the United States. Arterial injuries and repair processes occur throughout life, but these processes become less efficient during aging or in the presence of risk factors such as chronically elevated cholesterol in the blood. To study the contributions of aging and high cholesterol to atherosclerosis, a mouse “model system” was used: Mice engineered to lack Apolipoprotein E develop atherosclerosis from chronically high levels of cholesterol in their blood. With these “ApoE-null” mice, Dr. Goldschmidt analyzed molecular changes that take place during the injury repair process and identified a novel class of bone marrow cells that may be critical players in the repair process.
Bone marrow cells contribute to the repair process. If bone marrow of an ApoE-null mouse is entirely replaced by bone marrow from a normal (ApoE+) mouse, hypercholesterolemia is “cured” and atherosclerosis is absent; the disease was effectively cured because the primary cause of atherosclerosis had been removed. Whether there are other roles for the bone marrow cells in atherosclerotic repair was addressed by the following experiment: bone marrow cells from a donor ApoE+ mouse were injected into a recipient ApoE-null mouse maintained on a high fat diet. The hypercholesterolemia persisted in the recipient mouse but the atherosclerosis was dramatically reduced; the cause remained but the disease abated clearly suggesting a curative role for injected bone marrow other than reducing the level of circulating cholesterol. Bone marrow cells from the donor become resident in several tissues, such as spleen and liver. Importantly, they were shown to reside in the aorta of the recipient where they had differentiated to endothelial and smooth muscle cells, suggesting the donor cells had the capacity to repair or rejuvenate atherosclerotic arteries. Aging also contributes to atherosclerosis, and the following experiment suggests that part of the defect is in the aged bone marrow. When the donor is a young ApoE-null mouse, atherosclerosis is reduced in the recipient, but when the donor is an old ApoE-null mouse, repair of atherosclerosis was ineffective.
The development of atherosclerosis produces inflammatory signals that call for bone marrow cells to mobilize, then follow homing signals to the site of atherosclerosis, and finally enter the site and repair the atherosclerosis. Interleukin-6 (IL-6), which is increased by inflammation, elevated cholesterol, and aging is secreted by atherosclerotic arterial walls. Despite the concurrence of multiple factors controlling IL-6 levels, it was possible to show experimentally that IL-6 was correlated most closely with atherosclerosis. In the ApoE-null model system described above, if atherosclerosis was “cured” by treatment with young bone marrow cells, the levels of IL-6 were reduced irrespective of whether cholesterol levels were reduced or remained high. Bone marrow cells from aged ApoE-null donors also reduced IL-6 in the recipient, although cells from these aged donors were less effective than from young donors. Thus, there was a correlation between the relative abilities of bone marrow cells to repair atherosclerosis and to reduce inflammatory signals.
Three stages of atherosclerosis include the initial phases of lesion formation, development of the lesion – which is the inflammatory process that sends signals to the bone marrow – and subsequent progression of the lesion with narrowing of the artery. In the aorta, lesions are formed and repaired continuously in young mice, but the lesions are repaired less with increased circulating cholesterol and age, as noted above. In each of these stages of the disease there are characteristic genes expressed, i.e., each phase has a unique signature or gene-expression profile. Specifically, fewer than 200 of the thousands of genes tested were enough to distinguish each stage of disease progression in the aorta: predominantly genes of metabolism, of inflammation, and of repair were characteristic of each stage, respectively. In young mice, expression of the signature repair genes in the aorta was observed, but their expression in the aorta was diminished with age. Together with the previous results, it appears that aging and chronic disease reduce the ability of arteries to enable the repair mechanism but also reduce availability or effectiveness of bone marrow cells that are needed for arterial repair.
Which bone marrow cells are required for repair of atherosclerosis, and which specific class of bone marrow cells involved in this repair process decline with age or disease? There are multiple classes of bone marrow cells, and several are candidates for repair of atherosclerosis. Some bone marrow cells are able to differentiate into endothelial and smooth muscle cells, these can be isolated and shown to repair atherosclerotic lesions. These cells have established “marker proteins” that allow their identification and separation by employing fluorescently-labeled antibodies that are specific for each marker protein together with a means of detecting and sorting them, i.e., fluorescence-activated cell sorting technology (FACS). Based on this isolation by FACS, none of these “marked” bone marrow cell types fit the essential criteria for age- and disease-affected bone marrow cells. However, another feature of FACS is that cells are sorted by size and granularity (relative abundance of intracellular organelles); from this feature of FACS a population of “simple little cells” were identified that lacked the marker proteins mentioned above. When isolated and injected into the model ApoE-null mouse, these simple little cells could repair atherosclerotic lesions. They were capable of differentiating into endothelial cells, which is part of the repair process. Most importantly, these cells decrease in abundance with disease progression. Further work on these simple little cells will determine their importance for repair of atherosclerosis, and will elucidate the underlying mechanisms for their obsolescence leading to the reduced capacity of aged or diseased bone marrow to repair atherosclerosis.
Behavioral and Social Research: Plasticity of Longevity
Dr. Vaupel is founder of the interdisciplinary field of biodemography and is the Director of the Max Plank Institute on Demography and a professor at Duke University. Dr. Vaupel’s presentation focused on two salient aspects of gerontological research, namely (1) the plasticity of human life expectancy and (2) the plasticity of age-specific mortality patterns across species.
Up to 20 years ago, it was commonly believed that every species had a species-specific lifespan. Since then, several studies have underscored the plasticity of human life expectancy. For instance, record national life expectancy among countries that lead in these statistics increased from 45 years for Swedish women in 1840 to 85.3 years for Japanese women in 2003. Essentially, life expectancy in the “best practice” countries (or countries that have the greatest life expectancy over time) increased by approximately 40 years in a 160-year span. The nature of this rise is characterized by its linearity and steady increase of approximately 2.5 years per decade. Scholars have predicted a limit to further increases in human life expectancy. However, life expectancy has continued to rise at a steady rate with no sign of deceleration. Dr. Vaupel emphasized the need to support studies that address why life expectancy has risen at such a dramatic, yet steady pace. He advocated studies on the development of methods that utilize linear rise of life expectancy as a basis for future life expectancy forecasting.
With respect to the United States, Dr. Vaupel explained that life expectancy prior to 1950 rose at a rate of 3 to 4 years per decade. By 1950, the United States was close to becoming the world’s life expectancy leader. A period of stagnation in the 1950s and 1960s was followed by a further rise in the 1970s. However, beginning in 1980, U.S. life expectancy rose at a slower rate. Furthermore, life expectancy at age 65 has stagnated, particularly for females. The United States continues to lag behind Japan, France, and Germany, but the reasons for this are unknown. Thus, understanding the causes of this country’s poor performance in this area also should be a high priority for NIA-supported research.
Dr. Vaupel then turned to another aspect of the plasticity of longevity, namely the differences in patterns of age-specific mortality across species. He explained that recent theoretical and empirical research has demonstrated that a rise in mortality across the adult age span is not universal. It is sometimes evolutionarily optimal for age-specific mortality to decline with age, at least until an advanced old age, which few individuals attain. Empirical evidence suggests that, for many species, including many plant species and various animal species with indeterminate growth, mortality decreases with age while fertility usually increases with age.
Dr. Vaupel then described the emerging field of evolutionary demography, a field that addresses the study of the age trajectories of mortality, fertility, growth, and intergenerational transfers. He concluded by stating that he fully supported placing a high priority on the development of this field as recently concluded in the BSR Council review.
A Council member inquired whether the impact on average life expectancy from common causes of death had been determined. Dr. Vaupel replied that eliminating a particular cause of death has a limited effect on life expectancy. For instance, eliminating cancer causes life expectancy to increase by approximately 5 years. However, if cancer and cardiovascular disease were eliminated in men, the effect would be additive—total life expectancy would increase by approximately 15 years. Thus, as various causes of death are eliminated, life expectancy continues to rise.
A second question addressed the life expectancy variability in the U.S. population as compared to “best practice” countries and/or those with better access to health care. Dr. Vaupel pointed out that since 1980, a reduction in death rates before age 65 similar to that of the “best practice” countries has been observed in the United States. However, it is the life expectancy stagnation that occurs after 1980 among the 65 and older age group in this country that is not easily explained, particularly since Medicare and Medicaid coverage is in place for the elderly.
Another Council member inquired whether “best practice” countries also have the lowest age-specific mortality across all ages, or whether there is variation across countries. Dr. Vaupel explained that high life expectancy countries tend to do well across all ages as reflected by the small life expectancy variance observed. Thus, plotting life expectancy at every age yields a straight line as does plotting life expectancy over time in the highest socioeconomic status groups in each of the “best practice” countries.
Geriatrics and Clinical Gerontology: Changes in Reproductive Hormonal Patterns and the Hypothalamic-Pituitary-Ovarian Axis
Dr. Nanette Santoro is Professor and Director of Reproductive Endocrinology at Albert Einstein College of Medicine and currently Principal Investigator of the New Jersey Study of Women’s Health Across the Nation (SWAN). Dr. Santoro’s presentation focused on the causes of menopause and hypothalamic-pituitary sensitivity to estrogen.
The causes of menopause are not yet well understood. While there is some evidence that ovarian function declines progressively up to the final menses, there is also evidence that ovarian function remains sufficient, particularly in terms of estrogen production, until women reach the very late stages of the menopause transition process. To explain this paradox, Dr. Santoro introduced the working hypothesis that women entering menopause who fail to ovulate experience central nervous system (CNS) dysregulation, particularly in the hypothalamic-pituitary response to estrogen feedback and the luteinizing hormone (LH) surge mechanism. Supporting this hypothesis are several studies that show that anovulatory cycles occur in perimenopausal women in association with normal or high levels of estradiol/estrogens. In addition, exogenous estrogen administration to perimenopausal women is known to result in failure of the positive feedback response of estradiol on the central reproductive neural axis.
To determine if human menopause is associated with alterations in the hypothalamic-pituitary response to estrogen feedback, Dr. Santoro and her collaborators studied daily urinary hormone patterns in a subcohort of 840 women who participated in the Daily Hormone Study, a SWAN substudy. Daily urine samples were collected and measured for LH; follicle stimulating hormone (FSH); and the estrogen and progesterone metabolites, estrone conjugates and pregnanediol glucuronide, respectively. Objectively applied algorithms were used to separate cycles into luteal and aluteal patterns. The menstrual cycles of 160 women (19 percent) who did not have evidence of luteal activity (and therefore were presumed to have a failure of ovulation in the observed cycle) were carefully examined.
Three patterns emerged from the data: (1) Cycles with estrogen increases and LH surges (n=29), (2) cycles with estrogen increases and no LH surges (n=32), and (3) cycles with neither estrogen increases nor LH surges (n=98). There were no differences in basic demographics between the women in each of the three groups, although women in the third group reported more menopausal symptoms (i.e., hot flashes) than those in the other two. The frequent observation of anovulatory cycles with estrogen peaks equivalent to those in ovulatory cycles (yet without LH surges) indicated the failure of estrogen-positive feedback on LH secretion. In other anovulatory cycles, follicular phase increases in estrogen levels did not lower LH secretion, also indicating a failure of estrogen-negative feedback on LH secretion.
Dr. Santoro noted that these findings are compatible with the notion that hypothalamic-pituitary insensitivity to estrogen is a frequent event in the ontogeny of human menopause and support the applicability of similar findings in animal models of menopause to humans. She further elaborated that decreasing sensitivity to estrogen is speculated to be a function of aging. Finally, she posited that decreasing sensitivity may be responsible for the onset of puberty, when sensitivity is reduced to a threshold sufficient to allow regular menstrual cycling, and partially responsible for menopause, when sensitivity is reduced to the point that ovulatory failure results.
A Council member inquired whether there is evidence of CNS sensitivity changes to FSH, LH, and gonadotropin-releasing hormone (GNRH) in animal studies. Dr. Santoro replied that there are data indicating that gamma-aminobutyric acid (GABA), a neurotransmitter that regulates midcycle GnRH/LH release, increases with aging and that there is a decrease in expression of GNRH receptors resulting in less sensitivity and a significant reduction in GNRH signal transmission. She also mentioned that the degree of disruption of norepinephrine pathways during the transition to menopause is not clear since these disruptions involve circadian changes that are not present in humans at the time of menopause. However, some of the data published by Weiss and collaborators show that when the LH surge breaks down in rodents, circadian changes occur concomitantly.
Conclusion: Dr. Hodes and Council members thanked the presenters for stimulating talks and discussion.
VIII. Adjournment
The 95th meeting of the National Advisory Council on Aging was adjourned at 1:50 p.m. on May 25, 2005. Dr. Hodes closed the Council session by thanking all speakers and the Council members for their participation. The next meeting is scheduled for September 27-28, 2005.
IX. Certification
I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete.3
Richard J. Hodes, M.D.
Chairman, National Advisory Council on Aging
Director, National Institute on Aging
Prepared by Miriam F. Kelty, Ph.D.
With assistance by Rose Li and Associates, Inc.
Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
Bethesda, MD
Marie A. Bernard, M.D. (2005)
Donald W. Reynolds Chair
Department of Geriatric Medicine
University of Oklahoma College of Medicine
Oklahoma City, OK
Elizabeth H. Blackburn, Ph.D. (2006)
Professor
Dept of Biochemistry & Biophysics
University of California
San Francisco, CA
Melissa M. Brown, M.D. (2006)
Director
Center for Value-Based Medicine
Flourtown, PA
*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
*Linda P. Fried, M.D., MPH (2006)
Professor, Medicine, Epidemiology & Health Policy
Director, Division of Geriatric Medicine &
Gerontology
Director, Center on Aging and Health
The Johns Hopkins Medical Institutions
Baltimore, MD
Alan M. Garber, M.D., Ph.D. (2007)
Director
Center for Primary Care and
Outcomes Research
Center for Health Policy
Stanford University
Stanford, CA
F. Michael Gloth, III, M.D., (2005)
President
Victory Springs Senior Health Care
Reisterstown, MD
Paul Greengard, Ph.D. (2008)
Vincent Astor Professor
Laboratory of Molecular & Cellular Neuroscience
The Rockefeller University
New York, NY
*Eugene M. Johnson, Jr., Ph.D. (2005)
Norman J. Stupp Professor, Department of Neurology
Professor, Dept. of Molecular Biology & Pharmacology
Co-Director, Alzheimer's Disease Research Center
Washington University School of Medicine
St. Louis, MO
Ronald D. Lee, Ph.D. (2005)
Jordan Family Chair of Economics
Professor, Demography and Economics
Director, Center on Economics and
Demography of Aging
University of California
Berkeley, CA
*Virginia M.-Y. Lee, Ph.D. (2007)
Professor
Dept of Pathology & Laboratory Medicine
Univ of Pennsylvania School of Medicine
Philadelphia, PA
Spero M. Manson, Ph.D. (2006)
Professor of Psychiatry and Head
American Indian & Alaska Native Programs
University of Colorado Health Sciences Ctr
Aurora, CO
Mills, Terry L., Ph.D. (2008)
Associate Dean for Minority Affairs
and Special Programs
Office for Academic Support
and Institutional Services
University of Florida
Gainesville, FL
Peter W. Nauert, J.D. (2005)
Principal
Insurance Capital Management
Fort Worth, TX
Gary B. Ruvkun, Ph.D. (2007)
Professor, Molecular Biology
Massachusetts General Hospital
Boston, MA
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
*Leon J. Thal, M.D. (2005)
Professor and Chair
Department of Neurosciences
University of California San Diego
School of Medicine
(and Staff Physician, Neurology Service,
San Diego Veterans Medical)
La Jolla, CA
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
Michael O. Leavitt
Secretary
Department of Health and Human Services
Hubert H. Humphrey Building
Washington, D.C.
Elias Zerhouni, M.D.
Director
National Institutes of Health
Public Health Service
Bethesda, Maryland
James F. Burris, M.D.
Chief Consultant
Geriatrics & Extended Care Strategic
Healthcare Group
Department of Veterans Affairs
Washington, D.C.
Kenneth G. Pugh, M.D.
Commander, MC, U.S. Navy
Department of Medicine
National Naval Medical Center
Bethesda, MD
