In accordance with the provisions of Public Law 92-463, the meeting was closed to the public on Tuesday, February 1, from 3:00 P.M. 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. The meeting was open to the public on Wednesday, February 2, from 8:00 A.M. to 2:45 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 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code, and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix).
A total of 949 applications requesting $1,000,894,173 for all years underwent initial review. Council recommended 538 for a total of $701,713,235 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.
II. CALL TO ORDER
Dr. Hodes called the meeting to order at 8:15 A.M. on Wednesday, February 2, 2005, and welcomed members.
Director’s Status Report
Dr. Hodes began with remarks about the budget. The NIA budget shows a marked slowing in growth for the FY2003 through FY2005 period, and for the first time, an actual decline in constant dollars between FY2004 and FY2005. FY2006 budget figures have not been released yet, but another constrained year is expected. The proportion of the budget in FY2004 supporting research project grants remained steady at 67.7 percent. NIA also has maintained its investments in centers (8.1 percent), contracts for the support of specific research areas (5.5 percent), and the intramural research program (9.7 percent). Administrative costs represented 3.3 percent of the FY2004 budget.
The average cost of NIA competing grants from FY2003 to FY2004 increased by 2 percent, which reflects NIA’s planning to adapt to flatter budget trajectories, but the number of competing research project applications increased by 40 percent. It is not expected that such a magnitude increase will be seen in FY2005. NIA funded 419 research project grants in FY2004, up from 411 in FY2003. The success rate, or the number of successful grants over the number of applications received in a year, went from 28.6 percent in FY2003, which was very close to average for the previous decade, to 20.8 percent in FY2004 (associated with a 17 percentile payline).
To fund this number of grants, NIA reduced competing research project grants (RPG) by an average of 18 percent below levels recommended in peer review. NIA also instituted a dollar cap on program project (P01) applications. New and competing continuation P01 applications are limited to no more than $1.5 million in direct costs in the first year (exclusive of facilities and administrative costs on subcontracts). This policy became effective with applications submitted for the June 1, 2004, receipt date. The growth rate in P01 average costs has been so substantial as to challenge the research project grant success rate. In response to a Council member’s question, Dr. Hodes clarified that out-year commitments on P01s generally are limited to an inflationary increase, although there may be exceptional circumstances in which there are increased needs in out-years, and these would be addressed on a case-by-case basis.
To manage the budget, Dr. Hodes explained, NIA staff seek to establish a balance between new initiatives and ongoing and infrastructure activities. Program staff are aware of the effects on the success rate, the workforce, NIA’s ability to encourage rather than discourage new investigators as well as established investigators, and the need to balance regular research grants against other mechanisms, such as training and career development, at a time when it is difficult to project the near- and far-term future for research support.
NIA’s concerns are echoed at the NIH-wide level. An Institute and Center (IC) Directors’ retreat on March 1 will focus on planning for research support and the balance between ongoing research and new initiatives in times of constrained budgets. Dr. Hodes added that even in times of constrained budgets, substantial and worthwhile trans-NIH investments are made in high priority research that must be accommodated. Examples are the roadmap and the Blueprint for Neuroscience.
Dr. Hodes mentioned press coverage of NIH. The Washington Post covered a controversial NIA-supported clinical trial, The Alzheimer’s Disease Anti-Inflammatory Prevention Trial (ADAPT), involving nonsteroidal anti-inflammatory drugs. There also has been media coverage of conflict of interest regulations that affect NIH employees. One of the more controversial aspects of the conflict of interest regulations concerns staff interactions with categories of organizations that include pharmaceutical and biotechnology industries and certain foundations and academic institutes that are recipients of NIH support. The impact of the new policy on NIH staff recruitment and retention remains to be seen.
Dr. Hodes noted several NIA staff changes. Dr. Hodes praised the outstanding work of Ms. Vicky Cahan who has been the acting Communications Director of NIA for the past few months. A binder of NIA media coverage since the last Council meeting through January 30, 2005, was circulated for review. Dr. Hodes called attention to an article on racial and ethnic differences in human genetic linkage maps, which describe the relative locations of genetic markers on chromosomes (Jorgenson, E., et al., 2005, Am. J. Hum. Genet. 76:276–290).
Dr. Richard Suzman introduced Dr. Lis Nielsen who will be joining the Behavioral and Social Research (BSR) Program. Dr. Nielsen has been conducting postdoctoral work at Stanford University in social and affective neuroscience and collaborating with economists, psychologists, and neuroscientists on studies pertaining to emotion and decision making.
In response to a question about the projected FY2005 RPG payline, Dr. Hodes expected little change in the success rate and payline from the previous year. Council members commented on the outlook for FY2005 funding and expressed concern about the discouraging message being given to investigators entering the field of biomedical research and about the retention of physician scientists. It was noted that the impact of the constrained budget may not be obvious for many years since there is likely to be a lag effect. One Council member reported diminished interest on the part of trainees in careers in the field of aging. There was a comparable situation in the early 1990s from which lessons could be learned in terms of actions that can be taken to anticipate the budget crunch.
Dr. Hodes acknowledged the importance of work force issues, which are affected by NIA fellowship and career development programs. NIA tracks new investigators to ensure that they are not being discouraged disproportionately. To date, NIA has not detected a decrease in the success rate or proportion of new investigators. If there were a decrease, then NIA would consider preferential treatment for new investigators if that promised to protect the integrity of the workforce over the next five or ten years. One Council member suggested that the NIH assess institutional training (T32) grants, since the NIH is so instrumental in shaping the pipeline of new investigators.
Council members were interested in how to attract more funding for NIA. Dr. Hodes described the appropriations process and explained that NIA cannot lobby or advocate for more funds but certainly can provide forceful arguments for the importance and priority of the research that it funds.
A Council member noted for the record his concern that the constraints on outside activities by NIH staff is unfortunate, will be a major disincentive to recruiting new individuals, and will diminish the stature of the NIH. Dr. Hodes explained that the new policy was a difficult decision for the NIH, which convened an independent blue ribbon panel that made more discriminating recommendations in terms of the categories of people for whom constraints on outside activities be imposed. However, the NIH Director believed that in light of responses by policymakers and the public, a broader ban was necessary. Dr. Hodes clarified that the policy is formally an “interim final” policy established by DHHS and OGE after consultation with NIH. The policy will be re-examined in due course, and its permanency is uncertain at this point.
One Council member sought clarification about guidelines for evaluating foreign applications, recognizing that foreign applicants are competing with U.S. investigators for increasingly scarce funding. Dr. Hodes stated that guidelines for foreign applications are specific and address the uniqueness of the research. Awards to foreign institutions are made under those circumstances in which it would be impossible or at least extremely difficult to support such research at a U.S. institution. Council members are expected to address this criterion explicitly for every foreign application being considered for funding. Dr. Miriam Kelty added that the initial review by study section must assess as well the unique contribution that is unlikely to be made in the United States, for example, because of a unique population or the special expertise of an investigator.
Future Meeting Dates
May 24–25, 2005 (Tuesday-Wednesday)
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
Minutes of the September 2004 meeting were considered. A motion was made, seconded, and passed to approve the minutes.
III. PRESENTATION: National Institute of Neurological Disorders and Stroke
Dr. Story Landis, Director of the National Institute of Neurological Disorders and Stroke (NINDS), spoke on issues and priorities that relate to NINDS, NIA, and the NIH. NINDS' mission is to reduce the burden of neurological diseases through research into their causes, prevention, and treatment. Shared interests with the NIA mission and portfolio include the basic science related to neurogenetic disease, Alzheimer's disease and other dementias, stroke prevention, therapy, and rehabilitation.
About three-quarters of NINDS' $1.5 billion budget supports research project grants. Most of the RPG funds (51 percent) are for out-year commitments on noncompeting grants. 17.5 percent of RPG funds support new and competing continuation applications. About 5 percent of the budget is allocated to fund centers, 4 percent for training and careers, 5 percent for contracts, and 9 percent for intramural research.
Dr. Landis observed that there have been significant advances in the kinds of treatments that patients with neurological diseases receive, for example, tissue plasminogen activator for acute stroke, new antiepileptic drugs, deep brain stimulation for Parkinson's Disease, and two approved drugs (copaxone and b interferon) for multiple sclerosis. Neuroscience advances promise better therapies for the future. It is now possible to control the differentiation of human embryonic stem cells and mouse embryonic stem cells into neurons (including specific classes of neurons), astrocytes, and oligodendrocytes. The acceptance of neuroplasticity portends opportunities for rehabilitative therapies. Some of the frustration expressed by patient advocacy groups, particularly in the area of muscular dystrophy, stems from an unfulfilled promise that identifying the gene would make a difference. The identification of disease genes is an important step but only the first step. Finally, neuroimaging has transformed diagnoses, conceptualization, and treatment of neurological diseases completely.
Dr. Landis focused the remainder of her talk on three main opportunities or challenges: (1) the translation of basic science into clinical applications; (2) ensuring the next generation of physician scientists; and (3) neurosciences consortium and blueprint.
Along the translational research continuum from laboratory to clinical trials, the intermediate step of preclinical development has not been well understood. NINDS has been focusing on therapeutics discovery and development because the pharmaceutical industry has shown little interest in many of the diseases of concern to NINDS. Dr. Landis described three programs under way, in order from least risky to most risky: (1) drug screening programs; (2) program announcements for translational research projects; and (3) the Spinal Muscular Atrophy (SMA) Project.
The Anticonvulsant Screening Project is an annotated database of 25,000 compounds from more than 330 suppliers in thirty countries. It permits universities and pharmaceutical or biotechnology companies to subject promising compounds to efficacy and behavior testing in epilepsy models through a hierarchical series of in vivo and in vitro screens. Two drugs (felbamate and topiramate) already have come through this program, and twenty additional compounds have gone to clinical trial. Although the program is focused on epilepsy for historical reasons, it has become clear that drugs for epilepsy also can be used for other central nervous system disorders. NINDS is grappling with the question of whether to replicate this successful model for other neurological diseases.
Dr. Landis then discussed a screen of 750 Food and Drug Administration (FDA)-approved drugs for neurological diseases done by a consortium of twenty-seven extramural investigators funded through supplements to their grants from NINDS and foundations. Subjecting compounds to tiered assays worked well to identify promising candidates for testing in animal models of ALS, SMA, and Huntington's and Parkinson's Diseases, and promises to expedite development of therapeutics.
Based on the success of its screening efforts, NINDS has invested in a contract for a high throughput screening facility for neurodegenerative diseases and would welcome applications for assays from NIA investigators.
NINDS has a translational research program focused on therapeutic development leading to an Investigational New Drug application to the FDA, which requires evidence of a disease-specific assay or an efficacious compound that may be used in therapy. Grant awards for this program are contingent on meeting preset milestones. So far, gene therapy is perceived by the research community and reviewers as a promising strategy, and NINDS is supporting a relatively broad number of vector systems. Should there be strong preclinical data on the efficacy of a compound, a pharmaceutical company may be willing to take the compound through drug development.
Next, Dr. Landis described the Spinal Muscular Atrophy (SMA) Project, a contract-based, pilot program for rare diseases guided by a steering committee comprised of academic and government scientists (including from the FDA), and industry representatives. The goal is full preclinical development with at least one new candidate therapy available for clinical trial by September 2007. SMA was selected because there is a good target for therapeutic intervention, specifically to increase transcription and translation of the SMN2 gene, and it is known that histone deacetylase (HDAC) inhibitors can do that. Three projects already are funded and four more are in the pipeline. Advocates of other rare diseases have begun to clamor for similar initiatives. NINDS has learned from this experience the benefit of working in partnership with voluntary or advocacy groups for a common objective.
Dr. Landis turned next to the pipeline of physician scientists. Only about 40 percent of neurology residencies are filled by American graduates. To address pipeline concerns, NINDS has established an individual predoctoral fellowship (F30) for up to five years to support students who are in M.D./Ph.D. programs, either Medical Science Training Programs or non-Medical Science Training Programs, who are doing neuroscience thesis research. In 2004, the NIH received 110 applications to this program. NINDS is funding about a third of its seventy assigned applications. Dr. Landis described applicants as spectacular and suggested that NIA consider a similar program, particularly since there are more candidates than NINDS can support and few ICs currently participate.
As only about 15 percent of NINDS K-awardees have succeeded in obtaining R01 or P01 project funding, with most dropping out of research, NINDS has taken a more active role in supporting K-awardees. All NINDS K-awardees are invited to a meeting in their second and fourth years, usually coincident with a major professional meeting, and are provided with mentoring, networking, and professional development opportunities. The program has received positive feedback from participants. Dr. Landis offered to work with the NIA training committee to involve NIA K-awardees in allied fields.
In discussing the neurosciences consortium and blueprint, Dr. Landis reported that in the last five years there have been more than 60 cooperative programs across ICs on the nervous system. Neuroscience research funding across the NIH is more than $4.5 billion, with about a third from NINDS, 10 percent from NIA, and 15 percent from the National Institute of Mental Health (NIMH). NINDS considers all research it funds as neuroscience, compared to 50 percent at NIMH and slightly less than 50 percent at NIA.
Last year, the NIH Director commissioned ICs to develop a blueprint for neuroscience. The goal is to determine common tools and resources needed to advance research on the nervous system in terms of three different themes believed to be common to the mission of each of the participating ICs: development, plasticity, and degeneration. This requires a multilevel molecular, cellular, systems, circuits, translational, and integrative approach. Topics identified for the blueprint include molecular mapping, gene expression, determining gene function, developing tools for altering genes, and support for translational research. Fifteen participating IC directors meet at least once a month to set priorities and to consider how to distribute pooled funds dedicated to blueprint activities. The group will take inventory of the big science projects already under way to avoid duplication of effort, and there is interest to expand the Genset gene-mapping effort beyond the brain to include eyes, ears, and the peripheral nervous system. Training is a common concern, and there was consensus to enhance efforts to educate Ph.D. scientists about challenges and opportunities that diseases of the nervous system present by encouraging coursework in neurobiology of disease and including faculty from multiple departments in the design of curriculum. For FY2006, the consortium is looking forward to cross-institute training efforts, generating additional knockout mice, and coordinating centers' support to reduce redundancy and encourage theme-based research. Suggestions from the extramural community about scientific opportunities are welcome.
One Council member commented that given the increasing importance of primary prevention trials and the relevance to elderly populations, it may be worthwhile to consider common treatments that would be applicable to both neurological and aging research, and thereby, use one population to answer two questions. Dr. Landis responded that NINDS is trying to make clinical trials more efficient to achieve economies and to improve accountability by tying funding to enrollment targets. Another strategy has been to make a separate award to each participating site rather than have a large grant to one site with many subcontracts. It is an incentive when each clinical investigator has an R01 and helps promote careers of physician-scientists engaged in clinical research.
Another question centered on how portfolio decisions are made, in particular the balance between more prevalent and rare neurological diseases. Dr. Landis stated that NINDS has about $135 million invested in stroke, which is one of the most prevalent diseases under NINDS purview. Some rare disease advocates have been effective in attracting the attention of Congress. The decision about which diseases to focus on is dependent on a complex balance of disease burden, prevalence, opportunity, and Congressional mandate.
A number of ICs support core facilities, and individual centers have different policies about whether or not facilities funded by a core grant can be used by other neuroscience investigators. Dr. Landis reported consensus among blueprint members that larger cores that are cross-disciplinary in nature with cross-institute funding and cross-departmental representation could be more effective. The question is whether $1 million a year is enough of an incentive to generate greater integration and intellectual exchange, and to encourage collaborative activities that could lead to real breakthroughs.
In response to a Council member's question, Dr. Landis commented on the organizational challenges in working with the consortium, particularly with overlapping agendas. Program managers derive satisfaction from encouraging an area of science. It is important not to reward territorial behavior. Working groups are important vehicles for promoting collaboration (e.g., on Parkinson's, Alzheimer's, stroke, epilepsy). Although several are Congressionally mandated, working groups tend to be most constructive when initiated by NIH program staff and have benchmarks to assess their progress.
Dr. Landis agreed with one Council member's observation that the consortium may be an excellent way to study comorbidities and consider psychological, cognitive, and physical performance outcomes. Dr. Landis also acknowledged that there is strong interest in whether research makes a difference in quality of life and to consider the health outcomes in relation to investment of dollars. Overall, there is greater interest at the NIH to interact more with the Centers for Medicare and Medicaid Studies to assess whether an approved procedure makes a significant difference in quality of life.
IV. REPORT: Task Force on Minority Aging Research
Dr. Marie Bernard reviewed the purpose of the Task Force on Minority Aging Research, which was organized in 1990 to advise NIA on research on minority health and health disparities, and training initiatives. It works in collaboration with the NIA Working Group on Minority Aging and initiates Council actions. In 1999, a review of NIA’s minority aging research activities from 1993 through 1998 resulted in eight recommendations: (1) eliminate (reduce) health disparities; (2) define race, culture, ethnicity, and socioeconomic status; (3) implement longitudinal and life-course studies; (4) integrate biology, genomics, and genetics of aging; (5) refine methods and strategies; (6) improve recruitment and retention of minorities in research on aging; (7) strengthen and clarify NIH policy on the inclusion of minorities in clinical research; and (8) build capacity and enhance training and information dissemination.
The Task Force met to discuss these recommendations on February 1, and also developed a draft agenda for the May 2005 meeting that includes: (1) review of an article in the New York Times on the genome in black and white, and similar articles in Nature; (2) review of the Sullivan Commission Report on Missing Persons: Minorities in the Health Professions, which has stimulated discussion about how best to increase the numbers of minorities in health professions; and (3) a look at progress and recommendations from the 1999 review to determine what needs to be done in the future. Dr. Robin Barr reported on targeted enrollment versus actual enrollment in funded projects for NIA in FY2003. In those projects with a minority focus, recruitment was generally on target in terms of numbers of minorities. In those projects where there was not a minority focus, there was a lag in many cases. Dr. Bernard also brought to Council members’ attention the Journal of Aging and Health issue based on work from the Resource Centers on Minority Aging Research on recruiting and retaining people of color and health services research.
NIH policy requires that the Task Force review at least annually the appropriate inclusion of subjects by gender, race, and ethnicity in current research projects; certify that NIA is in compliance; and make this information available to the public. The NIH’s policy for inclusion is determined by the Office of Management and Budget (OMB) standards for racial and ethnic considerations, which were changed in 1997 to allow for multiple race reporting, Hispanic ethnicity reporting, and the addition of a Hawaiian/Pacific Islander category. The FY2003 and FY2004 Aggregate Enrollment Data for All Extramural Research Protocols were distributed. Using the 1997 OMB standards (and excluding the enrollment reported for the first time in FY2004 by a very large NIA study that accounts for 69 percent of the total increase in enrollment from FY2003 to FY2004), the American Indian/Alaska Native group comprised about 0.38 percent of total subjects reported in FY2004; Asians 15.37 percent (a substantial increase from 4.02 percent in FY2003 primarily due to the enrollment of 40,655 subjects in a follow-up survey being conducted in China); Black or African Americans 9.99 percent (down from 11.32 percent in FY2003); Hawaiian/Pacific Islanders 0.67 percent; and White 70.57 percent (down from nearly 80 percent in FY2003). About 0.58 percent reported more than one race, while 2.43 percent did not report on race. Half of all subjects reported in FY2004 were female.
A motion was made, seconded, and passed to accept the report on inclusion of women and minorities in clinical research as in compliance with the guidelines for inclusion of minorities and women.
V. REPORT: Working Group on Program
Dr. Linda Fried reported on deliberations of the Working Group on Program (WGOP), which met on February 1. The WGOP had a wide ranging discussion about the nature of the NIA leadership role in proactively anticipating the demographic imperative of an aging population to ensure that our country is prepared adequately ten years from now, particularly in light of current budget constraints. The WGOP also sought to revisit the issue of the physician investigator workforce, requesting a status report at the May meeting on a number of innovative initiatives that are under way. Dr. Suzman volunteered to organize a presentation on the demographic and economic issues associated with an aging population for the May meeting. Dr. Hodes suggested that the WGOP could request updates from a variety of organizations external to the NIH that have been considering scientific issues that need to be addressed, and the Public Information Office can address how NIA disseminates research findings to the public.
Dr. Judy Salerno updated the WGOP on NIH Roadmap initiatives, which are ongoing and supported by nine implementation working groups roughly under the three rubrics of (1) new pathways to discovery, (2) research teams of the future, and (3) re-engineering the clinical research enterprise. Additional information can be found on the Roadmap web site (www.NIHroadmap.NIH.gov), where those interested can sign up to be notified of new Roadmap initiatives including Requests for Applications (RFAs). Dr. Fried also announced that the RFA on Biology of the Perimenopause: Impact on Health and Aging in Non-Reproductive Somatic and Neuronal Tissues has been published (Application Receipt Date: May 16, 2005).
A. Plan for Biology of Aging Program Review
The Biology of Aging Program review is scheduled for May 2005. Dr. Huber Warner reported that a brief meeting was planned after the conclusion of the Council meeting to select members of the review committee from among the roster of current and former Council members, as well as other members of the extramural community, and to identify the materials that the review committee would want. A conference call will occur sometime among the review committee members, culminating in the program review immediately preceding the May Council. (Subsequent to the Council meeting, the Biology of Aging Program Review was postponed until September.)
B. Advisory Meetings, Conferences, and Workshops
Bench to Bedside: Estrogen as a Case Study
Dr. Andy Monjan reported on a meeting held September 28–29, 2004 to understand the discrepancies between findings of the Women’s Health Initiative and Women’s Health Initiative Memory Study on brain and cognitive function and some of the basic and longitudinal/epidemiological studies and to determine what information is needed before further hormone interventions are developed. The meeting was cosponsored by the Office of Research on Women’s Health, the NIMH, and the Alzheimer’s Association. It was agreed that new clinical trials involving hormone therapy should not be launched until it is determined why the conjugated equine estrogens (CEE, known as Premarin) medroxyprogesterone acetate (MPA, known as Provera) or Prem-ProÒ formulation caused harm. Three regional work groups have been formed. Investigators plan to teleconference through the coming year, and work group chairpersons will inform NIA of progress. NIA’s role continues to be facilitative, and information provided by the working groups will help NIA identify future research directions.
Older Workers’ Health and Safety
Dr. Suzman reported on the volume recently published by the National Academy of Sciences on the health and safety needs of older workers, available at no charge on CD-ROM. This activity was cosponsored by the NIA, National Institute for Occupational Safety and Health, the Environmental Protection Agency, and the Archstone Foundation. The main motivation for the meeting was the recognition that people spend a large portion of their lives at work, and that work significantly impacts health. The basic recommendation was that existing datasets do not meet current research needs. It was recommended that NIA consider developing a study comparable to the Whitehall Study in the United Kingdom. BSR is taking steps in this area including the development of a workshop on work and cognition.
NIH State-of-the-Science Conference on Management of Menopause
Dr. Sherry Sherman reported to the WGOP on this conference scheduled for March 21–23, 2005 at the Natcher Conference Center. Additional information is available on the NIH web site (http://www.nia.nih.gov/NewsAndEvents/Calendar/Menopause-Related+Symptoms.htm).
C. RFA Concept Clearance
A motion was made, seconded, and passed to approve the following two RFA concept clearance requests.
Elder Mistreatment
Dr. Sidney Stahl stated that the Elder Mistreatment initiative was stimulated by the dramatic difference in mortality observed over a course of thirteen years between those people with an adult protective services report and those without. The National Research Council’s study on elder mistreatment (National Research Council. 2003. Elder Mistreatment: Abuse, Neglect, and Exploitation in an Aging America. Panel to Review Risk and Prevalence of Elder Abuse and Neglect. Richard J. Bonnie and Robert B. Wallace, Editors. Committee on National Statistics and Committee on Law and Justice, Division of Behavioral and Social Sciences and Education. Washington, DC: The National Academies Press.) defined a series of fourteen agenda areas, including the need for clearer definitions and concepts; reliable, valid, and generalizable incidence measures; research in institutional settings such as nursing homes; and infrastructure for conducting elder mistreatment research. It was estimated that elderly mistreatment is thirty to forty years behind the field of child abuse. Dr. Stahl is negotiating with a number of other federal agencies and NIH ICs about cosponsorship.
Anemia in the Elderly
Dr. Susan Nayfield presented the Anemia in the Elderly RFA on behalf of the Geriatrics and Clinical Gerontology Program. The goal of this RFA is to improve the health and well being of elderly anemic patients by increasing the understanding of red blood cell physiology and pathophysiology as they relate to anemia in the elderly and the clinical implications of anemia, and ultimately to improve the medical management of anemia in older patients.
D. Approval of the Statement of Understanding
The Statement of Understanding between the Council and Institute staff is acted on once a year to allow the business of the Institute to continue between Council meetings. A motion was made, seconded, and passed to approve the Statement of Understanding with no changes.
E. Statistical Data on Extramural Program
There were no questions raised about statistical data on applications assigned to the February 2005 Council round.
VI. PROGRAM HIGHLIGHTS: Stress, Telomeres, and Aging
Dr. Hodes introduced Dr. Elias Zerhouni, NIH Director, who provided introductory remarks to the interdisciplinary mini-symposium on Stress, Telomeres, and Aging.
Dr. Zerhouni differentiated between multidisciplinary research where scientists come together to solve a problem and then return to their original disciplines and interdisciplinary research where scientists from different disciplines come together, and at the end of that interaction something novel occurs. Though individually trained in the fields of epidemiology, clinical medicine, statistics, and molecular biology, Drs. Michael Marmot, Burton Singer, and Elizabeth Blackburn are redefining public health research through the integration of the analytical strengths of epidemiology, economics, psychology, sociology, and biology. From an institutional standpoint, the challenge is to identify ways to make it easier to facilitate this type of interdisciplinary research.
Dr. Marmot, knighted in 2002 for his work analyzing social factors in health inequities, is Director of the International Center for Health and Society and Professor of Epidemiology and Public Health at University College in London. Dr. Singer is the Charles and Mary Robinson Professor of Public and International Affairs at Princeton University and a member of the National Academy of Sciences. Dr. Blackburn is the Morris Herzstein Professor of Biology and Physiology in the Department of Biochemistry and Biophysics at the University California, San Francisco. She is a member of the National Academy of Sciences and an internationally recognized molecular and cell biologist.
A. Social Patterning of Stress
Professor Marmot presented data on the social gradient of disease and the role that metabolic syndrome may play in explaining the social gradient in cardiovascular disease and diabetes, particularly on the influence of two psychosocial factors: (1) control over life circumstances and (2) social engagement. Dr. Marmot began with the observation that even for British civil servants not in absolute poverty, the higher the grade of employment, the lower the mortality over a twenty-five-year period. Twenty-five to thirty percent of this social gradient in heart disease mortality can be explained by standard risk factors such as age, smoking, systolic blood pressure, plasma cholesterol concentrations, height, and blood sugar. This type of social gradient in disease likely applies in the United States as well.
Data from the Whitehall II Study, a second study of civil servants funded by NIA and the National Heart, Lung, and Blood Institute, and the Medical Research Council in Britain, showed that both an individual’s self-reports and managers’ reports of the individuals’ job control predicted coronary heart disease.
Another investigation examined effort and reward imbalance. Those with high effort to reward ratios have increased incidence of coronary heart disease, independent of job control. (Low control predicts coronary heart disease independent of effort/reward imbalance.) It was hypothesized that control at work would be a more salient predictor for men and control at home would be a more salient predictor for women. Indeed, women reporting low control at home had four times the risk of coronary heart disease incidence compared with those who reported high control at home, but there was no such difference for men. National data from the Health Survey of England show that for both men and women, the lower the social class the more likely people are to report low control at work and at home.
Social support is also a risk factor for mental health. For both men and women, low support at work is associated with higher incidence of subsequent mental illness. Severe lack of social support is more common at lower levels of social status.
The Whitehall II data also have been used to examine metabolic syndrome, defined as being in the adverse quintile of three or more of the following indicators: (1) two-hour glucose (>7.25 mmol/l), (2) systolic blood pressure (>136 mm Hg), (3) fasting triglycerides (>1.90 mmol/l), (4) HDL cholesterol (<1.10 mmol/l), (5) Waist-to-hip ratio (>0.977). For men and women, the lower the employment grade, the more likely is metabolic syndrome. When adjusted for smoking, about 22 percent of the gradient in coronary heart disease can be explained; when adjusted for smoking, physical activity, and alcohol, about 31 percent of the gradient can be explained. When adjusted for the metabolic syndrome variable, about 43 percent of the gradient can be explained. Adding in biological variables, plus height as a marker of early life conditions, about two-thirds of the gradient in coronary heart disease can be explained.
Dr. Marmot and his colleagues are looking at smaller populations to try to understand why there should be a social gradient in metabolic syndrome. Those with high control at work and those with high emotional support have lower levels of glycated haemoglobin, HbA1C, suggesting better control of blood glucose. Control and support may be important in protecting against out of control blood sugar.
For both men and women, those with high heart rate variability are less likely to have the metabolic syndrome, suggesting that the metabolic syndrome is related to the balance of parasympathetic and sympathetic activity. On the other hand, those with high heart rate variability are less likely to have low job control, so high heart rate variability is thought to be protective. Those with metabolic syndrome also had higher output of urinary cortisol compared to controls, suggesting involvement of the hypothalamic pituitary adrenal axis and the sympathetic nervous system. To better understand what influences these pathways, Dr. Marmot and his colleagues have studied salivary cortisol, collected on awakening and later in the day. Subjects of lower socioeconomic position with high job demands had a steeper rise and higher level of cortisol through the working day.
Another stress marker is plasma viscosity. Acute stress stimulates increases in plasma viscosity. Men and women in lower socioeconomic positions have higher levels of plasma viscosity. Metabolic syndrome was found to be associated inversely with employment grade and explained about half of the social gradient in coronary disease. Metabolic syndrome is linked to low heart rate variability, high cortisol output, high IL-6 and C-reactive protein levels, high normetanephrine, and plausibly to psychosocial factors.
In response to a question, Dr. Marmot reported that some questions from the general health questionnaire that relate to sleep and sleep disturbance are highly predictive of coronary heart disease, but they were not found to impact metabolic syndrome. An examination of various patterns of dysfunction by age finds that people of lower social position (whether occupationally or by education) have the same level of disability fifteen years earlier than people of higher social position. People in their seventies with high education had the same level of cognitive function as people fifteen years younger with low education.
It is cumulative stress that affects the onset of disease and a person’s ability to function.
Dr. Marmot is hoping to explore the question of whether changes seen with age are similar to changes seen with stress, and indeed, whether some age-related changes may be due to the effects of chronic stress. Early life seems to be important for health because it determines where one ends up, not where one began.
B. Social Environments and Genetics of Aging
Dr. Singer has conducted seminal work on interactions among social environment, genetic and other biological factors, and their relation to health outcomes. He presented laboratory and epidemiological examples from his research with Dr. Carol Ryff (University of Wisconsin) that illustrate how social environments, particularly emotion in significant social relationships, influence gene expression and discussed implications of these examples for studies of gene environment interactions in existing large survey populations. He began by showing a table with a short list of diseases, assessing genotype frequencies associated with susceptibility genes, and identifying the fraction of those with susceptibility genes who actually progress to the diseases indicated. In each instance, there is always a considerable fraction of individuals who have susceptibility genes who do not progress to disease. Emphasizing what is protective turns the focus toward prevention among those who may be at highest risk.
Dr. Singer focused on two recently published studies that bring together gene and environment interactions. The first is a birth cohort study based in New Zealand (Caspi, et al., 2002, Science, 297: 851–4) that concerns low monoamine oxidase A (MAOA) activity and its connection with childhood maltreatment and adult antisocial and criminal behavior. MAOA is a gene that encodes Ma1A enzyme, which in turn metabolizes neurotransmitters such as norepinephrine, serotonin, and dopamine, rendering them inactive. Almost 80 percent of those with low MAOA activity are now experiencing or have experienced conduct disorders after being followed for more than thirty years. Dr. Singer is interested in environmental or other protective genetic factors that led the other 20 percent of individuals who did not experience conduct disorders to avoid negative consequences.
Dr. Singer also reported on studies that have related the serotonin transporter gene (5-HTT) to stress (employment, financial, housing, relationships) and later depression (Caspi, et al., 2003, Science 301: 386-9; Ryff & Singer, 2005, J. Gerontology, 60B [Special Issue I]: 12-23) and to efforts to examine the relationship between personality and genetics by measuring sibling pairs (Fullerton et al., 2003, Amer. J. Hum. Gen., 72: 879-90).
Dr. Singer turned next to coronary heart disease, susceptibility genes, and community interventions in North Karelia, Finland. Starting in about 1971, the North Karelia villages initiated workplace programs that focused on weight loss, smoking cessation, lower cholesterol, and reduced alcohol consumption. Lay leaders in the communities promoted discussion about smoking and diet, not just antismoking legislation was passed, and food manufacturers and supermarkets agreed to produce and carry foods with lower fat and salt contents. These steps all were aimed toward addressing coronary heart disease. Starting in 1977, these actions were scaled up to a national level, leading to a substantial decline in coronary heart disease, not only in the North Karelia villages but in all of Finland. By 1995, there was no significant difference in prevalence of coronary heart disease between North Karelia and the rest of Finland. Although genetics played no role in setting up the programs in Finland, there could be collaboration between those interested in genetics, particularly of heart disease, and those involved in the public health intervention. It is preferable for genotyping to be done at the same time as interventions to permit the evaluation of susceptibility genes and also consequences for the most susceptible people.
Dr. Singer concluded by presenting results from a study that compared two different social environments: 482 adults ages twenty-six to seventy-four in Japan with a U.S. national sample (MIDUS I) of almost 3,500 in the same age range. The variables of interest include measures of interdependence (respect, harmony, restraint) and independence (autonomy, choice, individual control, mastery). In contrast to the United States where a premium is placed on autonomy and personal growth, in Japan a premium is placed on interdependence. The interdependence and associated relationships with others in Japan has related to improved health compared to the U.S. population who were characterized by a strong sense of autonomy. An interesting question would be to ask whether interdependence offers protection from chronic health conditions broadly.
Given a general emphasis on autonomy and independence in the United States, one Council member asked about racial differences. Dr. Singer replied that African Americans tend to be more focused on interdependence. He noted that another round of MIDUS population data collection is in progress with an older sample focused on African Americans in Milwaukee. Part of the objective is to address racial differences.
C. Chronic Life Stress and Acceleration of Cellular Aging
Dr. Blackburn first presented a brief review of telomeric DNA and telomeres, the protective structures at the end of chromosomes that are essential for protecting the genetic material that resides in chromosomes. The established mechanism of DNA replication suggests that DNA will be lost from chromosome ends during cell division. This has been verified experimentally and has led to the discovery of an enzyme, telomerase, that replenishes telomeric DNA at the ends of chromosomes during replication. Human telomerase is regulated, but active in all stem cells and in several adult cell types such as activated mature T and B cells of the immune system and proliferating cells of the skin, intestinal lining, and hair follicles. However, in many other adult cell types, such as epithelial cells and fibroblasts, telomerase is diminished. In cells with plenty of telomerase, telomere length homeostasis is in balance and cells can keep dividing (cancer cells, with their many other alterations, fall into this category). Conversely, it is predicted that if some, but not enough telomerase activity is present in cells, then cells eventually undergo senescence. In humans, declining telomere maintenance is observed during aging in many cell types in vivo. In adults, this DNA loss occurs at an average rate of approximately thirty to sixty base pairs per year, but shortening rates can vary with environment, e.g., telomere shortening can be accelerated by DNA damage caused by oxygen free radicals.
Variations in telomere maintenance in humans may reflect human disease. Telomere shortening has been implicated in heart disease because in arterial endothelial cells, telomeres are shorter by the equivalent of eight years in heart disease patients versus controls. People aged sixty years or older with shorter blood cell telomeres have higher mortality rates from all causes. Notably, shorter telomeres associate with a 3.2-fold higher mortality rate from heart disease, 8.5-fold higher mortality rate from infectious disease, and with poorer survival overall. However, it is not just bulk telomere length that is important for a cell’s ability to multiply and for tissue renewal, but also the presence of the telomerase protein molecule itself. Some telomerase is needed for cell viability in normal cells. In a rare inherited disease, where one copy of the telomerase RNA gene is mutated, the telomerase mutation causes death in early adulthood to middle age, primarily because of progressive bone marrow failure.
In a recent study, chronic psychological stress and other risks factors for cardiovascular disease were linked to lower telomerase, shorter telomeres in white blood cells, and higher levels of oxidative stress in the body. The study involved sixty-two healthy premenopausal women (aged twenty to fifty) who were all biological mothers of either one or more healthy children (control mothers) or a chronically ill child (caregiving mothers). The study asked whether the level of perceived stress (both groups) and duration of caregiving was related to three markers of cell aging: telomerase activity and telomere length in peripheral blood mononucleocytes (PBMCs), and systemic oxidative stress index (isoprostanes/antioxidant vitamin E ratio). Perceived stress was associated with shorter telomeres, lower telomerase activity, and higher oxidative stress, as was years of caregiving. When telomerase and telomeres in the lowest and highest stress quartiles of the whole sample were compared, telomerase activity was 48 percent lower in the high stress group compared with the low stress group. The excess telomere shortening in the high stress group was roughly equivalent to nine to seventeen years of extra “aging” of these PBMCs; hence, stress perception and caregiving duration are linked to cell aging markers. An in vivo link between telomere maintenance and risk of cardiovascular disease was also found in this study group. The six most prominent factors for cardiovascular disease are smoking, poor lipid profile, high blood pressure, diabetes, abdominal obesity, and psychological stress, and Dr. Blackburn’s laboratory has found that all six risk factors are associated with lower PBMC telomerase activity. This is the first evidence in vivo that low telomerase alone, in the apparent absence of telomere shortening, may be atherogenic.
Possible mechanisms to explain these associations remain an open question.
One Council member asked about exercise as a stressor with positive associations, and how it interplays with the psychological stressors. Dr. Marmot responded that people who exercise frequently tend to have heart rate variability, and thus, the protective pattern.
Dr. David Abrams, the Director of the Office of Behavioral and Social Sciences Research, NIH, sensed a paradigmatic shift in approaches to complex problems. In particular, intraorganismic individual differences, that is, gene susceptibility and expressions of behavioral variance like heart rate reactivity, are examined along with environmental variation. It has become clear that interaction or multiple interactions need to be studied. He contended that anomalies and findings that are inexplicable at one level may be understood in terms of interactions with factors at another level.
VII. INTRAMURAL RESEARCH PROGRAM REPORTS
Dr. Dan Longo, Scientific Director, NIA, celebrated the realization of a ten-year plan to build the intramural program. With the recruitment of Dr. Jerry Medoff from Washington University, who started in December 2004 as the clinical director, the intramural program has assembled all critical components. The celebratory mood was tempered, however, as Dr. Longo was not optimistic that the quality of the intramural program can be maintained in light of new ethics guidelines established by NIH for its staff. Dr. Longo introduced the presentations, beginning with four vignettes of work ongoing in the Laboratory of Clinical Investigation, followed by
Dr. Steven Sollott’s presentation on behalf of the Laboratory of Cardiovascular Sciences. In the closed session, Dr. Longo reviewed other scientific achievements of the past year and discussed the process of science management in the intramural program.
A. Laboratory of Clinical Investigation
In introducing the Laboratory of Clinical Investigation, Dr. Darrell Abernethy considered a general theme of the laboratory to be the identification of new therapeutic targets for the treatment of age-related diseases.
Naturally Occurring Splice Variants of the Human Ca2+ Channel: New Insights into Atherosclerosis and Cardiovascular Excitation-Contraction Coupling
L-type voltage-gated calcium channels are involved in regulating many physiological processes, including the contraction of cardiac and vascular smooth muscle cells (VSMCs). These channels regulate intracellular calcium levels by opening and closing in response to changing membrane potentials. Depolarization of the membrane causes a conformational change in one of the channel proteins, the pore-forming alpha subunit (a1C). This voltage-gated conformational change allows movement of calcium ions (Ca2+) through the channel, which transiently increases the intracellular calcium level causing muscle contraction.
In the human calcium channel, the a1C subunit is expressed naturally in several different isoforms, each differing only slightly in amino acid composition. This diversity is caused by alternative splicing at five of the approximately fifty exons within the protein map. A key question that Dr. Nikolai Soldatov, Molecular and Clinical Pharmacology Section, sought to answer in this research was whether the expression level and distribution of these splice variants (isoforms) were altered in VSMCs affected by atherosclerosis. Dr. Soldatov’s research team compared atherosclerotic and nonatherosclerotic regions of surgically removed artery preparations in order to address this question.
Using qRT-PCR, they discovered that there was nearly a three-fold decrease in the level of L-type calcium channel transcripts present in the cells affected with atherosclerosis. Moreover, when cells were isolated and the distribution of splice variants was determined, there was a striking difference between cells from affected and nonaffected areas. Five different a1C subunit isoforms (one to five) all containing exon 21 were found in normal VSMCs. Diseased cells, however, displayed only one isoform in which exon 21 had been switched with exon 22. A key question was whether the presence of the exon 22 isoform (isoform 2) played a pathogenic role and was responsible for the proliferation and migration of VSMCs seen in atherosclerosis-affected cells.
The researchers studied Ba2+ and Ca2+ currents that can pass through the channels of each isoform by imposing a stepwise membrane potential between resting -90 mV and +20 mV. Normally, the maximum Ca2+ current occurs when the potential is first stepped to +20 mV and quickly decays due to calcium-induced activation. A surprising finding was that in isoform 3 the decay was incomplete, suggesting that some Ca2+ current remained even during depolarizations sustained for up to thirty seconds.
Isoform 3 is very similar to isoform 2, differing only by a two amino acid deletion. When researchers investigated distributions of these isoforms in VSMCs from various tissues, they discovered that isoform 3 was not expressed in hippocampus but was expressed highly in human heart cells. One hypothesis is that in heart muscle, isoform 3 accounts for the “late” L-type Ca2+ current, which controls the shape of the action potential plateau. This raised the possibility of an association of isoform 3 with cardiac excitation-contraction (EC) coupling and arrhythmia. Additionally, the fact that this isoform was missing in diseased areas suggested that isoform 3 also may contribute to vascular tone and the maintenance of vascular elasticity of arterial walls. Thus, it may be that the absence of isoform 3 in atherosclerosis-affected cells, and not the presence of isoform 2, was responsible for the VSMC dysfunctions observed.
Entero-Endocrine System
Dr. Josephine Egan presented on type II diabetes mellitus and the identification of new targets for its treatment, which are the focus of the Diabetes Section as it relates to drug discovery and development. The pathogenesis of type II diabetes mellitus involves two components: insulin resistance in insulin-sensitive tissues followed by an inadequate compensation by pancreatic beta (ß)-cells to secrete more insulin. The inadequate compensation probably is due to a combination of factors: (1) an insufficient increase in b-cell mass, (2) a decline in functioning secretory capacity, and (3) alterations in endogenous modulators of insulin secretion.
One group of insulin secretion modulators is referred to as incretins. There are two incretin hormones, GIP and GLP-1, which are secreted from entero-endocrine cells of the gut in response to food (glucose and fat) and bind to their own specific receptors on ß-cells of the islets of Langerhans’. Upon binding, adenylyl cyclase is activated, resulting in increased levels of intracellular cAMP. As a consequence, the amount of insulin secreted in response to glucose in food is approximately two-fold more than the response to glucose alone. Pharmacological doses of GLP-1 have been shown to be capable of normalizing blood glucose in type 2 diabetic patients because of increased insulin secretion. Its biological half-life is only a few minutes, so when given subcutaneously, its insulin-secreting effect is not long enough to be beneficial to patients long term. When given continuously by a subcutaneous pump, it has positive effects on insulin secretion for up to three months. This is not a practical way to treat diabetic patients, so attention has turned to studying analogs of GLP-1 and GLP-1 receptor agonists that may be of use in type 2 diabetic patients. An agonist of the GLP-1 receptor, called exendin-4, has been shown to lower blood glucose when given subcutaneously twice a day. This work has provided the scientific basis, both preclinical and clinical, that has made this therapeutic target and drug attractive to the private sector where it is now in later stages of clinical development.
Dr. Egan also was involved in developing, under a Cooperative Research and Development Agreement (CRADA) mechanism, a GLP-1/human transferrin fusion protein (GLP-1/Tf), which may have a half-life of several days. For diabetic mice, blood glucose is lowered in treated animals, and a glucose tolerance test after GLP-1/Tf treatment is much improved. Should this prove to be the case on clinical screening, it may be that a weekly injection is all that is required to maintain lower blood sugars in patients.
The mechanisms by which glucose and fat cause GLP-1 secretion from entero-endocrine L-cells are just now being studied. Long-chain fatty acids recently have been shown to activate GPR120 receptors (receptors with unknown functions) on L-cells, causing GLP-1 to be secreted. Dr. Egan recently has found that L-cells contain all of the elements required for the sensing of bitter and sweet by taste buds on the tongue. Work currently is under way to test the hypothesis that sugars induce GLP-1 secretion by activation of sweet receptors in L-cells. Non-nutrient-based GLP-1 secretagogues ultimately may be found to be of use to increase endogenous secretion from L-cells and may be of use to treat diabetes. Interestingly, a number of gut hormones, including GLP-1, are present in the taste cells of taste buds, which contain receptors for bitter and sweet sensing. This links the gut, tongue, and brain together in a manner not appreciated previously. The Diabetes Section plans to study the function of these so-called ‘gut’ hormones in taste buds and examine if they are involved in regulating satiety and/or release of entero-endocrine hormones from the gut and insulin from the ß-cells of the pancreas.
Immobilized Cell Membranes as On-Line Screens in Drug Development and Drug Discovery
Dr. Irving Wainer, Bioanalytical Chemistry and Drug Discovery Section, discussed how therapeutic targets are identified and evolved into real drug products. He described the group’s process of making columns with the final goal of actually mimicking human capillaries. The system is essentially a chromatographic system, and the group has been moving slowly toward doing pharmacology and drug discovery in a flow system. The approach is to immobilize cell membranes as on-line screens in drug development and drug discovery. Direct or differential screening can be used to determine affinity constants, IC50s or EC50 values, as well as allosteric interactions.
The columns can be used to screen biological and chemical mixtures, which provide a direct approach to looking at the biotica or extracts out of other living organisms, or essentially taking a chemical library and screening it directly against the target. With a primary target such as acetylcholine receptor, one can look for secondary effects such as GABA receptors and so on. Successfully immobilized targets include GPCRs such as the opioid and b-adrenergic; ligand-gated ion channels such as the nicotinic receptor, GABA, NMDA, and AMPA receptors; voltage-gated ion channels such as hERG potassium; transporters such as p-glycoprotein and human organic cation transporter; and the future targets mentioned earlier such as GLP-1 receptor, taste buds, Ca+2 channel, and splice variants. Dr. Wainer sees this section as providing tools to further work for pharmacological exploration, as well as exploiting these targets for new therapeutic agents.
Dr. Wainer next focused on nicotinic acetylcholine receptor antagonists, which have been called recently a “new direction for drug discovery” and are clinically useful in the treatment of nicotine dependence, opioid addiction, and maybe clinical depression. Antagonists of the nicotinic acetylcholine receptor have been responsible for a number of side effects of drugs. Membranes from cell lines that express the receptor are immobilized either on a silica support or directly onto glass. Researchers confirmed that immobilized receptors maintain their functional integrity.
One of the applications is to determine an IC50 value of noncompetitive inhibitors directly, and this is extremely difficult to do. Dr. Wainer’s section did something quicker, easier, and reproducible by making a column, in particular the a-3-b-4 nicotinic acetylcholine receptor (nAChR). This was a single experimental chromatographic experiment; the column was running and hooked up to a mass spectrometer. The compound was run through it, which took about thirty to forty minutes. The goal is to rapidly separate groups of compounds qualitatively into likely inhibitors and not.
The next step is to take these compounds and screen tobacco leaf extracts and tobacco smoke condensates for new drugs. Many observational clinical studies have associated tobacco smoking with delayed progress in Alzheimer’s Disease and with improved responses in schizophrenia and rheumatoid arthritis. Tobacco smoke contains more than 10,000 compounds and only a few have been identified and characterized, so compounds are tested first and then identified. The approach first is to take tobacco leaves and identify what is active in the tobacco leaves against these nicotinic receptors, and then test the tobacco smoke because the very act of smoking changes the chemical composition. The a-3-b-4 nAChR and the a-7 nAChR (two of the well-characterized columns available) as well as a negative nAChR column, will be used to screen tobacco leaf extracts and tobacco smoke condensates in an activity-based screen.
The idea is that all compounds from the tobacco smoke condensates that have an affinity to the nicotinic receptor will be captured in the first nicotinic column, and these compounds then will be put through a second chromatograph. This second column has higher selectively and higher efficiency to permit greater separation of all of the compounds that had some affinity to the nicotinic receptor. Passing the eluted compounds through the mass spectrometer generates the lead drug structures.
Use of receptor-immobilized columns for the nicotinic receptor, for example, is leading to better understanding of the on-off kinetics for various ligands that, coupled with animal or clinical pharmacodynamic data, suggest structural modification of known ligands or prediction of structure for ligands to be synthesized to achieve improvement in ligand-receptor binding characteristics. Similar studies are under way with the drug transporter, p-glycoprotein, and are beginning in collaboration with Dr. Rui-Ping Xiao in the Laboratory of Cardiovascular Science, on the b-2-adrenergic receptor.
When approached by a ligand, the b-2-adenergic receptor undergoes a series of conformational changes that are increasingly understood and provide the opportunity to think about the structure of ligands and how they may be optimized in order to create a target. A prototypic compound that Dr. Xiao has identified would be the old b-2-adenergic agonist fenoterol, which indeed does appear in her cellular systems to have this GS signaling selectivity that may be a useful target. Although this compound is of interest, unfortunately it will never become a drug because it was patented a long time ago, and there is no interest by the pharmaceutical community to move it forward. But there are promising signs that the compound can be optimized into a number of other variants, and one or more of these analogs may someday have utility for congestive heart failure.
B. Laboratory of Cardiovascular Science
Age-related Changes in Mitochondrial Mechanisms of Cardioprotection
The aged heart has a diminished functional and adaptive reserve capacity, an increased susceptibility to incur damage (e.g., as a result of ischemia, etc.), and a limited practical ability for repair and regeneration. Thus, there has been considerable interest in harnessing the heart’s endogenous capacity to resist such damage, known as ischemic preconditioning, as well as other cardioprotective mechanisms.
The Cardioprotection Unit, under the direction of Dr. Sollott, has shown that reoxygenation after prolonged hypoxia reduces the reactive oxygen species threshold for the mitochondrial permeability transition (MPT) in cardiac myocytes and that cell survival is correlated steeply and negatively with the fraction of depolarized mitochondria. A wide variety of cardioprotective agents acting via distinct upstream mechanisms (including PKA, PKB, PKC, and p70s6k) promote cell survival by limiting MPT induction. The convergence of these pathways via the inhibition of glycogen synthase kinase-3β (GSK-3β) on the end effector, the permeability transition pore complex, to limit MPT induction is the general mechanism of cardiomyocyte protection (Juhaszova et al., 2004, The Journal of Clinical Investigation 113(11):1535–49).
In an aging Wistar rat model, age was found to have a significant effect on the resistance of the MPT pore complex to oxidative stress. Compared to young rats, the MPT reactive oxygen species threshold in the aged rats is reduced by 40 percent. Furthermore, cardioprotection signaling is impaired significantly in ad libitum-fed, twenty-four-month-old rats. Caloric restriction (CR) substantially (but incompletely) restored the ability to activate cardioprotection. Coenzyme Q10 supplementation is effective to enhance the protection of mitochondria from the oxidative stress in cardiac myocytes from aged rats but not in young adult rats. While both CR and CoenzymeQ10 exert beneficial effects on cardioprotection signaling in aged animals, these interventions cannot restore cardioprotection to levels achievable in young animals.
At present, the translation of basic research findings into clinical practice largely has been inadequate; there have been few, if any, successful implementations in terms of viable therapies activating cardioprotection mechanisms to limit infarct size in humans. Dr. Sollott proposed that aging not only reduces the threshold to sustain injury (and limit repair), but it both increases the threshold for activating protection signaling and decreases the resulting magnitude of protection. Furthermore, clinical treatment strategies designed to inhibit the "master switch" kinase, GSK-3β, to protect the permeability transition pore complex from MPT induction by bypassing upstream signaling defects could be effective to reduce the size of infarction by preventing the death of cardiac myocytes. Since mitochondrial function can decline with aging, future research efforts should examine whether a causative link exists and by what mechanisms. The prevention of loss of mitochondrial function with aging could be central to the prevention and treatment of hypertension and high cholesterol.
VIII. ADJOURNMENT
The 94th meeting of the National Advisory Council on Aging was adjourned at 2:25 P.M. on February 2, 2005. Dr. Hodes closed the Council session by thanking all speakers and Council members for their participation. The next meeting is scheduled for May 24–25, 2005.
Attachments:
A. Roster of Council Members
B. Director’s Status Report to the NACA
IX. CERTIFICATION
I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete.
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 from Rose Li and Associates, Inc.
