The 109th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, January 26, 2010, at 3 p.m. in Building 31, Conference Room 10, 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, January 26, from 3 p.m. to 5 p.m. for the review, discussion, and evaluation of grant applications in accordance with the provisions set forth in Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code and Section 10(d) of Public Law 92-463.1 The meeting was open to the public on Wednesday, January 27, from 8 a.m. to 2:07 p.m.
Dr. Lisa Berkman (January 26 only)
Dr. Dale Bredesen
Dr. Peggye Dilworth-Anderson
Dr. Hugh C. Hendrie
Dr. S. Michal Jazwinski
Dr. Sundeep Khosla
Dr. Andrea LaCroix
Dr. Victor Molinari
Dr. Lennart Mucke
Mr. Daniel P. Perry
Dr. Ronald C. Petersen (provisional member)
Ms. Orien Reid
Dr. Arlan G. Richardson
Ms. June Simmons
Dr. James P. Smith
Dr. Susan L. Swain
Dr. Terrie F. Wetle
Ex Officio Participant:
Mr. John Wren, Administration on Aging
Absent Ex Officio Participants:
Dr. James F. Burris, Department of Veterans Affairs
Dr. Kenneth G. Pugh, National Naval Medical Center
The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as attachment A.
In Addition to NIA Staff, Other Federal Employees Present:
Dr. Francis S. Collins, Director, NIH
Dr. Samuel Edwards, Center for Scientific Review, NIH
Dr. René Etcheberrigaray, Center for Scientific Review, NIH
Dr. Elisa Klein, Office of Behavioral and Social Sciences Research, NIH
Dr. Emilee Pressman, Office of Extramural Research, NIH
Dr. Luci Roberts, Office of Extramural Research, NIH
Dr. Laurent Taupenot, Center for Scientific Review, NIH
Dr. Kevin Walton, Center for Scientific Review, NIH
Members of the Public Present:
Dr. Kimberly Acquaviva, George Washington University and Friends of the NIA
Mr. James Appleby, The Gerontological Society of America
Ms. Deborah Bittner, Social & Scientific Systems, Inc.
Dr. Carol W. Greider, Johns Hopkins University
Mr. Rick Hansen, Digicon, Inc.
Ms. Mary Jo Hoeksema, Population Association of America
Mr. Todd Kluss, The Gerontological Society of America
Ms. Pat Kobor, American Psychological Association
Dr. Rose Maria Li, Rose Li and Associates, Inc.
Dr. Frank M. Longo, Stanford University School of Medicine
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Mr. Jason Michelitch, National Capitol Captioning, LLC
Dr. R. Sean Morrison, Mount Sinai School of Medicine
Dr. Christina H. Paxson, Princeton University
Ms. Amy Pollick, Association for Psychological Science
Dr. David Scalzitti, American Physical Therapy Association
Ms. Branka Sekis, Social & Scientific Systems, Inc.
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).2
A total of 1193 applications requesting $499,953,058 for all years underwent initial review. The Council recommended 711 awards for a total of $329,437,562 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.
Dr. Hodes welcomed members to the open session of the 109th NACA meeting and called the meeting to order at 8:00 a.m. on Wednesday, January 27, 2010.
Dr. Hodes acknowledged several attendees, including Mr. James Appleby, Executive Director of The Gerontological Society of America, then circulated a book of NIA media coverage, which summarized potential exposure from print and the Web. He noted a print audience of 27 million people and an Internet audience of more than 3 billion.
The NIA received an appropriation of $1.079 billion for fiscal year (FY) 2009, two-thirds of which was devoted to research project grants. Although this figure is stable compared with past years, current dollar figures continue to show budget increases at a lower rate than that of inflation, and constant dollars, a measure of NIA spending power, continue to decrease. Despite an increase of 11.7 percent in current dollars, the actual buying power of the NIA has decreased by 15 percent, based on the inflationary index. In addition, the success rate of grant applications (the percentage of applications received that is actually awarded) has declined from near 30 percent during the NIH budget doubling to 17.5 percent in FY 2009, with a payline of 11.8 percent. (Not counting funds from the American Recovery and Reinvestment Act (ARRA) in 2009). The payline for 2010 is anticipated to be 8 to 9 percent.
Dr. Hodes briefly noted the five broad areas of priority research opportunities identified by Dr. Francis Collins, NIH Director: 1) genomics of fundamental biology; 2) translational research; 3) health care reform; 4) global health; and 5) empowerment of the biomedical research community (Science 327 (5961): 36-37; 2010 January 1). Dr. Hodes then highlighted a number of NIA achievements in translating basic science discoveries into better treatments, which includes not only studies to identify and build links for moving basic science results into applied research, but also studies on effectively implementing evidence-based interventions in real-world settings.
Supported by the NIA and the National Institute of Nursing Research (NINR), the Resources for Enhancing Alzheimer’s Disease Caregiver Health (REACH) study addresses the stress inherent in the dyad between caregiver and patient. It is a randomized clinical trial of individualized intervention. REACH has found that these interventions significantly decreased the prevalence of clinical depression and the placement of patients in institutions, and they proved effective across racial and ethnic groups. Findings from REACH have been translated into an online training manual and the implementation of REACH interventions at 20 Department of Veterans Affairs (VA) sites. The NIA also has met with the Administration on Aging (AoA), the Centers for Medicare & Medicaid Services (CMS), and the Alzheimer’s Association to discuss implementation of REACH.
The NIA also has supported studies exploring risk factors involved in motor vehicle collisions among older drivers. A history of falls, the presence of neurological disorders and arthritis, and impairment in the useful field of view (UFOV), (the area from which one can extract visual information at a glance) contribute significantly to risk, whereas binocular acuity and contrast sensitivity do not. NIA-supported researchers have found that UFOV training can reduce the risk for crashes. Several states have now implemented a UFOV assessment of older drivers, and some insurance agencies offer discounts for individuals who undergo this training.
NIA studies also have found that exendin, a peptide extracted from Gila monster lizard saliva, lowers blood glucose levels and increases the release of insulin from the pancreas, similar to glucagon. These findings have led to the development of a synthetic drug that has been approved by the U.S. Food and Drug Administration (FDA) for type 2 diabetes. In addition, treatment of diabetes has shown promise against some neurological diseases, and animal models treated with exendin have shown reduced brain damage.
In response to questions from Dr. Petersen, Dr. Hodes noted that with rare exceptions, such as the creation of a new Institute or Center (IC) or the implementation of a dramatic initiative, changes in budget allocations from year to year tend to be parallel across all NIH ICs. Although there is potential for funds to be reallocated according to the changing health landscape, it rarely happens. Mr. Perry noted that this has been the case for the past 15 years but that the same could not be said further back in history. For example, the National Heart, Lung and Blood Institute received much higher allocations during the 1960s and 1970s and has stayed at those levels, whereas the National Institute of Allergy and Infectious Diseases received a large bump in the 1980s. Only since the mid-1990s have the ICs moved in lockstep. Dr. Smith expressed concern that NIA funding levels remain flat at a time when the average age of the U.S. population is increasing.
The remainder of the discussion then focused on the anticipated payline. In response to questions from Dr. Khosla, Dr. Robin Barr mentioned three factors that contribute to the tighter payline: the decline in the number of small, 2-year grants (i.e., R03, R21) awarded and the corresponding increase in 5-year grants; the advancement of science to the point where the NIA is supporting more large clinical trials, which consume more of the budget; and the rise in the costs of R01 grants, reflecting inflation, even as budget increases have not matched the rate of inflation. The number of R01 applications rose substantially from 2005 to 2007, and although this number has tapered off some, it is still well above the numbers seen between 2003 and 2004.
Council members expressed concern about the increasing gap in funding level between the NIA and the NIH overall, particularly the potential impact on submissions. Dr. Hodes noted efforts to address this gap and the challenges associated with supporting the best science, including the proper balance between large studies (e.g., program projects, clinical trials) and individual research projects, and achieving a payline competitive with other ICs. He added that, in light of the current economy, what was once viewed as a short-term difficulty might become a longer-term constraint, but he also cautioned against relying solely on an arithmetic solution. He also discussed the continuing shortfall in support for clinical trials by the pharmaceutical industry, particularly in areas with low market profitability. Evaluating the NIA research portfolio with respect to public health need, talking with relevant advocacy groups, and holding town hall meetings were suggested as ways to address budgetary difficulties. NIA staff welcomed opportunities to share information about research findings and funding opportunities with interested parties.
Discussion closed with Dr. Wetle expressing concern about the coming “crash” once ARRA funding ends. Dr. Wetle suggested that the NIA collect stories and anecdotes about the effects of funding difficulties on institutions to assess the amount of damage.
May 25–26, 2010 (Tuesday and Wednesday)
September 21–22, 2010 (Tuesday and Wednesday)
January 25–26, 2011 (Tuesday and Wednesday)
May 24–25, 2011 (Tuesday and Wednesday)
September 20–21, 2011 (Tuesday and Wednesday)
The minutes of the September 2009 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.
Dr. Hodes began by describing Dr. Francis Collins as someone from a strong science background, displaying remarkable scientific breadth and support of NIH and NIA areas. Dr. Collins acknowledged Dr. Hodes and NIA staff for their efforts in comparative effectiveness research, as well as their work in disbursing ARRA funds in a short time in 2009. He reported that 84 percent of NIH funds, approximately $26 billion, support more than 325,000 scientists and research personnel at more than 3,000 institutions. He then highlighted a few examples of exciting scientific areas that address the research agenda of the NIA:
Dr. Khosla asked about the Clinical and Translational Science Award (CTSA) program and how it might evolve. Dr. Collins responded that CTSAs, which constitute a complete reformatting of the way the NIH supports clinical research, will be a critical part of the NIH agenda for translating and applying discoveries. However, he acknowledged that the NIH is still trying to get a better sense of the kinds of projects CTSAs will do.
The rest of the discussion focused on rapamycin and on the differences in health between the United States and Europe. Dr. Smith, who has been involved with international comparisons, and Dr. Richardson, who studies mouse models of longevity and health, elaborated on their respective projects. They pointed to grassroots efforts and large population studies such as the Health and Retirement Study as transformative engines in their areas of research. Dr. Collins closed by praising the NIA for its leadership in health economic research and the importance of exploring models to assist health care reform.
Dr. Dilworth-Anderson reminded the Council that the task force has been reviewing various centers programs to identify opportunities and needs for center-based research, lessons learned, models for successful career development, directions for future plans, and recruitment and retention strategies for diverse populations. She reported that the previous day’s discussion focused on the Claude D. Pepper Older Americans Independence Centers. The Pepper Centers program, established in honor of Claude D. Pepper, a Florida representative who championed successful aging and quality of life for older adults, currently receives an appropriation of about $1 million in direct costs for each of 12 centers. These centers aim to increase scientific knowledge to maintain and restore independence in older adults. More specifically, they are expected to provide intellectual leadership and innovation, stimulate research translation, facilitate and develop novel multi- and interdisciplinary research projects, stimulate the incorporation of emerging technologies, serve as a source of advice and collaboration, and provide career development opportunities.
All Pepper Centers have had minority research trainees affiliated with them (mean = 5.6). Trainees are diverse across gender, race and ethnicity, and physical disability. Nearly all the trainees have remained in academic research, and nearly all of them focus on aging and disability or functional status. Trainee interests span basic, translational, clinical, and community research. Nine of these trainees focus specifically on health outcomes in minority older populations. Pepper Centers have generated 102 minority-related research publications and received several diversity supplements, K awards, and R01s. Pepper Center researchers go on to obtain desirable academic appointments and promotions.
Pepper Centers are engaged in four collaborations, including one with CTSAs and one with Alzheimer’s Disease (AD) Centers, and they serve as a successful model for recruitment and retention of both trainees and study participants. The task force primarily discussed mentoring, including best practices and lessons learned, as well as several trainee recruitment strategies, including ongoing mentorship benchmarks, T32 training grants, pilot support for manuscript and grant development, and interfacing with other studies such as the Women’s Health and Aging Studies and the Baltimore Study on Aging. With respect to study participant recruitment, the task force discussed the Healthy Aging in Neighborhoods of Diversity Across the Lifespan Study (HANDLS), a collaboration with the NIA Intramural Program designed to untangle race from socioeconomic status in health outcomes.
Dr. Dilworth-Anderson closed by announcing that Summer Institute applications are due March 5, 2010, and by highlighting the Health Disparities Resource Persons Network. She invited Council members to join the network and visit its Web site.
Dr. Jazwinski briefly reviewed several recommendations from past meetings, an upcoming advisory meeting on AD and preclinical therapies, and five funding opportunities proposed for concept clearance.
Dr. Ronald Kohanski, of the Division of Aging Biology, requested clearance for an RFA on cell lineage determination and tissue homeostasis. Aging phenotypes often are associated with changes in tissue composition and turnover, but no direct assays are available to study how this occurs. The proposed initiative expands on an earlier opportunity that supported the development of techniques and methodologies for tagging cells; these techniques will now be used to study migration and establishment of stem cells in damaged tissues, as well as signaling and overall microenvironments that support cell differentiation. A motion to approve this initiative was forwarded, seconded, and passed unanimously.
Dr. Lis Nielsen, of the Division of Behavioral and Social Research (DBSR), proposed an initiative on the science of wellbeing and advances in the application of its measurement to aging. Wellbeing encompasses two perspectives: the individual’s perceptions of his or her wellbeing, and societal perception of quality of life. The proposed initiative would represent a collaboration between psychology and economics and support analyses of wellbeing from both perspectives, with the goal of identifying areas of intersection and possible objective measures of wellbeing. Dr. Mucke expressed concern that this initiative, though important, might not translate directly into advances in public health, particularly because of a historical emphasis on the negative (i.e., depression). Dr. LaCroix added that this initiative would be exciting in light of the need to focus on the positive in aging and that other disciplines, such as epidemiology and sociology, should be included. Other Council members discussed how the proposed initiative dovetails with the positive psychology movement and a global interest in wellbeing. Use of the NIH Toolbox, which has developed instruments to measure cognition and emotion, was suggested. A motion to approve this initiative was forwarded, seconded, and passed with one abstention.
Ms. Georgeanne Patmios, of the DBSR, proposed an initiative to support research across international boundaries to assess differences in institutions, health habits, and health behaviors and thus identify possible factors that contribute to older people becoming sick sooner in the United States, compared with other countries. A motion to approve this initiative was forwarded, seconded, and passed unanimously.
Dr. Basil Eldadah, of the Division of Geriatrics and Clinical Gerontology (DGCG), proposed an initiative to support early career development in clinical aging research for medical and surgical specialties. Mechanisms to support the training of physician scientists have been in place, but because specific programs have ended, there is a perceived lack of support. The proposed initiative garners support from several professional organizations. Dr. Khosla noted that this initiative will support career transition and provide research experience for physician scientists. A motion to approve this initiative was forwarded, seconded, and passed unanimously.
Dr. Sherry Sherman, of the DGCG, proposed an initiative to support a specimen repository for the Study of Women’s Health Across the Nation (SWAN). This study has been ongoing for the past 18 years but is now transitioning to become a resource for broader research, and such a repository could serve as a resource for other investigators. More involvement and oversight from the NIA is needed. A motion to approve this initiative was forwarded, seconded, and passed unanimously.
Dr. Barr referred the Council to the statistical packages, which show trends in the number of applications received by the NIA and how the Institute is doing in review. This year’s packages also include one specifically focused on ARRA funds. Dr. Barr also referred to the report on participation of women and minorities in research, which provides data on recruitment of diverse study populations by NIA-supported projects.
The Council then reviewed and reconsidered the Statement of Understanding. This statement had been modified in 2009 to include expedited clearances for applications submitted in response to ARRA-supported initiatives. That modification is still in place to cover ARRA applications coming in 2010. Otherwise, the terms of the statement remain the same.
A motion to approve the Statement of Understanding for another year was forwarded, seconded, and passed unanimously.
Dr. Hodes acknowledged retiring members Drs. Eisdorfer and Brummel-Smith, both of whom were absent. He then thanked and gave certificates to Drs. Friedman, Ganguli, Morris, and Schatten.
Prior to his service on NACA, Dr. Friedman had been a long-term senior member of the NHLBI staff. His expertise has been valuable as the NIA invests increasingly in intervention research. Dr. Friedman commented that serving on NACA had given him an appreciation for the wisdom of Council advice, that he had learned much during his service, and that he appreciated the strengths of the NIA staff and the kind of research being done at the NIA.
Dr. Ganguli provided a broad perspective and served as an outstanding mentor to new Council members. She commented that her service on the Council had debunked myths she had held regarding the power of Council, educated her about the inner workings of Government, and helped her appreciate the care and fairness with which the NIA spends taxpayer dollars. She noted that she had learned from other Council members, program staff, and speakers, and she expressed gratitude for the opportunity to serve.
Dr. Morris has shown great leadership in AD research; chaired a large number of committees; and exhibited high standards in his character and in his interactions with colleagues, peers, and patients. Dr. Morris thanked the NIA for the opportunity to serve on Council and expressed that it is a privilege to understand the depth, breadth, and quality of science supported by the NIA. He also noted how much he enjoyed interacting with other Council members.
Dr. Schatten was acknowledged as an active and, when required, provocative Council member. He commented that working with Council had been a privilege and honor and that he has learned a great deal about fields he had not appreciated before joining Council. Dr. Schatten expressed concern about the future of research and how it would affect investigators, noting that the work his colleagues do is heroic but receives little reward. He pointed out that although the numbers of applications will continue to increase, the constraints will remain the same, and NACA will have to consider the emotional toll related to dwindling resources on grantees and investigators who have devoted their scholarship and life’s work to aging research. Dr. Schatten stated his appreciation for the collegial nature of the Institutes and Centers of the NIH but feels it is vital that the NIA’s budget grows at a faster rate than it has as too many good ideas are at risk of not receiving support, and he pledged to redouble his efforts to help.
Dr. Jonathan King discussed NIH efforts to explore the science of behavior change (SOBC). A large percentage of premature deaths are related to modifiable behavioral patterns; thus behavior change might be a powerful way to address disease and mortality. Indeed, data from the Diabetes Prevention Program found that a weight reduction of 7 percent and an increase in activity of 2.5 hours per week led to a 58 percent reduction in the cumulative incidence of type 2 diabetes. Among adults aged 60 years and older, lifestyle change appears to be the only effective intervention.
Several NIH ICs focus on behavior change, but because they focus on changes most relevant to their individual missions, NIH research into behavioral change has been balkanized. The NIH is taking steps to encourage the emergence of a transdisciplinary SOBC and the identification of common mechanisms. Dr. Richard Suzman, director of the NIA DBSR, and Dr. Patricia Grady, director of the NINR, co-chair a workgroup that has been meeting monthly since June 2008, and SOBC has been selected as a focus for the Transformative R01 (TR01) program.
In June 2009, a meeting on SOBC brought together 130 registered participants (including 60 outside experts) to explore acquisition and prevention of behavior, changes in existing behavior, and maintenance of behavior change. Meeting participants identified several key themes, including a better understanding of basic mechanisms; integrated, multilevel approaches to change; and the need to target behavior “bundles.” Dr. King referred the Council to the SOBC meeting report, which is now available online (http://www.nihroadmap.nih.gov/behaviorchange/meetings/sobc061509/report.asp ).
The NIA is now leading 17 ICs in a funded Roadmap initiative devoted to SOBC, supported by the NIH Common Fund. This initiative will receive $4 million per year for 5 years, with escalation for inflation. (See http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-10-002.html .)
Council members were excited about this initiative. Dr. Hendrie was pleased to see the inclusion of cognitive and affective science, and Ms. Simmons noted that this work will tie into the efforts of the AoA and the Centers for Disease Control and Prevention.
Ms. Reid reported to the Council on the recent activities of the NIH Council of Councils (CoC), which was mandated under the 2006 NIH Reform Act to advise the NIH Director on the Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI) and IC directors on trans-NIH initiatives. CoC held a conference call in August 2009 to provide a second-level review of TR01 applications and early clearance of proposed program concepts. At the annual CoC meeting held in November 2009, Dr. Elizabeth Wilder reported that ARRA funding provided $137 million for FY2009–2010 to support Common Fund initiatives, including new technologies in epigenetics, stem cell research, testing what works in behavior change, and education in science, technology, engineering, and mathematics. Dr. Antonio Scarpa, Director of the Center for Scientific Review, reported on a survey of TR01 projects. Of 740 applications submitted in 2009, 720 were reviewed, using a two-tiered editorial board approach, and 42 were funded. Of the investigators who were funded, the majority were male (79 percent) and white (71 percent). Dr. Scarpa also noted that of the applications submitted, 320 were unlikely to have received funding from other sources. Ms. Reid closed her presentation by announcing that the CoC will hold its next annual meeting on November 8–9, 2010, with a conference call possible in August.
Nagi’s model of disability posits that disease leads to impairment, which in turn leads to functional impairment and disability. Dr. Sean Morrison, of the Mount Sinai School of Medicine, proposed that this model is incomplete. He pointed out that pain could lead to impairments, functional limitation, and disability, which in turn could lead to more pain. Although the conventional wisdom suggests that treating the disease addresses the impairment, Dr. Morrison argued that treating pain could have an independent effect.
Dr. Morrison and his colleagues use hip fracture as a research model for pain and disability in older adults. Hip fracture is a useful model because it occurs in older adults across a broad range of cognitive functions, is associated with symptom burden and has a defined onset, is associated with the highest incidence of delirium and cognitive impairment, and is associated with long-term disability. In addition, care for hip fracture involves interdisciplinary teams and the entire continuum of care, from emergency service to long-term facilities. Dr. Morrison’s group assessed pain and analgesic prescribing practices among 571 older adults admitted to 4 hospitals in metropolitan New York. Not surprisingly, both the prevalence and incidence of pain were high among these adults. Eighty percent of older adults reported pre-operative pain, whereas 50 percent reported post-operative pain. Many reported pain associated with simply moving from their beds to a chair, and others reported moderate to severe pain when they walked. Yet most of these patients received 15 mg or less of oral morphine sulfate per day, and less than 5 percent of these patients received regularly scheduled analgesia before or after surgery. Dr. Morrison and his colleagues further found that patients with cognitive impairment received less than half the analgesia that those with intact cognition received.
Undertreatment of older adults in pain might arise in part from concerns that analgesic medication could precipitate delirium, which has been associated with mortality, depression, institutionalization, and cognitive impairment. However, studies by Dr. Morrison’s group of advanced dementia patients and those able to report their pain found severe post-operative pain to be an overwhelming risk factor for delirium. Low doses of opioids decreased this risk, and higher doses were protective. These results were replicated in four other studies. Moreover, Dr. Morrison and his colleagues found that pain affected physical therapy sessions, length of hospital stays, and ambulation both 3 days and 6 months after surgery.
Dr. Morrison and colleagues then conducted a prospective, controlled trial of intense analgesia and pain in an acute rehabilitation setting. Patients in the intervention group underwent pain assessments both by registered nurses and physical therapists and were given standing opioids every 4 hours, with additional opioids as needed for breakthrough pain. Protocols were implemented for constipation, sedation, and nausea, common side effects of analgesic treatment, and opioids were titrated until participants reported non-to-mild pain at rest and minimal interference with physical therapy and ambulation. As early as rehabilitation day 1, the number of patients reporting moderate to severe pain was dramatically reduced, and this difference continued through day 7. Hospital stays were shorter by a mean of 1.2 days for the intervention group, and although there were no differences in analgesic prescribing practices at discharge, when the intervention ended, patients in the intervention group were walking more, and less likely to be taking analgesics at 6 months following discharge.
Council discussion focused on the technical aspects of Dr. Morrison’s work, including the critical need for research about the interaction between pain and depression, better data on chronic pain syndromes, the need for pharmacological therapy and more research on nonpharmacological approaches, and the challenges of translating findings from animal models to the human condition.
Nobel Laureate Carol Greider, of Johns Hopkins University, discussed the field of telomere research as an example of the importance of curiosity-driven research in which the most interesting studies arise from unlikely sources. In this case, phenomena first observed in Tetrahymena have been shown to be involved in human disease.
Telomeres, the ends of chromosomes, protect the chromosomes from nucleases and end-to-end chromosome fusion. This protective function is carried out by tandem DNA repeats within the telomere and proteins that bind the length of it. During normal DNA replication, whenever a cell divides, telomeres lose some of their length, but telomerase, an enzyme composed of an RNA component (TERC) and a catalytic protein component (TERT), facilitates the addition of telomeric repeats following replication. Thus chromosomes are maintained by a balance of telomere shortening and lengthening.
Dr. Greider and colleagues have studied the RNA component of telomerase. They have identified its secondary structure and found that mutations in this component have important ramifications for human disease. They also have taken a genetic approach in mouse models to explore the effects of progressive telomere shortening, generating mice deficient in telomerase or mice heterozygous for TERC mutations and breeding them through the sixth generation. Early generations showed no phenotype, but later generations showed abnormal phenotypes in regions with a significant amount of cell turnover, such as the reproductive organs and the hematopoietic system. Thus, it is not the absence of telomerase but shortened telomeres that cause these phenotypes. On the basis of this data, Dr. Greider’s group have formed a working hypothesis that short telomeres induce a DNA damage response, but when telomeres are very short, there are no longer enough sequences for proteins to bind. At this point, cells undergo p53 signaling and ultimately apoptosis or senescence. The pathway through which short telomeres induce apoptosis or senescence is not clear.
Although shortened telomeres appear to be more important, telomerase is still important for cells that divide many times, such as cancer cells or those involved in tissue renewal. Dr. Greider has collaborated with another researcher at Johns Hopkins to study the role of telomerase and shortened telomeres in dyskeratosis congenita, a disease characterized by skin hyperpigmentation, oral leukoplakia, nail dystrophy, aplastic anemia, pulmonary fibrosis, and cancer. TERC mutations have been associated with autosomal dominant dyskeratosis congenita, but Dr. Greider and colleagues have also found mutations in TERT, indicating that abnormalities in both components contribute to the disease. Genetic anticipation also appears in affected families; later generations exhibit worse phenotypes and earlier disease onset.
Using their genetic approach, in which mice deficient in telomerase were bred with wild-type mice for seven generations, Dr. Greider and colleagues found that heterozygous mice were haploinsufficient in terms of telomere length. Shortened telomere length was associated with decreased survival rates in knockout mice derived from these genetic crosses. However, wild-type mice born to heterozygous parents also exhibited shortened telomeres and phenotypes such as testis apoptosis and reductions in spleen weight. These mice thus display a form of occult genetic disease, even in the absence of telomerase mutations, and might serve as a model for human genetic disease. In addition, many phenotypes from telomere-shortening syndromes share features with human age-related diseases such as pulmonary fibrosis, bone marrow failure, immune senescence, liver disease, and cancer, suggesting that shortened telomeres play a role in human age-related disease even in the absence of telomerase mutations.
Dr. Greider closed her presentation by noting ongoing molecular and genetic efforts to understand other diseases associated with shortened telomeres. She also noted the heterogeneity of telomere length among the human population and that individuals with shorter telomeres might be at risk for age-associated degenerative diseases.
Discussion focused on technical aspects of the presentation. Dr. Greider cautioned that it is difficult in these types of studies to discern cause and effect, that therapies involving telomerase and shortened telomeres might be tricky because of their role in tumor suppression, and that information about telomere shortening might be misused by companies selling untested therapies. She also emphasized the importance of supporting both problem-focused science and general science that allows for serendipity.
Neurotrophins are proteins that interact with cell surface receptors, which in turn promote a series of intracellular signaling events critical to neuron survival and integrity. Supplying exogenous neurotrophins is an often-tried therapeutic approach for several diseases, but this approach has often failed, possibly because it has not incorporated knowledge about the mechanisms of disease. Dr. Frank Longo, of the Stanford University School of Medicine, has taken a non-traditional approach by developing small-molecule ligands that interact with cell surface receptors such as p75.
Accumulation of amyloid beta (Ab) triggers activation of calpain and several kinases, inhibits CREB and Rho A, and induces excess tau phosphorylation, which all contribute to critical events in AD. The p75 receptor interacts with “death adaptors” to promote these events, and it is expressed in many neurons that degenerate at various stages of AD. However, p75 also can interact with “survival adaptors.” To identify and generate p75 receptor ligands that lean toward survival instead of death, Dr. Longo and colleagues have employed a virtual screening approach to identify neurotrophin domain mimetics. Candidate molecules are subjected to extensive testing to prove that they are indeed ligands, that they activate p75 signaling that favors survival, and that they block or inhibit the ability of Ab to induce its cascade of molecular events involved in AD. Through this approach, Dr. Longo and his colleagues have identified several ligands that prevent Ab-induced neuronal death, neuritic dystrophy, and synaptic dysfunction. Moreover, these small molecules inhibit Ab-induced spine loss, which is the best morphologic correlate of loss of cognition in AD.
All of this work has been done in vitro. Dr. Longo and colleagues now have a U01 grant to explore efficacy in vivo with respect to morphology, behavior, and signaling in mouse models, then to scale up the most effective molecules and eventually move to phase I trials. They have shown that two of their ligands reduce neuritic dystrophy and reverse spine loss, although Ab accumulation is unaffected. Moreover, mice treated with these ligands appear to learn just as well as wild-type mice in delayed matching-to-place, a behavioral paradigm involving working and episodic memory. Treatment with these ligands also appears to prevent or reverse basal forebrain cholinergic neuron (BFCN) atrophy, which has been associated with normal, age-associated memory loss. The ligands are effective even in older mice.
Discussion focused primarily on technical and hypothetical aspects of Dr. Longo’s work. Dr. Longo noted that these ligands are available for academic collaboration and expressed a desire to test them in different models.
According to Dr. Christina Paxson, of Princeton University, the relationship between health and wealth is quite robust, and the gradient begins early in life and becomes more pronounced with age. Across countries, within countries at any given point of time, and over time with economic growth (with a few caveats), wealthy individuals live longer and have lower morbidity on average than do the less wealthy. How health and economic status are related is under debate, but several theories have been proposed. It could be that poor health reduces educational attainment, earnings, and wealth accumulation, and/or that low incomes result in lower-quality medical care and living environments or shape health behaviors via stress or preferences. Both phenomena may operate at the same time, or different factors may become more prominent at different life stages.
Dr. Paxson and her colleagues are using data from several cross-sectional, birth cohort, and panel studies, as well as measures of childhood health, to examine the hypothesis that childhood health affects adult health, which in turn affects earnings and other measures of wealth. They have found that poor childhood health, as measured by prenatal smoking, low birth weight, shorter height, or the presence of chronic childhood conditions, is associated with reduced educational attainment, lower labor force attachment in adulthood, lower occupational status, lower earnings, poorer health in middle and older age, and worse cognitive function in old age. In one study based on data from the 1958 National Child Development Study, Dr. Paxson estimates that a boy who is exposed to prenatal smoking, born at low birth weight, and has one chronic childhood condition will show a reduction of educational attainment by an amount that corresponds to 8.6 percent lower earnings as an adult. This same child is predicted to have 30 percent lower earnings at age 33, and his probability of being employed is predicted to be 13.6 percentage points less.
Dr. Paxson cautioned that many of the cross-sectional, birth cohort, and panel studies have no good measures of what happened in childhood. Instead, they rely on adult recall of childhood health and use height as a proxy measure. Dr. Paxson and her colleagues have performed regression analyses of height, education, employment, and earnings across surveys and found that taller height is consistently associated with more schooling, higher probability of being employed, and higher earnings. On the basis of later-life measures of health and cognitive function, taller individuals show better self-reported health and are less likely to have long-standing illnesses or be registered as disabled. Dr. Paxson’s research further suggests that the link between height and earnings can be explained by links between height and early childhood cognitive development.
Research by Dr. Paxson and her colleagues pointing to large associations between childhood health and adult economic outcomes highlights the significant role that education and cognitive development play. Although more work is needed to identify the mechanisms underlying these associations, it is possible that effective interventions in early childhood could yield substantial long-term economic payoff.
In response to questions from Dr. Smith, Dr. Paxson noted that the association between height and economic outcomes appears to be similar between men and women. Council members also discussed possible roles for self-esteem, genetics, and environment as mediating variables.
The Laboratory of Cellular and Molecular Biology (LCMB) studies the molecular and cellular changes that occur with advancing age, particularly with respect to age-associated loss in physiologic function and onset of age-related diseases. Within LCMB, the RNA Regulation Section (RRS) studies the post-transcriptional control of age-related gene expression, with a focus on the microRNAs and RNA-binding proteins (RBPs) implicated in these processes. The long-term goal of RRS and LCMB is to elucidate the mechanisms that regulate gene expression after exposure to damaging and proliferative signals, as these responses are critically impaired with aging. Fully understanding the gene regulatory mechanisms that become aberrant with advancing age will yield valuable insight into age-associated diseases and the aging process itself.
Dr. Myriam Gorospe, a senior investigator in LCMB, presented two specific projects to illustrate how the RSS investigates age-related gene expression. The first project explores changes in mitogen-activated protein kinase (MAP) kinase 4 (MKK4), an upstream activator of MAP kinases, c-Jun N-terminal kinase, and p38, in replicative senescence. Dr. Gorospe’s group has found that the level of MKK4 protein increases in senescent human diploid fibroblasts through enhanced MKK4 translation. This increase in MKK4 further inhibits cell proliferation and enhances the phosphorylation and activity of p38 and p38-regulated/activated protein kinase (PRAK). Dr. Gorospe’s group has further identified four microRNAs whose levels decrease in both tissues from older persons and during replicative senescence. These microRNAs target MKK4 RNA, and although each one does not appear to affect MKK4 levels by itself, all four work collectively to inhibit MKK4 translation through the 5’ and 3’ untranslated regions (UTRs) of the MKK4 messenger RNA. Thus multiple microRNAs act on a single target to influence MKK4 abundance during replicative senescence.
The second project focuses on RBPs that, like microRNAs, are potent post-transcriptional regulators of gene expression. Dr. Gorospe’s group has found that the RBP HuR reduces c-Myc expression by associating with the c-Myc 3’ UTR, next to the site where the microRNA let-7 interacts. Lower levels of either HuR or let-7 reduce repression of c-Myc, but surprisingly, these molecules are interdependent in regulating c-Myc translation. On the basis of these findings, HuR might inhibit c-Myc expression by recruiting a let-7–loaded RNA-microRNA-induced silencing complex to the 3’UTR of c-Myc.
Discussion focused on technical aspects of the work Dr. Gorospe presented. She noted that targeting microRNAs therapeutically might be possible, but more computational ability and further understanding of their targets are needed.
There are several DNA repair pathways, all of them highly complex and involving several different proteins. Among these is base excision repair, a major pathway involved in the repair of spontaneous, alkylation, and oxidative DNA damage. This pathway is a major determinant in cellular sensitivity to environmental and clinical DNA-damaging agents and plays important roles in somatic hypermutation, telomere maintenance, premature aging and disease, cancer susceptibility, and neurodegeneration. The Free Radical Theory of Aging suggests that oxidative damage accumulates over the life span, leading to functional decline and death. Dr. Vilhelm Bohr, Chief of the Laboratory of Molecular Gerontology (LMG), highlighted projects aimed to further explore this theory.
One joint interest of several sections within LMG focuses on segmental progerias, which involve accelerated aging processes and serve as models for the study of aging. All of these disorders involve defects in DNA repair. LMG studies the RECQ helicase family, a group of five human helicases associated with progerias such as Werner syndrome, Bloom syndrome, and Rothmund-Thomson syndrome. LMG investigators have shown that the helicase WRN is involved in telomere maintenance and interacts with shelterin proteins. Using a gene-specific assay in fish, mice, and yeast, this group also has found that deficiencies in removing base lesions leads to an accumulation of telomere damage and that damage in the telomere inhibits binding of telomeric proteins, suggesting that oxidative damage interferes with telomere maintenance.
LMG also has characterized RECQL4, a helicase associated with Rothmund-Thomson syndrome. Investigators have identified interactions with several proteins involved in base excision repair and shown that RECQL4 localizes to the mitochondria. They also have shown that RECQL4 has helicase activity, although it is more limited than that seen with WRN or the helicase BLM. The helicase of RECQL4 appears to be stimulated by the presence of shelterin proteins on the telomeric D-loop, which protects the telomere, and RECQL4 itself appears to stimulate the ability of WRN to unwind the D-loop.
The Mitochondrial Theory of Aging proposes that DNA damage accumulates much faster in the mitochondria, eventually destroying mitochondrial processes and ultimately leading to cellular dysfunction and aging. LMG investigators studying Cockayne syndrome, which involves defects in transcription-coupled and base excision repair and serves as a model for neurodegenerative processes, have characterized several proteins and found that one, CSB, participates in mitochondrial DNA repair processes. Future work will focus on possible connections between telomeres and the mitochondria.
This portion of the meeting was closed to the public in accordance with the provisions set forth in Section 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 2).
The open session of the 109th meeting of the National Advisory Council on Aging adjourned at 2:07 p.m. on January 27, 2010. The next meeting is scheduled for May 25 and 26, 2010.
I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete.3
Richard J. Hodes, M.D.
Chairman, National Advisory Council on Aging
Director, National Institute on Aging
Prepared by Robin Barr, D.Phil.
With assistance by Rose Li and Associates, Inc.
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING
(Terms end December 31) (*WGoP Member)(**Provisional member whose appointment is not yet official)
Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
*Lisa F. Berkman, Ph.D. (2012)
Director and Professor
Harvard School of Public Health
Dept of Society, Human Development, and Health, and Dept of Epidemiology
Dale E. Bredesen, M.D. (2011)
Professor, Director & CEO
Buck Institute for Age Research
**Robert M. Califf, M.D. (2013)
Vice Chancellor for Clinical Research, Duke University
Director, Duke Translational Medicine Institute
Peggye Dilworth-Anderson, Ph.D. (2010)
Professor, Health Policy & Management
Associate Director, Aging and Diversity/ Institute on Aging
University of North Carolina, Chapel Hill
Chapel Hill, NC
Hendrie, Hugh C., MB, ChB, DSC (2013)
Professor, Department of Psychiatry, Indiana University School of Medicine
Research Scientist, Regenstrief Institute, Inc.
Center Scientist, Indiana University Center for Aging Research
*S. Michal Jazwinski, Ph.D., (2010)
Department of Medicine
Tulane University Health Sciences Center
New Orleans, LA
*Sundeep Khosla, M.D. (2010)
Professor, Endocrine Research Unit
Division of Endocrinology, Metabolism, & Nutrition
Mayo Clinic College of Medicine
Andrea Z. LaCroix, Ph.D., M.P.H. (2012)
Fred Hutchison Cancer Research Center
Women’s Health Initiative Clinical Coordinating Center
Victor Molinari, Ph.D. (2012)
University of South Florida
Department of Aging and Mental Health
*Lennart Mucke, M.D. (2012)
Director and Professor of Neuroscience
Gladstone Institute of Neurological Disease
University of California, San Francisco
San Francisco, CA
Perry, Daniel P. (2013)
President and CEO
Alliance for Aging Research
Washington, DC 20006
Petersen, Ronald C., M.D., Ph.D. (2013)
Professor of Neurology
Cora Kanow Professor of Alzheimer’s Disease Research
Director, Mayo Alzheimer’s Disease Research Center
Director, Mayo Clinic Study of Aging
Orien Reid (2010)
Chairman, Alzheimer's Disease International
President, Consumer Connection
Richardson, Arlan G., Ph.D. (2013)
Barshop Institute for Longevity and Aging Studies
University of Texas Health Science Center
San Antonio, TX
June Simmons (2012)
Chief Executive Officer
Partners in Care Foundation
San Fernando, CA
James P. Smith, Ph.D. (2012)
Department of Labor and Population
Santa Monica, CA
*Susan L. Swain, Ph.D. (2011)
President and Director
Saranac Lake, NY
Wetle, Terrie F., Ph.D. (2013)
Associate Dean and Professor
Program in Public Health
Division of Biology and Medicine
Department of Health and Human Services
Hubert H. Humphrey Building
Francis S. Collins, M.D., Ph.D.
National Institutes of Health
Public Health Service
James F. Burris, M.D.
Geriatrics & Extended Care Strategic Healthcare Group
Department of Veterans Affairs
Deputy Assistant Secretary for Policy and Management
U.S. Department of Health and Human Services
Administration on Aging
Kenneth G. Pugh, M.D.
Commander, MC, U.S. Navy
U.S. Naval Hospital Rota