The 118th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, January 29, 2013, at 3 p.m. in Building 31, Conference Room 6, National Institutes of Health (NIH), Bethesda, Maryland. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA), presided.
In accordance with the provisions of Public Law 92–463, the meeting was closed to the public on Tuesday, January 29, 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 the Public Law 92–463. 1 The meeting was open to the public on Wednesday, January 30, from 8:00 a.m. to 2:00 p.m.
Dr. Norman Anderson
Dr. Robert Califf
Dr. Dennis Choi
Dr. Ana Maria Cuervo
Dr. Hugh C. Hendrie
Dr. Andrea LaCroix
Dr. Victor Molinari
Dr. Richard Morimoto
Dr. Lennart Mucke
Dr. Eliseo Perez-Stable
Mr. Daniel P. Perry
Dr. Ronald C. Petersen
Dr. Arlan G. Richardson
Dr. Jonathan Skinner
Dr. Stephanie Studenski
Dr. Terrie (Fox) Wetle
Dr. Laura Carstensen
Ms. June Simmons
Dr. Jon Fuller, Department of Veterans Affairs
Mr. Robert Hornyak, Administration for Community Living
Mr. Edwin Walker, Administration for Community Living
Dr. Kenneth G. Pugh, National Naval Medical Center
Mr. James Wren, Administration for Community Living
The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as attachment A.
Dr. Sara Dodson, Office of Science Policy Analysis, Office of the Director, NIH
Dr. Valerie Durrant, Center for Scientific Review (CSR), NIH
Dr. Samuel Edwards, CSR, NIH
Dr. Rene Etcheberrigaray, CSR, NIH
Dr. Adam Felsenfeld, National Human Genome Research Institute, NIH
Dr. Melissa Gerald, CSR, NIH
Dr. Claire Gutkin, CSR, NIH
Mrs. Kimberley Hetkowski, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Dr. Yuan Luo, CSR, NIH
Dr. Sally Rockey, Office of Extramural Research, NIH
Dr. Geoffrey Schofield, CSR, NIH
Dr. Laurent Taupenot, CSR, NIH
Dr. Michelle M. Washko, Administration on Community Living
Mr. James Appleby, Gerontological Society of America
Dr. Andrea Baruchin, Foundation for the National Institutes of Health (FNIH)
Dr. Anne Brunet, Stanford University
Ms. Linda Harootyan, Gerontological Society of America
Ms. Mary Jo Hoeksema, Population Association of America
Dr. Rose Maria Li, Rose Li and Associates, Inc.
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Ms. Judith Mun, American Association of Colleges of Osteopathic Medicine
Ms. Michelle Rodrigues, SRI International
Dr. Dennis Villareal, University of New Mexico School of Medicine
Dr. Heidi Williams, Department of Economics, Massachusetts Institute of Technology
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 981 applications requesting $1,499,516,623 for all years underwent initial review. The Council recommended 563 awards for a total of $983,574,383 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 118th NACA meeting and called the meeting to order at 8:00 a.m. on Wednesday, January 30, 2013.
Dr. Hodes reported that NIH is under a continuing resolution through March 27. The American Taxpayer Relief Act, which was passed on January 1, 2013, addressed the immediate threat of a sequester, which would have resulted in an 8.2 percent reduction in the NIH budget. However, if Congress does not reach a budget resolution, a new sequester will be ordered on March 1 and implemented by March 27. It is estimated that this sequester will decrease the FY2013 NIH budget by 6.4 percent, when the fiscal year is half over. In addition, the Federal debt limit was reached on December 31, and Congress must reach a resolution by the end of February to raise the debt ceiling. Dr. Hodes noted that, although NIH and the ICs are not altering or ramping down activities, they are proceeding cautiously, and plans are in place to accommodate a compromise if the budget is reduced. Such plans will allow NIH to maintain a viable payline for competing awards, even under the worst-case scenario. Dr. Hodes reminded Council that NIH buying power has decreased steadily since 2003 and is now down by 28 percent. He also pointed out that the success rate for R01 applications for NIA is 16.4 percent, which places NIA in the middle of all NIH Institutes and Centers (ICs).
NIA is participating in the planning of several initiatives that are based on the themes and recommendations generated at the 2012 Alzheimer’s Disease (AD) Research Summit. These initiatives, which all work toward the cure, prevention, or delay of AD by 2025, include a request for applications (RFA) that focuses on broad systems biology approaches to discovering new therapeutic targets, as well as initiatives to support clinical trials of approaches to prevention. These initiatives have received a large number of applications, which still must undergo review. Although these initiatives were planned in the context of a possible addition of $80 million requested by the President’s Statement for AD Research, the budget is not yet known. Dr. Hodes cautioned that the payline for these initiatives must await resolution of the budget. A matrix of activities and milestones has been developed.
Dr. Hodes noted the extraordinary year experienced by the NIA Intramural Research Program (IRP) and commended Dr. Luigi Ferrucci, Scientific Director, for steering the IRP and reorganizing the scientific laboratories during a time of increasing budgetary constraints. Dr. Hodes closed his presentation by thanking past Chairs of the Friends of NIA—Mr. Daniel Perry, Dr. Kim Acquaviva, and Ms. Mary Jo Hoeksema—and acknowledging Ms. Linda Harootyan, who will serve as Chair in 2013–2014.
In response to questions about varying success rates at NIH, Dr. Hodes noted that both policy and the size of the community generating applications will determine those success rates. For example, the National Institute on Deafness and Other Communication Disorders, which does not support program projects, and the National Human Genome Research Institute, which primarily solicits applications including center applications, are among the ICs with higher success rates. Dr. Hodes added that NIA continues to be concerned about the impact of lower success rates, in terms of discouraging applications, but he emphasized that during this time of budget constraints, NIA remains near the average of NIH institutes.. He also pointed to areas of overlap among the ICs.
Dr. Ronald Petersen clarified that the matrix for Alzheimer’s Disease presented by Dr. Hodes includes short-, medium-, and long-term goals so that progress can be monitored. Short-term goals have been generated from projects that are already funded and under way. The RFAs described by Dr. Hodes aim toward medium-term goals, and longer-term goals will be more expansive. Dr. Petersen acknowledged the program staff for its work in planning initiatives and identifying relevant projects.
In response to questions about the potential $80 million in additional funding, Dr. Hodes clarified that this increase would be for one year only and that planning for RFAs accounted for all years being funded in that one year. In the event that these funds do not materialize, NIA and collaborators will have to determine what fraction of applications in response to these RFAs can compete with other applications also competing for funding during the year. How well that would be managed also depends on whether a sequester is ordered in March. The International Alzheimer’s Disease Portfolio (IADRP), a searchable database of AD research, could be used to categorize ongoing research according to target areas from the AD Research Summit; information from that database, combined with expert opinion, could aid NIA and others in prioritizing applications to maximize investments in therapies for AD according to the National Alzheimer’s Project Act. Dr. Hodes again emphasized the need for balance.
Another research summit, this one on non-AD dementias, will be held May 1–2, 2013.
June 4–5, 2013 (Tuesday and Wednesday)
September 17–18, 2013 (Tuesday and Wednesday)
February 25–26, 2014 (Tuesday and Wednesday)
Dr. Robin Barr noted that because of the later meeting date in June, NIA will likely request an expedited review of applications.
The minutes of the September 2012 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.
Dr. Eliseo Perez-Stable reported on the Task Force’s review of NIA programs on workforce diversity and health disparities research. The review group defined diversity as the inclusion of underrepresented racial and ethnic minority groups, individuals of disadvantaged socioeconomic status (SES), or individuals with disabilities. The review group also defined health disparities research as research in which SES or racial and ethnic differences were mentioned in at least one aim or an estimated 10 percent of the aims or abstract. The group reviewed all NIA grants awarded from 2002 through 2011.
Of a total of 1,670 potentially eligible grants, 985 were included in the sample following a review of abstracts and specific aims. For an estimated 40 percent of the sample, health disparities or diversity training was a major emphasis. Eighteen percent of the sample comprised R01s, and 32 percent were K01, K08, or K23 awards. Approximately 44 percent of the grants were funded under program announcements and 18 percent under RFAs, although only 16 percent of NIA program announcements and 10 percent of RFAs focused on health disparities or diversity. Thirty-eight percent of the grants were investigator initiated. The majority of health disparity- or diversity-focused grants were concentrated in the Division of Behavioral and Social Research (DBSR), while the fewest were supported by the Division of Aging Biology (DAB). Funded research on biological variables in health disparities focused on the neurobiology of Alzheimer’s Disease within the Division of Neuroscience. The Division of Geriatrics and Clinical Gerontology supported the bulk of intervention studies while all research that could inform policy directly was supported by DBSR. A bibliometric analysis found that 911 grants had yielded a total of more than 44,000 publications, many in high-impact journals with a high number of subsequent citations. Dr. Perez-Stable also mentioned the Resource Centers for Minority Aging Research (RCMAR) program, which currently supports seven centers across the United States and includes all racial and ethnic minority groups, and the AD Research Center (ADRC) program, which has supported 176 diversity projects, more than 11,000 events targeting diversity, and satellite clinics in minority communities.
The review group recommended that NIA:
Training and career development was another area of emphasis for the review group. The group particularly noted the importance of research supplements in promoting diversity and encouraging mentoring relationships. Supplement recipients seek as much funding from other ICs as from NIA, and the overall success rate among research project grant applications from these recipients is comparable to the average NIH success rate from 2002 through 2011. However, few supplement recipients have received R01s. NIA also has helped to train 394 participants from 2002 through 2011 through its Summer Institute on Aging Research (SI), and aided a total of 457 participants through its Technical Assistance Workshops. SI participants have published a total of 655 papers, and a third of them have gone on to become assistant professors. Approximately a quarter to a third of participants from both programs have successfully applied for NIH funding. However, the review group noted that race and ethnicity data were available for slightly more than half of SIA participants and even fewer Technical Assistance Workshop participants.
The review group recommended that:
The final report of the task force’s review will be completed by March 1.
Dr. Perez-Stable concluded his presentation with a brief reminder about the NIH Strategic Plan on Health Disparities. The Strategic Planning Committee has identified six priority areas, including one on the expansion of workforce diversity, and a parallel committee of NIH staff has been charged with implementing the Strategic Planning Committee’s recommendations.
Council members agreed that NIA, as the first IC to collect this type of information and conduct a review, has been a leader and could serve as a model for the rest of NIH. NIA can continue to serve a leading role and inspire efforts by distributing the final report to leadership at other ICs, continuing conversations with leadership within the National Institute on Minority Health and Health Disparities, and participating in subsequent trans-NIH working groups on health disparities. Dr. Hodes thanked the Task Force for its efforts.
Dr. Barr reminded the Council of the biennial legal requirement that NACA review and approve NIA’s inclusion report, which summarizes total enrollment across all NIA grants by race/ethnicity and gender. He pointed out, however, that the original legislation led to a report form that can be distorted by single large studies. For example, NIA’s report indicates that Asian participants made up 26 percent of all participants in 2011 and 28 percent of all participants in 2012. However, one of the leading grants is a study of 82,000 individuals in China. Thus, the report does not provide an accurate sense of the NIA’s success in including a diverse subject population. Dr. Lennart Mucke noted that efforts are under way to improve the structure of the report, and Dr. Barr added that the separation of international from national samples is under consideration.
With these reservations in mind, Council members made and seconded a motion to approve the NIA Inclusion Data Report. The motion passed unanimously.
Dr. Richard Morimoto reported that the Working Group had considered nine proposals, including two sets of recommendations from advisory meetings and concept clearance for seven RFAs or requests for proposals (RFPs). He noted the enthusiastic, thorough discussion within the Working Group, and he acknowledged the care and thoughtfulness of program staff in preparing their presentations.
With the exception of the vitamin D clinical trial, which was voted on separately (see below), the Council voted on the proposals “en bloc.”
Dr. Robert Califf reported on a meeting of the Clinical Trials Advisory Panel (CTAP), which comprises NIA staff, NACA members, and external experts. During this meeting, the panel agreed to move forward a proposal for a vitamin D supplementation trial. CTAP also discussed the difficulties in moving trials through panel review. At present, concepts are presented and discussed, then revised through a large amount of iterative activity. Few trials actually move forward. In addition, guidelines on clinical practice and medical decision-making offer little evidence to guide the design of clinical trials. NIA staff has developed a white paper calling for a new process, where CTAP approves concepts and a second phase focuses on the specifics of a particular protocol, to promote more orderly prioritization of concepts. Other suggestions include a more expeditious review of concepts, the identification of evidence gaps, enhanced communication between clinical and basic science researchers, and a planning and pilot-testing stage to ensure that feasible ideas move forward. CTAP also suggested improvements in training for junior researchers to create a stronger pool of investigators, as well as the establishment of a study section specifically to review clinical trials. Dr. Califf expressed concern that the cost of clinical research and funding restraints has meant that many trials are not designed to be definitive, or to end when investigators obtain the information they need to advance to a larger trial that could be definitive. He contended that a fundamentally different structure for clinical trials is needed to execute them within cost constraints.
Dr. Morimoto reported on the AD Genome Sequencing Project, which aims to generate or collect sequences of the entire genome for a subset of affected families. The project will include 5,000 age-matched controls and at-risk individuals. Dr. Morimoto emphasized the need to ensure that genomic information, once collected and validated, will be made available to the entire scientific community, as well as the need for infrastructure support to allow investigators to analyze these data.
Dr. Andrea LaCroix discussed a concept for Dose Response and Efficacy Studies on the Effects of Vitamin D Supplementation on Functional Outcomes in the Elderly. This RFA would support a clinical trial to determine which doses of vitamin D could improve gait speed and reduce the risk for falls among at-risk older individuals. Safeguards will be built in to ensure the early end of such a trial if recruitment is unsuccessful or if no doses are shown to be efficacious. Although CTAP rated the trial highly, the working group could not reach consensus on the concept. Some members questioned whether trials motivated by community practices based on relatively contentious data should be supported in a time of budget constraints and high pressures for prioritization. Other members questioned the importance of such a trial when many are already taking vitamin D, and others felt more basic research was needed to understand potential mechanisms. One member expressed concern that placing funds in this concept would prevent NIA from responding to emergent public health needs. However, other working group members argued that vitamin D might not be innocuous, as currently supposed. These members further noted that no currently ongoing trial will resolve questions about possible effects of vitamin D on gait speed and falls, and they argued that a trial such as this one is needed precisely because it will address practices already taking place in the community. A motion to approve this concept was forwarded and seconded. The motion passed with two Council members opposed.
Dr. Ana Maria Cuervo described a concept for the Optogenetic Tools for the Study of Neural Systems in Aging and AD, which would support research incorporating technologies from other fields to track neuronal connections, neuronal function in situ, and gene activation. Such research offers advantages for the study of functional alterations in the aging brain, as well as differences between normal aging and disease. The working group agreed that the concept offered clear potential for research and clinical applications.
Dr. Petersen discussed a concept for a Trans-NIH Person-Centered Outcomes Research Resource. This program would set aside funds for a 4-year project to transition three instruments (one for patient-reported outcomes, one for cognitive, sensory, motor, and emotional changes, and one for quality of life) developed by the NIH to a not-for-profit resource within the NIA. The resource would assume control of the instruments, develop newer versions, and maintain the existing platform, and it would be expected to be self-sustaining at the end of the 4-year period. The working group unanimously agreed to present this concept to Council for approval.
Dr. Stephanie Studenski reviewed a request for a small set-aside to support a cooperative agreement that would begin to create infrastructure to outline a pathway for translating knowledge about the genetics underlying resilience, healthy lifespan, and multiple morbidities into therapeutic targets. The 5-year cooperative agreement would aim to outline a pathway of key steps, knowledge, and work for this kind of development. The working group expressed no concerns and supported this request.
Dr. Fox Wetle described the Mechanisms of Cognitive Remediation in Older Adults, an initiative that would support one to two well-powered intervention trials to prevent or remediate cognitive decline. The initiative would emphasize an integrative model that includes the complex, multifaceted designs needed to determine the outcomes of multiple interventions, and it would include functional imaging and other measures of biological and behavioral markers. The working group agreed that this initiative addresses a major concern of many older Americans and has substantial implications for public health.
Dr. Jonathan Skinner described the concept for Research on Mid-Life Reversibility of Early-Established Biobehavioral Risk Factors, an initiative that would support the next generation of studies focused on the effects of early-life experiences on events in mid- and late life. It is well established that adverse environmental experiences early in life can have long-lasting effects. This initiative would focus on identifying both the factors underlying these effects and possible interventions. Dr. Skinner noted that the initiative also would incorporate person-centered metrics of outcomes, rather than focusing solely on over- or underexpression of genes. The working group expressed strong support for this concept.
Dr. Norman Anderson described a concept for High-Priority Behavior and Social Research Networks. This concept would provide infrastructure support to facilitate the formation of integrative, trans-disciplinary collaborations that will address complex questions in behavioral and social science research. Specifically, the initiative would support networks focused on reversibility; economic valuation of health research; development of more sophisticated, valid, and reliable measures of stress; replicability of research in the behavioral and social science of aging; and economics and psychology. The working group expressed strong support for this concept.
A motion was forwarded and seconded to approve these concepts “en bloc.” The motion passed unanimously.
Dr. Petersen reported that a review of DN is under way. The review committee has divided into subcommittees, which meet regularly via teleconference, and the subcommittee Chairs have met and presented preliminary reports to each other. On the basis of feedback and recommendations from that meeting, the subcommittees will finalize their recommendations. The report will be shared with DN and finalized by this spring, and it will be reported at the June Council meeting.
Dr. Sally Rockey, Deputy Director for Extramural Research, NIH, reported on a proposed implementation of the recommendations made by the ACD Working Group on the Biomedical Research Workforce. The working group was charged with developing a model and recommendations to build a sustainable and diverse workforce that will advance science and promote health. The working group began with the assumptions that training for a biomedical career takes too long and is getting longer, that too many individuals with Ph.D.s are produced for the number of available jobs, that the average age of investigators receiving their first regular research grant (R01) is too old, and that these conditions are turning away the best and the brightest new investigators. Despite these negative trends, however, the working group also assumed that the construct in place for the biomedical community is productive and should not be changed. After a preliminary look at the data in hand, the working group also decided to focus its efforts on Ph.D. scientists, because the data did not allow for an in-depth analysis of clinician scientists.
As illustrated by data collected through collaboration between NIH and the National Science Foundation (NSF), the number of trained Ph.D. and M.D. scientists has grown substantially, partly because of the doubling of the NIH budget between 1998 and 2003. Although the number of Ph.D. students supported on training grants has remained stable over time, the number of those trained on research grants has grown exponentially. On average, students graduate with Ph.D.s in 6.5 years, at an average age older than 30 years. The number of postdoctoral fellows also has grown; the number supported by NIH grants has grown significantly, but the number supported by industry also has grown. Overall growth has included an increase in the number of postdocs who are not U.S. citizens. At NIH, 65 percent of postdoctoral fellows supported by research grants are not U.S. citizens. At the same time, the data have shown that on average, Ph.D. scientists are 37 to 39 years old by the time they enter tenure-track positions, and they are 42 years old by the time they receive their first R01s. In addition, the average age of all principal investigators supported by R01s has increased from 36 or 37 years in 1980 to 54 years in 2010, partly because many senior investigators are not retiring.
Women constitute more than half of the biomedical trainee population. However, only 27 percent of NIH-supported principal investigators are women, and that proportion is rising only slowly. There are also differences at the point in the biomedical career when women drop out. For example, women are as successful as men in obtaining their first R01, but they return for renewals less often and are less successful when they do. The proportion of White principal investigators mirrors the proportion of Whites in the 2010 Census. However, only 1.1 percent of principal investigators are Black or African American, and only 3.5 percent are Hispanics of any race, whereas the 2010 Census shows that African Americans comprise 12.6 percent of the population and Hispanics comprise 16.3 percent.
There is also a proliferation of Ph.D.s in non-tenure-track positions, and the earning potential of biomedical research scientists lags far behind individuals with degrees in disciplines such as business, engineering, or computational science. Even within the Federal government, postdocs supported by NIH earn less than those supported by the NSF or the U.S. Department of Energy. A snapshot compiled by the working group also shows that the majority of trainees move on to science related careers, including non-research careers, government research, academic research or teaching, or industrial research. However, the current training programs do little to prepare biomedical trainees for anything besides an academic research career, even when only 43 percent of trainees go on to academic careers and only 23 percent are able to obtain tenure-track positions.
On the basis of its analysis, the ACD working group made several recommendations:
Through the establishment of a Pre-Implementation Team, vigorous discussion with IC Directors, and feedback obtained from the Leadership Forum, an implementation plan has been developed. The centerpiece of this plan is the Broadening Experiences in Science Training (BEST) program, a Common Fund program that seeks to encourage institutions to complement traditional training of biomedical scientists with innovative approaches to expose students to other career fields. Institutions will be encouraged to work together and with outside entities, including industry, to develop BEST practices in diversifying biomedical training. Dr. Rockey emphasized that the BEST grants are not intended to provide for positions or slots; instead, they are designed to encourage pilot projects in developing practices and must include rigorous analyses and demonstrate impact.
The implementation plan also includes several approaches to improve graduate and postdoctoral training, including individual development plans for postdocs, an expectation that institutions establish anticipated durations of doctoral programs, an expectation that NIH support for doctoral study be limited to 5 years, and that all ICs support F30 and F31 fellowship awards. In addition, the plan calls for increasing initial postdoctoral stipends; NIH is soliciting feedback from the community about developing a minimum standard of benefits for postdocs. The implementation plan aims to expand the K99/R00 and Early Independence Awards, that help scientists launch independent academic careers. It also includes steps to encourage review committees to accommodate a range of career outcomes, support staff scientist positions on grant applications, and consider all graduate students in relevant programs. Other components of the implementation plan include a long-term approach to assess NIH support of faculty salaries and the creation of a functional unit at NIH to continually assess the biomedical research workforce and provide a unified source of information on workforce issues.
However, a large piece of the implementation plan focuses on tracking race, ethnicity, and SES as meticulously as possible. Institutions will be expected to identify all students and postdocs supported by NIH and to use that information to pre-populate forms. They also will be encouraged to report the aggregate career outcomes of their graduate students and postdoctoral fellows so that they can provide that information to prospective trainees. A Federal-wide biosketch system, unique and persistent research identification codes, and automated National Research Service Award training tables also will be developed and implemented to facilitate tracking of NIH-supported trainees.
Dr. Rockey noted that the working group did not make any recommendations about the number of scientists that should be trained. Instead, the group recommended a classical economic/labor force analysis to generate a dynamic model of inputs and outputs. She also reported that another ACD working group has been assessing diversity in the workforce and that Dr. Lawrence Tabak, Principal Deputy Director, NIH, will discuss that working group’s recommendations at a later date. A follow-on analysis of clinician/physician scientists is also planned. Council members were encouraged to visit the ACD website (acd.od.nih.gov) and the subsection on the Biomedical Workforce to access the full report and the data reviewed by the working group.
Dr. Morimoto and Dr. Cuervo acknowledged issues with the time to complete the Ph.D., but they cautioned that NIH should consider several factors when establishing a policy for support of doctoral study. For example, students from other countries might be pressured to finish their degrees within a certain amount of time, and students might differ in the amount of training they have already had. Dr. Rockey clarified that the aim of this suggestion is to prevent unnecessarily prolonged doctoral training, but she acknowledged that limiting NIH support to 5 years could have unintended consequences, such as a lower number of publications by trainees.
Council members also expressed concern about the impact of the increase in postdoctoral stipends and the working group’s recommendation to reduce NIH support for faculty salaries. They expressed concern that in the light of other budgetary constraints, institutions might cut positions, and faculty members might adjust their hiring practices. Dr. Rockey acknowledged these points and added that NIH also would have to accommodate differences in local cost-of-living and other factors. She emphasized, however, that postdoctoral fellows should make a living wage. In response to questions from Dr. Richardson, she noted that NIH has looked at the proportion of research funding spent on graduate students and postdocs, but that proportion has not been translated yet to dollar amounts.
Dr. Mucke commended the working group for assessing this issue in a logical and quantitative manner, and he supported the proactive encouragement of institutions to help with career development and monitoring. He highlighted programs at the University of California, San Francisco, which emphasize early career development for postdocs and include discussions in which fourth- or fifth-year graduate students can assess progress and develop exit plans.
Dr. Perez-Stable pointed out that Ph.D. scientists who are not at the bench (for example, behavioral and social scientists) might have different postdoctoral experiences from those who are in the laboratory. Dr. Rockey noted that behavioral and social sciences related to biomedicine were represented in the working group’s data and that the working group saw differences in the postdoctoral experience between industry and academia. In response to questions from Dr. Califf, Dr. Rockey noted that BEST could accommodate, for example, individuals who train in the laboratory, leave the lab, then come back to manage clinical research in industry.
Age is a prime risk factor for a wide range of diseases. Even in the absence of disease, however, aging is accompanied by a decline of function in many tissues. It is not clear whether these declines and the marked increase in disease with age represent inexorable processes or reversible ones. Over the past two decades, evidence has accumulated to suggest that aging and longevity are plastic processes regulated by a combination of genetic and environmental factors. For example, the environmental component of aging can comprise about 70 percent of the regulation of human longevity. However, the molecular mechanisms that mediate environmental influences on aging and longevity are not known. Efforts to identify and understand these mechanisms have focused so far on factors, such as transcriptional responses, that are fairly transient. There may exist molecular mediators that operate on a longer time scale but are still plastic; however, they have not been identified.
Dr. Anne Brunet, of Stanford University, described a line of research that aims to identify such mechanisms. Her laboratory has focused on chromatin, the protein-DNA structure that packs DNA into the cell nucleus. Chromatin is a dynamic structure, existing in active or repressed states governed by post-translational modifications to histones, or the proteins around which DNA is wrapped. For example, trimethylation of lysine 4 in histone 3 is associated with active chromatin, whereas trimethylation of lysine 27 or lysine 9 is associated with the repressed state. These different states are long-lasting and can be changed by environmental stimuli.
In the model nematode Caenorhabditis elegans, Dr. Brunet and her colleagues have conducted a RNA interference (RNAi) screen for methyltransferases and demethylases that regulate aging. They have identified one methyltransferase complex, COMPASS, that regulates longevity through trimethylation of histone 3 at lysine 4. Indeed, knockdown of the COMPASS complex or expression of the corresponding demethylase increases the worms’ lifespan. Dr. Brunet and colleagues also found that the role of the COMPASS complex in longevity depends on an intact germline, suggesting epigenetic regulation of the lifespan. Through a series of genetic crosses, Dr. Brunet’s group has found that descendants of worms deficient in trimethylation of histone 3 at lysine 4 live longer than descendants of wild-type worms. This extended lifespan is seen in several generations of descendants before it reverts to normal. Work is under way to identify additional molecular and environmental mediators of the COMPASS complex’s effects on lifespan. Because the COMPASS complex is conserved across species, including humans, Dr. Brunet and her colleagues are expanding their inquiry to other model systems to examine the conservation of epigenetic inheritance of longevity.
Discussion focused primarily on technical aspects of Dr. Brunet’s work and possible interpretations of her results.
Investigators who study aging and lifespan in invertebrate models often do so at the level of the organism. Yet too often the measure of aging is simply whether the animal is alive or dead. Dr. David Walker, of the University of California, Los Angeles, looks at changes at several levels, including cellular and molecular changes and changes in organ or tissue homeostasis, that increase risks for disease and death.
Mitochondrial dysfunction has been implicated in several age-onset diseases, cancer, and neurological disorders. In addition, several published studies that have used microarrays to examine altered gene expression indicate that genes involved in electron transport are switched off with increasing age. These include members of the PGC1 family of transcription coactivators, which are major regulators of mitochondrial energy metabolism whose increased activity leads to the upregulation of other mitochondrial genes. Dr. Walker and his colleagues have used Drosophila genetics to explore the effects of increased expression of the Drosophila PGC1 homolog (DPGC1). As expected, they have found that overexpression of DPGC1 increases the abundance of respiratory enzyme complex, which in turn leads to increased respiratory chain activity.
They also have been surprised to find that increased DPGC1 activity, particularly in the gut, extends the lifespan. This was especially true when Dr. Walker and his colleagues targeted DPGC1 expression to stem and progenitor cells in the gut. Further work has shown that DPGC1 activity in the gut declines with age and that this decline can be reversed by transgenic DPGC1. In collaboration with Dr. Leanne Jones’ group at the Salk Institute, Dr. Walker and his colleagues have looked further at the behavior of stem and progenitor cells in the gut and found that with age, the numbers of these cells increase in the intestinal epithelium and several cellular markers are expressed inaccurately. These changes can be suppressed with DPGC1 overexpression. Thus targeted expression of DPGC1 in a cell population within the intestine has effects on mitochondrial metabolism, with increased mitochondrial activity and decreased production of reactive oxygen species. Using a noninvasive assay, Dr. Walker and his colleagues also have shown that DPGC1 overexpression suppresses the increased intestinal barrier dysfunction normally seen with age.
Discussion focused on technical aspects and possible implications of Dr. Walker’s work. Although there is broad consensus that innovation drives economic growth, it is not clear what level of innovation is optimal from a social perspective. Despite longstanding economic and policy interest in how public policies, such as intellectual property rights, affect incentives for innovation, it is difficult to capture the full social value of individual innovators’ inventions. In addition, generating empirical evidence is difficult, as there are no equivalents to randomized trials of patents across inventions. Economists therefore must rely on natural experiments that approximate what they could learn in randomized trials.
Dr. Heidi Williams, of the Massachusetts Institute of Technology, described two projects exploring the effects of policy on innovation. The first looked at sequencing of the human genome to determine the effects of rules governing access to scientific materials on subsequent innovation. The sequencing of the human genome involved two major efforts: the public Human Genome Project (HGP), which started in 1990, and the private efforts of Celera, which started later. Genes sequenced by HGP were subject to the “Bermuda Rules” and therefore openly accessible, whereas the genes sequenced by Celera were restricted by the company’s intellectual property protections. However, Celera published its results in 2001 and ended its sequencing efforts, while HGP continued to sequence and resequence genes. Thus, all of Celera’s genes were in the public domain by 2003. Dr. Williams and her colleagues compared innovation outcomes, such as subsequent publications or the use of genes in commercially available tests, between the HGP genes and Celera genes sequenced by 2001. The group found that the more open Bermuda rules spurred more innovation outcomes than Celera’s intellectual property rights did. This difference persisted over time, despite the amount of subsequent scientific research conducted on those genes.
The second project explored whether patents fail to provide incentives for research and development. Current patent rules aim to encourage investment by promising that firms can have a monopoly on technologies they develop for 20 years from the date they file a patent application. However, Dr. Williams and her colleagues found that the actual commercial time for such monopolies depends on the time needed for clinical trials to show outcomes. For example, trials testing therapies in patients with metastatic prostate cancer take a shorter time to show impact than those testing therapies in patients with localized prostate cancer. This difference affected private support of clinical development and ultimately, the amount of research and development done. Dr. Williams and her colleagues thus concluded that the existing patent system does little to incentivize research and development on certain diseases, specifically those for which long clinical trials are required, cutting into the time remaining on a patent.
Dr. Williams closed her presentation by noting challenges in following discoveries from the laboratory to the market as a key constraint in this kind of research.
Dr. Califf expressed concern about the use of economic or intellectual returns as study endpoints, because of the many examples where inappropriate endpoints have led to massive investments in therapies that turned out to be harmful. He suggested the need for a balance between health and economic outcomes and cautioned that increased investment does not necessarily mean improvement. Dr. Williams agreed and clarified that the ultimate goal of her research is to determine the value of innovation based on valid endpoints. She and her colleagues do not aim to endorse further use of the existing, flawed endpoints.
Other discussion points included the limitations of natural experiments, the ability to determine the type of research that is restricted by intellectual property rights versus research that benefits from them, and the possible implications of Dr. Williams’ work at a time when universities are strongly encouraging their investigators to obtain patents and disclosures on all discoveries.
The genetic map of AD began with the identification of the APOE4, PSEN1, PSEN2, and APP genes and has expanded through the use of genome-wide association studies (GWAS) that have increased scientists’ understanding of risk alleles. Further progress has come with recent work showing not only that some APP variants can cause disease, but that other APP variants actually can protect against that same disease. While work continues on these types of studies, however, a new area of interest involves the rare gene variants that confer a medium level of impact.
The NIA Laboratory of Neurogenetics (LNG) has undertaken exome and genome sequencing for a variety of neurodegenerative diseases, either among families that exhibit rare heredity or among cohorts of patients with the diseases. Exome sequencing approaches have been particularly successful, leading to the identification of new genes and mutations related to ataxia, frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and childhood-onset motor neuron diseases, among others. This work has both revealed novel genes and demonstrated that genetic defects can manifest in clinical symptoms of highly variable severity.
Dr. Andrew Singleton, Senior Investigator in LNG, described three projects. The first, led by Dr. Bryan Traynor, started with a GWAS in a cohort of Finnish patients with ALS. His group found a strong novel signal on chromosome 9 , which overlapped candidate regions for both ALS and FTD. Through next-generation sequencing, LNG and collaborators found an association between ALS and an expanded hexanucleotide repeat in C9ORF72, an open reading frame of unknown function. Another collaborative group led by Dr. Rosa Rademakers at the Mayo Clinic in Jacksonville discovered the same expansion independently. This mutation accounts for a remarkably high number of cases: it causes disease in about half of familial cases and 20 percent of sporadic cases of ALS in Finland; and 40 percent of European familial ALS and about 7 or 8 percent of European sporadic cases. It further causes about 30 percent of familial FTD in Finland and about 6 percent of sporadic FTD in Europe. Expanded hexanucleotide repeats in C9ORF72 also underlie approximately 1 percent of clinically diagnosed AD cases.
The second project is a collaboration with a Turkish laboratory to perform exome sequencing in a cohort from consanguineous families with a form of FTD. These efforts have led to the discovery of a previously identified TREM2 mutation, which has been identified as the cause of Nasu-Hakola syndrome, a young-onset disease characterized by bone cysts and presenile dementia.
This led to the third project, in which LNG conducted exome sequencing studies in 200 patients with AD. They found an excess of TREM2 variants in AD patients, and whole genome and Sanger sequencing identified an overrepresentation of a variant in which arginine 47 has been replaced by histidine. After replicating its findings with genotyping and examination of publicly available GWAS data, LNG published these findings along with DECODE, who had found these results independently.
Dr. Singleton concluded his presentation by emphasizing the value of working with families and looking across diseases. Collaboration, risk-taking, and data sharing are also critical to success. Although exome sequencing can be challenging in cohorts, existing family data can be used to focus the search. Dr. Singleton particularly noted that a lot of this work has involved collaborations with previous competitors.
Discussion focused on technical aspects of the work, next steps, and possible implications. In response to questions about working with previous competitors, Dr. Singleton noted that investigators have realized that they cannot advance this work alone. He added that the collaborations have been successful.
The prevalence of obesity is increasing across all age groups, including those individuals older than 65 years. A quarter of older adults are obese. Although the association between body mass index (BMI) and mortality appears to decrease with age, obesity often exacerbates age-related physical dysfunction. Obese older persons often experience weakness not only because of age-related sarcopenia, but also because of infiltration of the muscle mass by adipose tissue. In addition, contrary to the dogma that older obese persons are not frail because they are not wasted, studies by Dr. Dennis Villareal, of the University of New Mexico School of Medicine, and his colleagues have revealed an association of obesity with frailty. Although obese older adults in this study had the highest amount of muscle mass, they also had the lowest muscle quality, indicating that they are not getting the appropriate muscle strength. However, because of concerns about the potential harmful effects of weight loss in older adults, the appropriate clinical approach to obesity in that population is not clear.
Dr. Villareal and his colleagues have conducted a pilot study to assess the effects of weight loss and exercise on physical function and fat-free mass. Older adults were randomized into a control group or a group that received an intervention comprising a daily energy deficit of 750 calories, weekly group meetings, and group exercise training emphasizing flexibility, endurance, resistance, and balance. Dr. Villareal and his colleagues found that obese older adults could change their habits and looked forward to their weekly visits. They lost 10 percent of their body weight, and their weight loss was predominantly a loss of fat. The intervention ameliorated objective parameters of frailty and the metabolic syndrome, and it improved both upper- and lower-extremity measures of muscle strength. Individuals in the intervention group also showed lower levels of circulating inflammatory markers such as C-reactive protein (CRP) and interleukin (IL) 6, as well as improved beta-cell function in the pancreas. However, exercise training was unable to prevent weight-loss-associated reduction of bone mineral density or increased bone turnover.
The study team then conducted a randomized controlled clinical trial to assess further the additive effects of weight loss and exercise on clinical outcomes among adults aged 65 years or older with a BMI of 30 or more. Individuals were randomized to one of four conditions: control, diet only, exercise only, or diet combined with exercise. Only the diet and diet/exercise groups showed a 10 percent weight loss by 6 months. Although diet or exercise improved physical function, the combination provided greater improvement than either intervention alone. The most significant differences in body composition across the groups were in fat-free mass, and Dr. Villareal and his colleagues saw evidence of improved muscle quality and increased muscle strength with the intervention groups. They also saw positive effects of the combined diet and exercise intervention on insulin sensitivity and the metabolic syndrome, but the additive effect of exercise training depended on preceding weight loss. In addition, exercise attenuated the adverse bone outcomes associated with weight loss, as illustrated by increased bone mineral density, decreased rate of bone turnover, and measurements of hip geometry.
Dr. Villareal concluded his presentation by discussing possible molecular mechanisms underlying the effects of exercise on weight loss-associated bone outcomes, as well as effects of diet and exercise interventions on cognitive function and quality of life.
Discussion focused primarily on technical aspects of Dr. Villareal’s work. However, Dr. Villareal also highlighted that individuals in the diet group and diet/exercise group were able to maintain their weight loss even at 13 months following the intervention.
Glucose homeostasis is a balance between insulin secretion and insulin sensitivity. Carbohydrates from food are converted into glucose, causing a rise in blood sugar levels, which in turn stimulates the activity of the enzymes GLP-1 and GIP and the secretion of insulin. Insulin secretion stimulates DPP4, which inhibits GLP-1 and GIP. Diabetes disturbs insulin signaling by impairing insulin secretion (type 1) or by reducing peripheral sensitivity to insulin (type 2). Novel treatment approaches with DPP4 inhibitors focus on lowering blood sugar in individuals diagnosed with diabetes, but are complicated by the fact that pre-diabetic, elevated blood sugar levels higher than 110 mg/dL already render GIP ineffective.
Dr. Josephine Egan, of the Laboratory of Clinical Investigation, described the laboratory’s interest in diabetes and the optimal time at which to intervene among those at risk. Diabetes affects 26 million individuals in the United States, and 27 percent of them are older than 65 years. However, 79 million individuals in the United States have pre-diabetes, defined as blood sugar levels between 100 and 125 mg/dL. In addition, both fasting and 2-hour postprandial blood sugar levels increase with age, although average blood sugar levels are lower among women aged 75 years and older. Whitehall II, a study of London civil servants, indicated that diabetes diagnosis can be predicted by average blood sugar levels measured 20 years earlier. In addition, among individuals who eventually develop diabetes, blood sugar levels increase exponentially during the two years immediately preceding diagnosis.
These data suggest the need for interventions at the pre-diabetic stage, particularly to prevent that final exponential rise in blood sugar levels. Dr. Egan emphasized that individuals with pre-diabetes should exercise and aim toward a normal body weight. However, she also suggested that individuals should monitor their fasting sugar, similarly to the way blood pressure or cholesterol is monitored, and that health care professionals should counsel their patients if their blood sugar starts to rise by 1 or 2 mg/dL. Dr. Egan also noted work on cannabinoid receptor inhibitors as potential treatments for individuals with pre-diabetes.
Discussion focused on speculation about the implications of gastric bypass surgery on diabetes.
Dr. Edward Lakatta, of the Laboratory of Clinical Science (LCS), described a system of continuous signaling across the levels of DNA, cell, tissue, organ, body, and various types of environments (for example, sociocultural, built, and global environments) and defined aging as a constellation of failures in that system. A systems biology approach is needed to examine the systemic failures associated with aging. LCS therefore aims to bring together different disciplines to define failures and mechanisms, integrate information, and translate that information into proof-of-concept intervention studies.
Dr. Lakatta focused his presentation on LCS’ work on the arterial wall. Aging hearts and arteries operate on the edge of cardiovascular disease. Even without a clinical diagnosis or the presence of risk factors, the remaining lifetime risk for cardiovascular disease (CVD) among individuals 40 years of age is as high or higher than individuals 70 years of age. Although central arterial stiffness is a risk factor, it is closely correlated with systolic blood pressure and therefore difficult to dissociate or to track over the age range. However, according to SardiNIA (http://sardinia.nia.nih.gov ) and Baltimore Longitudinal Study on Aging (BLSA) data, both central arterial stiffness and systolic blood pressure increase with age, and the rate of arterial stiffening accelerates among men. However, blood pressure also starts to fall among men at much older ages. Thus, suggestions that arterial stiffness can be addressed by blood pressure therapies might not hold.
LCS studies arterial aging in several models and has defined an age-associated arterial secretory phenotype (AAASP), where endothelial and vascular smooth muscle cells start to secrete “junk” with increasing age. LCS has found that the cellular and molecular pathophysiology underlying AAASP is the same as that underlying atherosclerosis and hypertension. The laboratory also has found that age-related changes in milk fat globule E8 (MFG E8), which is related to clotting factor VIII, increase the invasiveness and proliferation of vascular smooth muscle cells. Further study of epigenetic regulation of arterial genes in non-human primates has shown that overexpression of a microRNA, miR34A, in the vascular smooth muscle cells increases expression of MFG E8 and SIRT1. Although miR34A is involved in cell cycle regulation and cellular senescence, cells overexpressing miR34A are not blocked because of the increased expression of MFG E8.
Dr. Lakatta also reviewed several translational research projects related to inflammation and the arterial wall. For example, LCS discovered that paclitaxel-coated stents block inflammation in injured arteries. This discovery has been licensed and generated millions of dollars in royalties for the NIA IRP. LCS also has discovered that a soluble receptor for advanced glycation end products (sRAGE) can reduce arterial inflammation, and the laboratory has patented an anti-fibrotic antibody to the sodium-potassium pump. With each discovery, LCS expands its model of a pro-inflammatory mechanism underlying arterial remodeling.
Dr. Lakatta concluded his presentation by noting that arterial inflammation and stiffening, often seen as “normal aging,” represent a target for preventing the age-associated CVD epidemic. He emphasized that basic research discoveries about aging are not good enough unless they are translated into novel therapies.
In response to questions from Dr. Mucke about assessing the impact of therapies, Dr. Lakatta highlighted the need to understand as much as possible about the various factors underlying the differences associated with older age. He added that the signaling diagram he presented is only one of a network of processes, and that multiple approaches will be needed to treat the bigger picture of disease. Dr. Lakatta further noted that the biomedical approach to aging has failed so far because of difficulties in finding the network nodes underlying the aging process. For example, treatment at the node could have a higher impact on disease, but it also could increase the risk for side effects.
This portion of the meeting was closed to the public in accordance with the provisions set forth in Section 552b(c)(6), Title 5 U.S. Code and Section 10(d) of the Federal Advisory Committee Act as amended (5 U.S.C. Appendix 2).
The open session of the 118th meeting of the National Advisory Council on Aging adjourned at 2:00 p.m. on January 30, 2013. The next meeting is scheduled for June 4–5, 2013.
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.
(* Terms end December 31)
(** WGoP Member)
(*** TFMAR Member)
Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
9000 Rockville Pike
Building 31, RM 5C35
Bethesda, MD 20892
Norman B. Anderson, Ph.D. (2014)
Chief Executive Officer and Executive Vice Chair
American Psychological Association
Washington, DC 20002
*Robert M. Califf, M.D. (2013)
Vice Chancellor and Professor
Department of Medicine
Duke University Medical Center
Durham, NC 27710
Laura L. Carstensen, Ph.D. (2015)
Department of Psychology
Stanford, CA 94305
Dennis W. Choi, Ph.D., M.D. (2015)
Professor and Chair,
Department of Neurology
Director, of Neurosciences Institute
Stony Brook Medicine
Stony Brook, NY 11794
Ana M. Cuervo, Ph.D., M.D. (2015)
Albert Einstein College of Medicine
Department of Development and Molecular Biology
Bronx, NY 10461
*Hugh C. Hendrie, DSC, Ph.D. (2013)**
Professor of Psychiatry
Indiana University School of Medicine and Regenstrief Institute, Inc.
Indiana University Center on Aging Research
Indianapolis, IN 46202
**Richard I. Morimoto, Ph.D. (2014)
Bill and Gayle Cook Professor of Biology
Departments of Biochemistry, Molecular and Cell Biology
College of Arts and Sciences
Evanston, IL 60208
**Eliseo J. Perez-Stable, M.D. (2014)
Department of Medicine
University of California, San Francisco
School of Medicine
San Francisco, CA 94143
*Daniel P. Perry (2013)
President and CEO
Alliance for Aging Research
Washington, DC 20006
*Ronald C. Petersen, Ph.D., M.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
Rochester, MN 55905
*Arlan G. Richardson, Ph.D. (2013)
Barshop Institute on Longevity and Aging Studies
University of Texas Health Science Center
San Antonio, TX 78245
Jonathan S. Skinner, Ph.D. (2015)
Professor of Community and Family Medicine
Department of Economics
Institute for Health Policy and Clinical Practice
Lebanon, NH 03755
Stephanie A. Studenski, MPH, M.D. (2014)
Department of Medicine
University of Pittsburgh
Pittsburgh, PA 15213
*Terrie F. Wetle, Ph.D. (2013)**
Associate Dean and Professor
Brown University Medical School
Providence, RI 02912
Department of Health and Human Services
Hubert H. Humphrey Building
Washington, DC 20202
Francis S. Collins, Ph.D., M.D.
National Institutes of Health
Public Health Service
Building 1, Room 126
Bethesda, MD 20892
Edwin L. Walker
Deputy Assistant Secretary
U.S. Department of Health and Human Services
Administration on Aging
Administration for Community Living
Washington, DC 20001
Kenneth G. Pugh, LCDR, MC
Department of Medicine
National Naval Medical Center
Bethesda, MD 20889
Robin A. Barr, D.Phil
Director, Office of Extramural Activities
National Institute on Aging
Bethesda, MD 20892