The 120th Meeting
September 17–18, 2013
- REVIEW OF APPLICATIONS
- CALL TO ORDER
- REPORT: Task Force on Minority Aging Research
- REPORT: Working Group on Program
- COMMENTS FROM RETIRING COUNCIL MEMBERS
- PRESENTATION: Preliminary Report on Review of Division of Behavioral and Social Research (BSR)
- PRESENTATION: Enhancing Reproducibility and Transparency of Research Findings
- PROGRAM HIGHLIGHTS
The 120th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, September 17, 2013, at 3 p.m. in Building 31, Conference Room 10, National Institutes of Health (NIH), Bethesda, MD. Richard J. Hodes, M.D., 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, September 17, from 3 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, September 18, from 8 a.m. to 1 p.m.
Dr. Kimberly Acquaviva
Dr. Norman Anderson
Dr. Robert Califf
Dr. Laura Carstensen
Dr. Ana Maria Cuervo
Dr. Kevin P. High
Dr. Bradley T. Hyman
Dr. Richard Morimoto
Dr. Eliseo Perez-Stable
Dr. Ronald C. Petersen
Dr. Arlan G. Richardson
Dr. Jonathan Skinner
Dr. Terrie F. Wetle
Dr. Hugh C. Hendrie
Mr. Daniel P. Perry
Ex Officio Participants:
Mr. Robert Hornyak, Administration on Aging
Absent Ex Officio Participants:
Dr. James F. Burris, Department of Veterans Affairs
Dr. Kenneth G. Pugh, National Naval Medical Center
Mr. Edwin Walker, Administration on Aging
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:
Ms. Judy Dulovich, Office of Human Resources (OHR), Office of the Director (OD), NIH
Dr. Samuel C. Edwards, Center for Scientific Review (CSR), NIH
Dr. Martha Hare, CSR, NIH
Dr. Yuan Luo, CSR, NIH
Dr. John H. Newman, CSR, NIH
Dr. Karyl Swartz, CSR, NIH
Dr. Laurent Taupenot, CSR, NIH
Dr. Jane Tilly, Administration for Community Living
Dr. Ping Wu, CSR, NIH
Dr. Wei-Qin Zhao, CSR, NIH
Members of the Public Present:
Mr. James Appleby, Gerontological Society of America
Dr. Shalender Bhasin, Harvard Medical School/Brigham and Women’s Hospital
Dr. Sarah Cavanaugh, Physicians Committee for Responsible Medicine
Dr. Andrew Dillin, University of California at Berkeley
Ms. Erica Froyd, Lewis-Burke Associates
Ms. Linda Harootyan, Gerontological Society of America
Dr. C Kate Von Hull, University of Chicago
Dr. Rose Maria Li, Rose Li and Associates, Inc.
Ms. Michelle Rodrigues, SRI International
Dr. Eric E. Schadt, Icahn School of Medicine at Mt. Sinai
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 1530 applications requesting $899,642,211 for all years underwent initial review. The Council recommended 796 awards for a total of $539,978,625 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 120th NACA meeting and called the meeting to order at 8:00 a.m. on Wednesday, September 18, 2013.
Director’s Status Report
Dr. Hodes began his report by reminding the Council that since its peak in Fiscal Year (FY) 2003, the purchasing power of NIH has declined by 20% because of flat budgets and the sequester. He also pointed out that U.S. investment in biomedical research is declining at a time when countries such as China, Germany, Japan, and South Korea have increased their investments. Since 2010, appropriations for NIA have hovered around $1.1 billion, with a slight infusion of funds for Alzheimer’s disease (AD) research in 2012. In FY2013, sequestration brought the NIA appropriation down to $1.04 billion, even with the transfer of $40 million to NIA for AD research by the NIH director. Although the President has requested approximately $1.2 billion for NIA in FY2014, actual funding remains uncertain. NIA has reduced funding for non-competing awards to ensure a tenable success rate for competing applications; every 1% reduction in non-competing awards saves $5 million, and the average cost per percentile added to the pay line requires $8 million. The 1% decrease in 2011, the removal of inflationary increases, and the 5.5% cut from sequestration have affected competing awards and interfered with investigators’ ability to carry out their proposed research.
Dr. Hodes next reviewed the National Alzheimer’s Project Act (NAPA), which calls for a national plan for AD research, care, and support. At the AD Summit held in 2012, experts made a series of recommendations that were subsequently translated into milestones toward a goal of curing or preventing AD by 2025. A total of $45 million, of which $40 million was contributed by the NIH Office of the Director, allowed NIA to fund three new requests for applications (RFAs) to support phase I phase II and III prevention trials, and interdisciplinary approaches to identify and validate novel therapeutic targets. All awards were funded as cooperative agreements to maximize their coordination and to ensure that resulting data will be made public.
NIA also has entered into a partnership with the Patient-Centered Outcomes Research Institute (PCORI), a non-governmental entity supported in part by a Congressional appropriation and in part by a tax on health insurance under the Affordable Care Act. Within this partnership, PCORI has committed up to $30 million toward a 5-year study for prevention of fall injuries in older adults. NIA has developed a Funding Opportunity Announcement and will oversee the project, including the application process and peer review, and PCORI will commit funds toward the cost of the study, should NIA receive at least one meritorious application in response to the Funding Opportunity Announcement.
Dr. Hodes also reminded the Council about the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative, a multi-year project involving NIA, Defense Advanced Research Projects Agency, National Science Foundation, and private organizations such as the Allen Institute for Brain Science, Howard Hughes Medical Institute, the Salk Institute for Biological Studies, and The Kavli Foundation. The BRAIN initiative will build on progress in neuroscience, optics, genetics, nanotechnology, informatics, and other disciplines to further understanding of the interactions between and among neurons and systems.
Dr. Hodes closed his report by welcoming Stephanie Studenski, M.D., who will join NIA as the director of the Baltimore Longitudinal Study of Aging and chief of the Longitudinal Studies Section, and Carl Hill, Ph.D., who has joined NIA as extramural director in the Office of Special Populations. He also highlighted NIA position openings and noted the following events:
- Launch of a searchable database of instruments to detect cognitive impairment in older adults (See http://www.nia.nih.gov/research/cognitive-instrument).
- The 2015 AD Research Summit scheduled for February 9–10 at the NIH.
- Advances in Geroscience: Impact on Healthspan and Chronic Disease, a conference scheduled for October 30–31 at the NIH Natcher Conference Center to discuss the extent to which the physiological effects of aging represent a common risk factor for chronic diseases affecting the aging population (See http://www.geron.org/gerosciencesummit).
- Submission of recommendations regarding AD-related dementias and approval of these recommendations by the National Advisory Neurological Disorders and Stroke Council. These recommendations were developed as part of NAPA and will be integrated into overall NAPA planning.
Discussion focused on ways to lower costs for large projects such as clinical trials. NIA encourages but does not require applicants to leverage funds. However, Dr. Hodes acknowledged that the availability of cofunding might influence NIA funding decisions in some cases. NIA places caps on each Division in terms of how much can be spent on large applications, incentivizing Divisions to encourage applicants to leverage funds. However, Divisions have flexibility in how to manage that cap. Robert Califf, M.D., indicated that the National Heart, Lung, and Blood Institute is not funding any randomized controlled trials (RCTs) without cofunding, which has forced applicants to think creatively about alternative strategies for large projects. Although Dr. Hodes noted this could prove challenging for some NIA studies, for example those exploring surrogate markers that have not yet been validated, he acknowledged that NIA may have to encourage applicants to explore alternative and innovative strategies to lower costs. He invited Dr. Califf to share, at a later date, more detail on some of the innovative approaches seen by PCORI-sponsored networks, such as relying more on electronic health records.
How to maximize the number of funded applications was also a focus of discussion. For junior faculty, in response to questions from Arlan Richardson, Ph.D., Dr. Hodes noted that NIA was able to maintain a payline similar to that for FY2012. However, he underscored that NIA had to take great pains to work around the sequester to maintain its payline. It is not yet clear how the NIA payline will compare with that from other Institutes and Centers (ICs). In response to questions from Richard Morimoto, Ph.D., about using a sliding scale, Dr. Hodes pointed out that NIA might decide, on an individual basis, to reduce funding for an application. However, this tends to occur for applications just beyond the payline; it is not an institutional policy. He and Robin Barr, D.Phil., also noted that decisions to reduce funding for an application have implications in terms of accomplishing research aims and for review and renewal. Kimberly Acquaviva, Ph.D., cautioned against notifying applicants that their applications have been approved for funding but that no funds are available, as has been her experience with other funding agencies. She noted that such a notification could be just as harmful as rejecting a grant application outright.
Future Meeting Dates
Feb. 25–26, 2014 (Tuesday and Wednesday)
May 20–21, 2014 (Tuesday and Wednesday)
Sept. 16–17, 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.
Consideration of Minutes of the Last Meeting
The minutes of the June 2013 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.
Eliseo Perez-Stable, M.D., reported that the Task Force had heard a presentation from Ernest Moy, M.D., of the Agency for Healthcare Research and Quality (AHRQ), on health disparities. Health services researchers at AHRQ have created several measures and used a standardized definition of disparity to make standardized comparisons by race, poverty level, presence of insurance, and education level. On all health care measures, African Americans and Latinos fared worse than whites. Although Asians fared slightly better, they still experienced worse health on average compared with whites. Poorer, less-insured, and less-educated individuals also fared poorly on these measures. Dr. Perez-Stable pointed out that, although the gaps are not narrowing, overall quality is improving.
The AHRQ study did not include data from the Indian Health Service, which accounts for approximately half of all the health care provided to American Indians. In addition, the study did not emphasize or focus on older Americans; there were no data, for example, on cognitive impairment or AD. Although there were some measures of safety comparing older adults with younger ones, Dr. Perez-Stable assumed that most, if not all, of the older individuals included were hospitalized patients. He suggested that NIA could collaborate with AHRQ to ensure that the AHRQ measures can be applied to older Americans. He also pointed out that the study noted a recent increase in mortality among younger white women and he suggested that this might be driven by behavioral issues that have been explored in NIA-funded projects. Dr. Perez-Stable suggested that this and other gender-specific issues could be another point of NIA-AHRQ collaboration. Yet another area of collaboration could involve measures of poor care quality or excess care, which have been addressed by the NIA health economics portfolio.
Dr. Perez-Stable reported that the Task Force also heard a presentation from Nina Silverberg, Ph.D., on the trans-NIH Native American Research Interest Group, to which Resource Centers for Minority Aging Research at the University of Colorado and the University of Washington have contributed. The Task Force also heard an update from Cerise Elliott, Ph.D., on the Women of Color Resource Persons Network, which now includes 1,000 individuals. Dr. Perez-Stable indicated that infrastructure could serve as a model for distance mentoring.
Dr. Perez-Stable also reported that the NIA Summer Institute has been renamed as the Butler-Williams Scholars Program and that the next program dates will be August 4–8, 2014.
The Working Group on Program considered a funding opportunity concept clearance and a Council task force.
- Concept Clearance: Development of Fatigability Measures in Older Adults
Terrie F. Wetle, Ph.D., reported on a proposed funding opportunity announcement that had been refined by the NIA staff following a previous review. Although fatigability has been recognized as a predictor of mortality and a contributor to reduced quality of life among older individuals there are no validated measures of fatigability among older individuals and existing measures of tiredness and situational fatigue are not appropriate. The proposed request for applications is a set-aside and will solicit exploratory, developmental research applications to develop sensitive, reliable, and appropriate measures of fatigability, distinct from measures of depression, frailty, or sleepiness. The working group recommended that the concept be approved. The motion was seconded and passed unanimously.
- Council Task Force on K Awards
Kevin High, M.D., reported that during a discussion of the statistics package, members of the working group noted that the number of K awards was lower than in previous years. This decline was attributed primarily to normal peaks and valleys in applications. However, the working group discussed the value of the K award in the current climate of academic medicine, with shrinking margins, difficulty in protecting research time and cross-funding from other grants, and the inability of K awards to fund fully 75% of investigators’ time. The working group proposed a Council task force to assess the current K award structure, how it fits the current realities in academic medicine, and potential modifications that could be proposed to NIH. The motion was seconded and passed unanimously.
Dr. Hodes acknowledged Dr. Califf, Ronald Petersen, M.D., Ph.D., Dr. Richardson, and Dr. Wetle, who are rotating off the Council.
Dr. Califf noted that serving on the Council has been an honor and a pleasure and he particularly acknowledged the NIA staff for helping him to manage his disclosures. He observed that the rapid aging of the American population means that society is highly concerned about many issues NIA is trying to address. However, Dr. Califf expressed frustration that the right strategy for clinical care and the appropriate dose of any drug are still not known for older adults over 80 years of age. He suggested that NIA take on the question of appropriate dosing, but not alone, and he suggested that the new infrastructure under development for NAPA presents an opportunity to leverage resources.
Dr. Petersen considered it an honor to have served on the Council and he acknowledged the NIA staff and leadership for their flexibility, dedication, and poise during difficult times and perturbations. Dr. Petersen cited NIA’s response to its tightening payline as an area where the Council weighed in and he expressed appreciation to NIA for seeking Council input as it developed solutions. He also noted the investment of the scientific committee in the Division of Neuroscience (DN) and NIA in general, as illustrated by the large amount of participation in the DN review. Dr. Petersen expressed appreciation for the opportunity to get to know the NIA staff and his fellow members on the Council.
Dr. Richardson commended NIA on its response to its payline and funding crises and the overall budget situation. He pointed out that NIA developed solutions that were respected across the board and he praised NIA’s determination to maintain the payline, even in light of sequestration. Dr. Richardson noted that, because of his time on the Council, he learned and appreciated how much each Division varies in terms of funding strategies. He closed his remarks by cautioning against viewing the current budget situation as similar to that seen in the 1990s, by encouraging NIA to allow Divisions to think creatively about how to support the best science, and by suggesting that NIA find ways to fund more grants.
Dr. Wetle noted that she has worked with NIA in some form since 1995, when she served as Dr. Hodes’ first deputy director. She acknowledged Dr. Hodes as a humble, principled, and deliberate decision-maker. Dr. Wetle also noted her time on the Council as an opportunity to work with a group of stellar scientists and learn new perspectives in the areas of science, science policy, and science management. She also expressed her appreciation to program staff for their support.
Laura Carstensen, Ph.D., (Stanford University) provided the Council with a brief overview of the BSR review, which she is co-chairing with Jonathan Skinner, Ph.D., (Dartmouth College). She noted the wide array of topics explored by BSR and pointed out that the review committee established nine subcommittees to ensure the depth of expertise needed to assess this array. These subcommittees examined the portfolio, past accomplishments, and future directions of their respective topic areas, then provided preliminary reports to the overall committee. Dr. Carstensen noted the considerable overlap in recommendations across subcommittees, which is reflected in the interdisciplinarity of BSR.
So far the BSR review committees have identified the following overarching themes:
- BSR should support research that illuminates the pathways by which the environment or outside behavior affects health and wellbeing. This includes continuation of international cohort studies collecting data on activity, biomarkers, and time-use; studies examining the health impact of expanding insurance coverage and quality differences across systems; continued investment in the genetics of individual differences and how they mediate stress and disease; and additional research on the pathways underlying cognition, emotion, and motivation.
- BSR should support research to identify ways to modify organizational and individual behaviors associated with positive and negative aging outcomes. Such research includes the basic science of behavior change, environmental defaults that might improve self-regulation and conscientiousness, and effects of work and retirement on cognition and physical health.
- BSR should invest in research on reversibility, including critical periods or optimal timing for interventions. This includes research on the reversibility of insecure attachment, individual differences in conscientiousness and self-control, and the leveraging of social networks to support commitment regimens.
- BSR should support research to understand and ameliorate the effects of persistent disadvantages. This includes research on key race/ethnicity- or social class-associated behaviors that affect health and the effects of stereotypes and stigma on habitual behavior and thinking across the life course, as well as increased training and career development to increase the diversity of the scientific community.
Dr. Carstensen closed by noting that the nine subcommittee reports will be integrated into a draft committee report, which will be refined through an iterative process between the committee and DBSR staff. This report will be presented at the February 2014 NACA meeting.
In response to questions from the Council, Richard Suzman, Ph.D., BSR director, noted that the Division collaborates with Steve Suomi, Ph.D., of The Eunice Kennedy Shriver National Institute of Child Health and Human Development, who conducts behavioral studies in rhesus macaques. BSR also collaborates with the DN and is interested in collaborating with the Division of Aging Biology (DAB). Drs. Suzman and Jonathan King, Ph.D., added that genetic information collected as part of DBSR-supported studies, such as the Health and Retirement Study, are deposited into the database of Genotypes and Phenotypes (dbGaP). Other data are also available, although investigators will have to go through security steps for the more sensitive information. Drs. Suzman and King indicated that BSR has considered the addition of other biological parameters and imaging to its cohort studies but they also noted the potential costs. Council members suggested connecting with ongoing studies, for example Dr. Suomi’s reversibility studies in rhesus monkeys and the inherited epigenetics studies supported by DAB.
Lawrence Tabak, Ph.D., NIH deputy director, discussed ongoing concerns about the lack of reproducibility and transparency in research findings, focusing primarily on preclinical work. He referenced a seminal paper, published in Nature Reviews Drug Discovery, which found that approximately two-thirds of projects done by the pharmaceutical industry could not replicate data published by others. Dr. Tabak also noted other examples of widespread deficient reporting, for example of methodological approach, sample size calculations, and blinding and randomization. He pointed out that the failure of a publication to report something does not necessarily mean it was not done but could be in part a symptom of shrinking journal pages. However, he acknowledged that at a time when stakeholders demand that NIH translate its basic discoveries into tangibles to improve health, and at a time when NIH is aiming to accelerate translational efforts, the lack of reproducibility and transparency is a concern.
The inability to replicate preclinical findings arises partly from differences in study design between animal and human studies. Other factors include insufficient reporting, publication bias toward positive results, and varying definitions of reproducibility. Workshops held by the National Institute of Neurological Disorders and Stroke and the National Cancer Institute, along with discussions among IC directors, identified other root causes, such as poor training, poor evaluation, and perverse reward incentives (i.e., “publish or perish”).
In response to this issue, NIH has focused on raising community awareness, improving training in experimental design, promoting more systematic review of grant applications, and making efforts to increase stability for investigators. On the basis of these principles, an ad hoc group established by Francis Collins, M.D., Ph.D., NIH director, has made several recommendations:
- Encourage ICs to discuss the issue of reproducibility and transparency with their advisory councils, boards of scientific counselors, and stakeholder communities.
- Integrate modules or, if necessary, a course on experimental design, into existing required training courses and terms and conditions of award notices.
- Consider options for an evaluation process of the scientific premise of a grant application.
- Collaborate with scientific journals and the scientific community on efforts to improve rigor.
- Adapt the NIH biosketch to allow investigators to place their work into a functional context.
The ad hoc group also suggested that NIH consider the use of guidelines or checklists for systematic grant evaluations and the advisability and approach to, supporting of replication/reproducibility studies or centers.
Several ICs, including NIA, are involved in pilot projects addressing these recommendations and other projects are already under way. For example, NIA supports the Interventions Testing Program, which conducts preclinical studies with multi-site duplication, rigorous methodology, and statistical analysis. The Intramural Program is creating and piloting a new training module on research integrity related to experimental bias and study design. This module will be incorporated into the ethics training course all intramural fellows must take. Once the module is tested, the Office of Extramural Research will make the module available for institutions around the country to adopt and adapt for their use.
Dr. Tabak pointed out that, following discussions with IC directors about implementation of these recommendations, NIH is aware of several caveats, such as the differential effects on experienced versus new investigators, the additional costs and resources needed, the additional burden on reviewers, and the difficulty in publishing negative results. He also noted that “one size does not fit all” and acknowledged concerns that the emphasis on systematic reviews of scientific process could hamper creativity.
In response to concerns raised by Dr. Morimoto, Dr. Tabak clarified that when NIH mentions “integrity,” it is not talking about outright fraud but about increasing awareness of reproducibility and transparency issues to ensure the highest quality of science. He anticipated that, as scientists become more aware, additional steps would be integrated into their normal way of working. However, Dr. Tabak acknowledged that juxtaposing the word “integrity” with the issues discussed here is problematic.
Dr. Tabak also agreed with Dr. Morimoto’s point that training should be done in a multi and interdisciplinary way because each discipline has unique issues.
Dr. Califf raised concerns that defining reproducibility too rigidly could lead to a conclusion that almost nothing is reproducible. Dr. Tabak agreed that there are no absolutes in reproducibility and that it is not clear what threshold is acceptable. However, he pointed out that NIH should at least admit to and control for these issues.
In response to questions from Dr. Bradley Hyman, M.D., Ph.D., about training, Dr. Tabak speculated that NIH was closer to incorporating such training into T32 grants as they are renewed, rather than establishing new mechanisms for replication studies. However, he also indicated that NIH will have to consider funding mechanisms for replicating studies. At present, NIH is focusing on preclinical studies that form the basis for large clinical trials, but Dr. Tabak acknowledged that efforts will have to be broadened at some point. Dr. Hodes added that it would be useful for NIA to have a process to identify research activities or findings that meet a threshold for soliciting replication studies. He suggested, for example, that the NIA could periodically survey its research, identify findings of sufficient interest, and issue solicitations for review and replication studies.
Ana Maria Cuervo, M.D., pointed out that journals have a responsibility to involve statistical experts, for example, in their review processes to increase the rigor for papers they publish. She also noted the need for training to ensure more uniformity, for example, in data collection and recordkeeping. She observed that each institution varies in how investigators keep their notebooks. Dr. Tabak agreed with these points, commenting that increasing rigor in the peer review of grant applications is also important and that this is the responsibility of NIH.
Dr. Tabak concluded his remarks by emphasizing the importance of the scientific community continuing to view the increasing emphasis on reproducibility and transparency in a positive way to enhance the quality of the science.
Division of Aging Biology (DAB): Neuroendocrine Regulation of Mitochondrial Proteostasis – Pathways to Survival
Andrew Dillin, Ph.D., of the University of California at Berkeley, began his presentation by noting that NIA support was crucial in the work he would present. NIA made an early investment in a risky project that developed into interesting biology with clinical applicability.
For the last 50 years or so, mitochondria have been a focus of aging research. The Metabolic Theory of Aging states that the by-products of metabolism are reactive oxygen species, which are harmful to macromolecules and drive aging. On the basis of this theory, decreasing metabolism within a species should increase longevity and the degree to which longevity is increased will be proportional to the amount of time metabolism has been decreased. The insulin/insulin-like growth factor 1 (IGF-1) pathway has received a large amount of attention in studies on increased lifespan, but it is likely that other pathways also are involved.
Dr. Dillin’s laboratory carried out an interfering RNA screen in Caenorhabditis elegans (C. elegans)for genes involved in the lifespan and identified 100 that increased longevity. Of these, more than half were mitochondrial electron transport chain components encoded by the nucleus. The effects of these genes were dose dependent; simply reducing expression of these genes by half was sufficient to increase lifespan. The laboratory also found that it was the time point at which mitochondria proliferate, rather than the duration of time at which metabolism is reduced, that is critical to increasing longevity in this system. Further work showed that mitochondria and cells in the nervous system and the intestine are essential for increased lifespan, that perturbation of the mitochondria in the nervous system leads to a response to proteotoxic stress in the mitochondria of the intestine through a secreted signal, and that serotonin is essential for this signaling, though it is not the signal itself. These findings are contrary to the Metabolic Theory of Aging and suggest that, under starvation conditions, serotonin is involved both in the search for resources and the modulation of peripheral metabolism.
Discussion focused on speculations about the implications of this work, particularly for dietary restriction and critical time points. Dr. Dillin also noted strong epigenetic regulation, which will need to be considered moving forward.
Division of Geriatrics and Clinical Gerontology (DGCG): Steroid Hormone Interactome as a Therapeutic Discovery Platform for Aging-Related Disorders
Steroid hormone receptors include the androgen receptor (AR), the estrogen receptor, and the glucocorticoid receptor. Each participates in a interactome, where it is bound by its respective ligand and associated proteins, triggering the recruitment of additional cofactors and a series of reactions to induce transcription of genes involved in regulating growth, differentiation, and metabolism. Hormone receptor interactomes encompass multiple levels of signal amplification and selectivity and they exert both activational and epigenetic effects. Perturbations of steroid hormone receptor interactomes have been implicated in several aging-related diseases, including diabetes, heart disease, sarcopenia, and many types of cancer.
Shalender Bhasin, M.D., of the Brigham and Women’s Hospital and Harvard Medical School, described work exploiting the interactome as a platform for understanding the heterogeneity of human disease and for developing precision therapeutics. He focused particularly on the anabolic effects of testosterone and other androgens. In a series of trials, Dr. Bhasin and his collaborators have found that supraphysiologic doses of testosterone substantially increase fat-free mass and muscle strength, even in older men with multiple comorbidities and limited mobility. However, all these trials also revealed a slightly higher frequency of adverse events, including cardiovascular events. Thus Dr. Bhasin and his colleagues explored strategies to target various levels of the interactome and enhance the selectivity of testosterone action.
One strategy targeted the pre-receptor level by using 5-alpha reductase inhibitors to block the conversion of testosterone to dihydrotestosterone (DHT). This strategy is prescribed for men with benign prostate hyperplasia. In a randomized trial in which men received testosterone with placebo or a 5-alpha reductase inhibitor, Dr. Bhasin and his colleagues found no difference in fat-free mass or muscle strength between the two groups. Surprisingly, they also found no difference in prostate volume. On the basis of these results and other data, Dr. Bhasin and colleagues hypothesized that the effects of these inhibitors on the prostate depend on baseline testosterone levels.
A second strategy involved the development of selective androgen receptor modulators (SARMs). In a randomized trial, Dr. Bhasin and colleagues found that administration of SARMs can increase muscle mass and strength. They also have identified at least one SARM that increases muscle mass and strength without increasing prostate volume and they are working with oncologists to design a clinical trial for patients with prostate cancer.
The third strategy focused on downstream, tissue-specific mechanisms of action. They focused on the muscle progenitor cell, which can differentiate into both muscle cell and fat cell lineages. Although testosterone exerts its anabolic effects through classical AR signaling, it regulates the differentiation of muscle progenitor cells into muscle via non-canonical activation of the Wnt/beta-catenin pathway. A key target within this pathway is follistatin, which operates through the transforming growth factor beta pathway. Dr. Bhasin found that administration of recombinant follistatin in mice substantially increased muscle mass and resolved visceral adiposity, while sparing the prostate. In subsequent studies, he and his colleagues found that testosterone and follistatin differentially regulate a large number of genes in the prostate. Among these genes is the gene encoding ornithin decarboxylase, which is involved in the proliferation of prostate epithelial cells. Dr. Bhasin and his colleagues found that administration of testosterone and an ornithine decarboxylase inhibitor in a testosterone-deficient mouse model restored muscle mass without affecting the prostate. This approach is now under investigation by a drug company.
Dr. Bhasin further noted that the adverse effects of testosterone should be viewed in the context of the populations in which it is used. Whereas the frequency and severity of side effects is low when testosterone is given to healthy young men with classical androgen deficiency syndromes, two trials of testosterone therapy in older men with multiple comorbidities have observed an increase in cardiovascular events.
Division of Behavioral and Social Research (DBSR): Leveraging Age-Related Changes in Motivation to Improve Aging
Because of medical breakthroughs, technological advances, and behavior change, more and more individuals are living into old age. For the first time in human history, most children living in the developed world can expect to see old age. However, the culture in which individuals currently age centers around lifespans half as long and therefore presents many challenges. Among these is the need for individuals to change the way they live, for example maintaining physical fitness into their 70s, 80s, and 90s, and planning for lives that extend far past retirement. Bringing about behavioral change of this magnitude will require a focus on human motivation.
On the basis of earlier work, Dr. Carstensen developed a theory of socioemotional selectivity, in which motivation changes as a function of perceived time horizons. This theory states that human beings monitor both calendar time and lifetime and set their goals within a temporal context. Beyond the basic drives for food, water, sleep, and reproduction, human behavior is driven primarily by two types of goals—exploration and learning and emotional satisfaction and sense of meaning—and these types of goals compete daily. Younger individuals who perceive a long life ahead prioritize exploration and learning goals, but as they grow older and perceive their time growing shorter, their priorities shift to emotional satisfaction and meaning. These priorities direct humans’ cognitive resources and shape how they take in information. In several studies, Dr. Carstensen and her colleagues have found that older individuals prefer positive information over negative information, contrary to the axiom in psychology that negative stimuli gain the most attention for older adults. This is consistent with imaging studies that show greater amygdala activation in older adults responding to positive information.
Dr. Carstensen and her colleagues have conducted several studies to apply this theory to real-life behavior change. In collaboration with Alan Garber, M.D., Ph.D. (now at Harvard University), Dr. Carstensen studied effects on financial decisions and found that, among older adults, amygdala activation was higher in response to potential gains than to potential losses. More recently, Dr. Carstensen’s laboratory found that older adults walked more and engaged in more activities if they received positive information about the benefits of walking, compared with older adults who received negative information about the risks of not walking. This effect was maintained over a 30-day period. In collaboration with Hal Hershfield, Ph.D., now assistant professor at New York University, and Jerry Bailenson, Ph.D., of Stanford University, Dr. Carstensen conducted a study among younger adults in which they interacted with digital avatars of themselves. This study found that younger adults allocated more money to retirement saving if they interacted with aged avatars than they did if they interacted with avatars of themselves at their current age. In another study, individuals also saved more when the digital avatar was altered to display a positive emotion.
Dr. Carstensen further explained that the effect of perceived time is malleable, as demonstrated by data collected in younger individuals before and after the September 11, 2001 attacks and before and after the transfer of Hong Kong to the People’s Republic of China. All of Dr. Carstensen’s NIA-supported studies looked at racial and gender subgroups stratified by socioeconomic status and found no systematic differences by race or socioeconomic status. Dr. Perez-Stable observed that this work could have implications for doctor-patient communication, for example by suggesting that scare tactics are more effective with younger patients than with older ones.
Division of Neuroscience (DN): A Multiscale Biology Approach to Elucidating the Complexity of Human Disease Such as AD
With advances in –omics and imaging and the warehousing of clinical data in digital form, biomedical science has entered into the age of Big Data. However, despite the enormous amount of data generated, the molecular biology revolution has not lived up to its promise in terms of impact on human health. This disappointment arises in part from a continued focus on single genes or networks, which ignores the complexity of disease and health. All these molecules interact within non-linear networks, none of which act in isolation.
Eric Schadt, Ph.D., of the Icahn School of Medicine at Mt. Sinai, has employed a systems biology approach to better understand how perturbations in one part of the system propagate and ultimately affect health. He and his colleagues have used the large amount of digital information at their disposal to build predictive models and performed simulations of in silico perturbations to identify key drivers, or causal regulators, within networks. In one project, Dr. Schadt and his colleagues screened 50 to 100 networks with 163 loci identified through a genome-wide association study of inflammatory bowel disease (IBD) and identified a key network and genes that were potential causal regulators. In a separate study of late-onset AD versus non-demented controls, they found a small degree of differential gene expression but large differences in network connectivity. Strikingly, one of the sub-networks enriched in AD was nearly identical to the one that appeared to drive IBD. This network also appeared in other diseases, such as atherosclerosis, inflammatory pain, chronic obstructive pulmonary disorder, asthma, and fibrosis. Dr. Schadt and his colleagues went on to map marketed drugs, natural products, and potential and known drug targets and found that many interacted with genes participating in this network. On the basis of this work, a colleague in Dr. Schadt’s department compared the effects of topiramate, an anti-seizure drug, and prednisone, one of the leading treatments for IBD, in a rat model and found that topiramate did as well or better in reversing IBD.
Dr. Schadt noted that predictive models based on increased understanding of the networks underlying disease could affect clinical decision-making. He also envisioned a future in which such models could help patients to better monitor their overall health and health trajectories, for example on their smartphones.
Discussion focused on the technical aspects of Dr. Schadt’s work, particularly with respect to the completeness of the modeled networks, validation and refinement of the models, and the ability to infer causality.
The open session of the 120th meeting of the NACA adjourned at 1 p.m. on September 18, 2013. The next meeting is scheduled for February 25–26, 2014.
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.
- For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions or (b) in which a conflict of interest may have occurred. This procedure only applied to applications that were discussed individually, not to “en bloc” actions.(Back to text.)
- For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions or (b) in which a conflict of interest may have occurred. This procedure applied only to applications that were discussed individually, not to “en bloc” actions.(Back to text.)
- These minutes will be approved formally by Council at the next meeting on September 18–19, 2013, and corrections or notations will be stated in the minutes of that meeting.(Back to text.)
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING
Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
9000 Rockville Pike
Building 31, RM 5C35
Bethesda, MD 20892
Kimberly D. Acquaviva, Ph.D., MSW (2016)
Director of Faculty Affairs
The George Washington University
School of Nursing
Washington, DC 20037
Norman B. Anderson, Ph.D. (2014)
Chief Executive Officer and Executive Vice Chair
American Psychological Association
Washington, DC 20002
Laura L. Carstensen, Ph.D. (2015)
Department of Psychology
Stanford, CA 94305
Ana M. Cuervo, Ph.D., M.D. (2015)
Albert Einstein College of Medicine
Department of Development and Molecular Biology
Bronx, NY 10461
Jennie C. Hansen, MS, RN, FAAN (2016)
Chief Executive Officer
American Geriatrics Society
New York, NY 10036
Kevin P. High, M.D. (2016)
Associate Dean for Clinical Research
Department of Internal Medicine
Section of Infectious Diseases
Wake Forest University School of Medicine
Winston-Salem, NC 27157
Bradley T. Hyman, M.D., Ph.D. (2016)
Professor and Director
Department of Neurology/Alzheimer’s Research
Massachusetts General Hospital
Charleston, MA 02129
Richard I. Morimoto, Ph.D. (2014) (WGoP Member)
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) (WGoP Member)
Department of Medicine
University of California, San Francisco
School of Medicine
San Francisco, CA 94143
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
EX OFFICIO MEMBERS
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