Council Minutes -- May 2018
The 134th Meeting
May 22-23, 2018
- REVIEW OF APPLICATIONS
- CALL TO ORDER
- REPORT: Task Force on Minority Aging Research
- REPORT: Working Group on Program
- COUNCIL SPEAKER: ODP Strategic Planning and Trans-NIH Prevention Research and Related Activities
- COUNCIL SPEAKER: Translation and Implementation of the REACH II Intervention
- COUNCIL SPEAKER: IDeA Clinical and Translational Research Award 14
- INTRAMURAL PROGRAM REVIEW
The 134th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, May 22, 2018, at 3 p.m. in Building 31, Conference Room 10, National Institutes of Health (NIH), Bethesda, Maryland. Dr. Richard Hodes, Director, National Institute on Aging (NIA), presided.
In accordance with the provisions of Public Law 92–463, the meeting was closed to the public on Tuesday, May 22, 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 92–463.1The meeting was open to the public on Wednesday, May 23, from 8:00 a.m. to 2:15 p.m.
Dr. David A. Bennett
Dr. Maria Carrillo
Dr. Eileen M. Crimmins
Dr. Steven Ron Cummings
Dr. J. Taylor Harden
Dr. David M. Holtzman
Dr. Raynard S. Kington
Dr. James L. Kirkland
Dr. Stephen B. Kritchevsky
Dr. Richard Mayeux
Dr. Terrie E. Moffitt
Dr. Charles P. Mouton
Dr. Anne B. Newman
Ms. Susan K. Peschin
Dr. Thomas Rando
Dr. Reisa A. Sperling
Dr. Debra Bailey Whitman
Ex Officio Participants:
Dr. Jane Tilly, Administration for Community Living
Absent Ex Officio Participants:
Dr. Kenneth G. Pugh, National Naval Medical Center
The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as attachment A.
In Addition to NIA Staff, Other Federal Employees Present:
Dr. Rene Etcheberrigaray, Center for Scientific Review (CSR), NIH
Dr. David Murray, Director, Office of Disease Prevention, NIH
Members of the Public Present:
Mr. James Appleby, Gerontological Society of America
Dr. Danica Chen, University of California at Berkeley
Ms. Trish D'Antonio, Gerontological Society of America
Dr. Leisa Easom, Rosalyn Carter Institute for Caregiving and Georgia Southwestern State University
Ms. Brittany Harnett, Gerontological Society of America
Ms. Jocelyn Kaiser, Science
Dr. Jonathan Kipnis, University of Virginia
Dr. Rose Maria Li, Rose Li and Associates, Inc.
Dr. Cliford Rosen, Maine Medical Center Research Institute
REVIEW OF APPLICATIONS
This portion of the meeting was closed to the public, in accordance with the determination that it concerned matters exempt from mandatory disclosure under Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix)1.
A total of 1627 application requesting $3,850,388,544 for all years underwent initial review. The Council recommended 930 awards for a total of $2,717,478,206 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.
CALL TO ORDER
Dr. Hodes welcomed members to the open session of the 134th NACA meeting and called the meeting to order at 8:00 a.m. on Wednesday, May 23, 2018.
Director's Status Report
Dr. Hodes reported that the finalized fiscal year (FY) 2018 NIH budget includes an increase of $3 billion, for a total of $37 billion. This budget contains set-asides of $500 million for research on opioids and pain, $140 million for the Brain Research through Advancing Innovative Neurotechnology (BRAIN) initiative, $60 million for the All of Us/Precision Medicine Initiative, and $414 million specifically for Alzheimer's disease (AD) research. The increase also brings the NIA budget to approximately $2.6 billion, including an increase of $111 million, for non-targeted research. NIA is still awaiting technical approval to release information on how these increases translate into paylines. However, Dr. Hodes expressed the hope that the paylines for FY18 will be similar to those for FY17. He noted that the increase in funds targeted to AD research has led to several funding opportunity announcements (FOAs) addressing broad areas over the entire research continuum, including basic/discovery, clinical, clinical care and caregiving, health disparities, and training.
Dr. Hodes also reported that NIA leadership and leaders from the House and Senate appropriations subcommittees had visited Colombia, where a clinical trial among families with autosomal dominant AD is ongoing. He reported that Dr. Marie Bernard, NIA Deputy Director, participated in the announcement by the U.S. Postal Service of a fundraising stamp dedicated to AD. Dr. Bernard also testified about AD at a meeting of a House Foreign Affairs Subcommittee, and Dr. Francis Collins, NIH Director, and several Institute and Center (IC) Directors attended a meeting of the Senate Appropriations Subcommittee, whose members discussed aging and AD as they considered appropriations for FY19. Dr. Hodes announced that the second day of the 2018 AD Research Summit, which had been postponed because of inclement weather, has been rescheduled for May 24 on videocast. He also announced that the AD-related Dementias Summit will be held on March 24–25, 2019.
Dr. Hodes provided several other updates:
- The NIA-Alzheimer's Association Research Framework will support research to describe a neuropathological diagnostic continuum for AD based on a common set of objective criteria and markers.
- NIA has commissioned a two-part, evidence-based review by the National Academies and the Agency for Healthcare Research and Quality (AHRQ) to aid in identifying and promoting effective strategies, interventions, and services for dementia patients and their caregivers. There will be a public comment period.
- The 21st Century Cures Act, which was passed in 2016, required a workshop looking at age groupings and age exclusions in clinical research. In response to the Inclusion Across the Lifespan Workshop held in Bethesda in June 2017, NIH will now require applications and progress reports to include a plan that indicates inclusion of individuals across the lifespan or a rationale for age-based exclusions.
- NIA is soliciting input for the third Geroscience Summit, which will explore the contribution of geroscience in relieving the burden of specific chronic diseases.
Ms. Susan Peschin thanked Dr. Bernard for her work on inclusion of older adults in clinical trials. She also suggested that the National Academies include representatives from the patient and caregiver community and the Patient-Centered Outcomes Research Institute on its evidence review committee. Drs. Hodes and Jane Tilly noted that NIA cannot direct the National Academies in its independent review, but Dr. Tilly pointed out that Council members could encourage others to make comments about the inclusion of patients and caregivers. In response to Dr. Tilly's questions, Dr. Bernard noted that the new NIH policy on inclusion does not include a separate identification for sexual orientation. However, NIH will have individual-level data anonymized, which will allow for an assessment of how well various groups are included in NIH-supported research.
Future Meeting Dates
- September 13–14, 2018 (Thursday and Friday, Building 31)
- January 29–30, 2019 (Tuesday and Wednesday, Building 45)
- May 21–22, 2019 (Tuesday and Wednesday, Building 60)
- September 10–11, 2019 (Tuesday and Wednesday, Neuroscience Building, Executive Boulevard)
- January 21–22, 2020 (Tuesday and Wednesday, Building 31)
- May 26–27, 2020 (Tuesday and Wednesday, Building 31)
- September 8–9, 2020 (Tuesday and Wednesday, Building 45)
Consideration of Minutes of the Last Meeting
The minutes of the January 2018 meeting were considered. A motion to approve the minutes was made, seconded, and passed.
Comments from Retiring Council Members
Dr. Hodes recognized six retiring members.
Dr. Steven Cummings expressed his appreciation for the opportunity to serve NIA as a Council member. He acknowledged the NIA leadership for the impressive scientific rigor at NIA, and he acknowledged Dr. Robin Barr and Mrs. Diane Zwinak for running Council meetings efficiently. Dr. Cummings noted the increasing and more effective interactions between basic and clinical scientists, for example in the Geroscience Initiative. He also emphasized the need for public-private partnerships and noted that such agreements will help unleash the resources companies have to offer. Dr. Cummings closed his remarks by thanking other Council members.
Dr. Richard Mayeux discussed his experiences in leading NIA reviews and noted the passion the NIA staff brings to aging research. He expressed appreciation for the opportunity to help NIA with its work.
Dr. Charles Mouton thanked his fellow Council members and the NIA leadership for the wonderful experience he had as a member of the Council. He particularly appreciated the opportunity to look inside the leadership of aging research and what drives the science. He encouraged NIA and the Council to continue thinking about how things play out for the practicing physicians and providers on the front lines. He noted, for example, that translation and practicality should be advanced as research initiatives move forward. Dr. Mouton closed his remarks by encouraging NIA to continue its momentum in addressing health disparities.
Dr. Thomas Rando cited meeting individuals he would not otherwise have met and hearing about research outside of his field of expertise as particular advantages of serving on the Council. He thanked NIA for the opportunity to give back, and he noted that he would recommend that others serve on the Council.
Dr. Reisa Sperling was happy to see that funding opportunities at NIA, especially those to train the next generation of scientists, are increasing. She expressed appreciation for the ability to work with Council members from various fields, the opportunities to learn from those interactions, and the opportunity to see what happens "behind the scenes" at NIA. She acknowledged the hard work of the NIA staff.
Dr. Debra Whitman thanked Dr. Hodes for inviting her to serve on the Council, and she acknowledged the mentorship of the late Dr. Richard Suzman. She acknowledged the hard work of the NIA staff and Dr. Barr and Mrs. Zwinak's role in running the Council meetings. Dr. Whitman described her time on Council as an opportunity to "come back to school," as she has spent most of her time outside of academia and research. She closed her remarks by asking that NIA continue to work substantially with the AARP and on a way to translate research findings to consumer health.
REPORT: TASK FORCE ON MINORITY AGING RESEARCH
Dr. Mouton reported that the Task Force had heard two presentations focused on research in American Indian and Alaska Native (AI/AN) communities. In the first, Dr. Sheila Caldwell, Director of the Division of Research Capacity at the National Institute of General Medical Sciences (NIGMS), focused on the Native American Research Centers for Health (NARCH) program. This program is a trans-NIH initiative and a partnership between NIH and the Indian Health Service to increase research capacity in AI/AN communities. Specifically, the program supports collaboration between federally recognized AI/AN entities and research-intensive institutions, supports health research projects prioritized by tribal communities, supports the development and training of students, scientists, and health professionals engaged in AI/AN research, and increases research capacity for questions of interest to AI/AN communities. Applications must be submitted by federally recognized AI/AN entities and cannot exceed $1 million in direct costs. Since its inception in 2001, the NARCH program has disbursed 63 awards and added a capacity-building component. NIA has recently joined NARCH as a contributor. Dr. Caldwell's presentation included a success story about a student who has participated in NARCH since high school and is now entering an MD/PhD program.
The second presentation, from Dr. Shobha Srinivasan, of the Division of Cancer Control and Population Sciences at the National Cancer Institute (NCI), focused on efforts to expand the reach of cancer control research in small populations. Such efforts include ongoing tribal registries and partnerships, the Native Cancer Information Resource Center and Learning Exchange, the Education and Research Towards Health, and National Institute on Drug Abuse (NIDA)-supported research on tobacco cessation versus respectful or ceremonial use. Dr. Srinivasan noted gaps in data and reporting issues among AI/AN communities, but she also pointed to available data sources that aid in tracking morbidity and mortality rates. Her presentation also summarized the Intervention Research to Improve Native American Health (IRINAH) program, in which NCI partners with several ICs to train the next generation of researchers and to encourage existing researchers to build networks to advance AI/AN research.
Dr. Mouton reported that future directions at NCI and NIH include additional supplements to existing cancer centers, publications in Prevention Science focusing on research methods in these communities, and efforts to address issues related to data-sharing. He noted the creation of the new NIH Tribal Office, headed by Dr. Dave Wilson. He also pointed to genomics as an area where it is particularly important to obtain tribal approvals for research; some tribes do not approve it.
Dr. Mouton closed his report by noting that the 2018 Butler-Williams Scholars program will be held July 30 through August 3 in Bethesda and that the 2018 Director's Regional Meeting will be held at the University of Kansas Medical Center on November 1, 2018.
Dr. Whitman commended NIH on its funding efforts for AI/AN research, and she suggested that NIA look at this population to a greater extent, particularly as it focuses on AD care. In response to questions, Dr. Mouton clarified that the AI/AN populations did include Hawaiian natives, but he was not sure whether there were NARCH sites in Hawaii.
REPORT: WORKING GROUP ON PROGRAM
RFA/RFP Concept Clearances
The Working Group heard 12 concepts and recommended that they be forwarded to the Council for approval. A motion to clear the concepts en bloc was forwarded, seconded, and passed with one abstention by Dr. Whitman.
Building an Infrastructure to Synergize Research for Improved Care of Older Adults Across Specialties and Disciplines
This concept proposes a U13 series supporting the development of a clinical and research workforce in geriatrics. The proposed concept would build on the success of the Grants for Early Medical/Surgical Specialists' Transition to Aging Research and would support additional conferences, interactive webinars, and pilot funding focused on mentoring and career development. The concept would be a set-aside and would provide a multidisciplinary, cross-specialty review. Comments from the Working Group noted the tremendous energy across subspecialties with respect to care and research for older adults. The Working Group also noted that the proposed concept would build a nationwide platform to provide mentorship that might not be available at all home institutions.
Involvement of Small Business Concerns in the Preclinical Development of Novel Therapeutics Which Target Fundamental Mechanisms of Aging
The proposed initiative would support small businesses engaged in preclinical development of novel therapeutics targeting the fundamental mechanisms of aging. Small businesses can develop new therapeutics or repurpose FDA-approved drugs. The proposed initiative would advance early-stage development at the pharmacology/toxicology or investigational new drug application stage and thus serve as a bridge to the first in-human studies of these compounds targeting aging.
Small Business Innovation Research Early-Phase Clinical Trials of Novel Interventions to Prevent, Delay, or Treat Aging-Related Conditions by Targeting Aging-Related Mechanisms
This is the second half of a larger initiative including the abovementioned concept on preclinical development. Here, the proposed initiative would support clinical trials of therapeutics tested in that concept. The Working Group noted that these two concepts are needed to encourage small businesses to take risks to move new targets forward, as Big Pharma is highly conservative with respect to drug development. Working Group members also noted that these efforts would prepare new therapeutics for commercialization so that they could become attractive to Big Pharma for further development. However, the Working Group also cautioned that small businesses might shy away from repurposing because of concerns about intellectual property protections.
A Census of Cells and Circuits in the Aging Brain
The proposed FOA would build on and complement the BRAIN initiative by supporting the systematic identification, characterization, and mapping of the many cell types present in the mouse brain. This concept would include the identification of molecular signatures through single-cell –omics. The FOA, which would support pilot studies in young and old mice, will require that the census of cells and circuits be converted into a mouse brain atlas. Data generated from these studies will be available to the public, and collaborations with BRAIN researchers will be encouraged.
AD Genetics Consortium
The AD Genetics Consortium has been highly productive in identifying new areas that can increase understanding of the pathways to AD pathogenesis. The proposed concept would extend this work, with a focus on adding more minority cohorts to increase diversity and the applicability of the work to broader populations.
Integrative Research to Understand the Role of the Gut-Brain Axis and the Microbiome in Brain Aging and AD
The proposed concept would support work focusing on the multifactorial etiology of AD. Genetic, biologic, and epidemiologic evidence already supports a role for immune and biologic dysfunction in the development of AD. The proposed concept would focus on increasing understanding of the axis between microbiota and the brain and how that influences AD.
Network for the Identification, Evaluation, and Tracking of Older Persons with Superior Cognitive Performance for their Chronological Age
The proposed concept, which emerged from the Cognitive Aging Summit, would support the establishment of a network to study cognitive "superagers." The Working Group expressed enthusiasm about the potential research that could be done with this new resource and the potential for identifying protective factors. Working Group members had questions about the definition of a cognitive "superager," who will serve as the informative comparison group, and the feasibility and content of the data-collection protocol, but they expressed confidence that these questions would be addressed.
Low-Cost Detection of Cognitive Decline in Clinical Settings
The proposed concept will support the development and validation of new tools, including electronic and digital data collection, that can be used in primary care and other settings for both active and passive monitoring of cognitive decline. The Working Group noted the importance of norming in the targeted populations, as well as the time needed to validate new tests. However, the Working Group supported the concept overall.
Development and Maintenance of Aged Rodent Tissue Bank
The proposed concept will renew the contract for this bank, which has been supported by NIA since 2001. The tissue bank provides tissue from three mouse strains and three rat strains. The Working Group discussed how to increase awareness in the research community about the availability of this resource.
Exploring Molecular Links Between Dietary Interventions and Circadian Rhythm
Caloric restriction is the most effective way to improve life- and healthspan, but some effects of caloric restriction can be blocked by blocking components of the circadian clock. Likewise, some effects can be extended depending on the time of day that feeding occurs. The proposed FOA will support collaborative and comprehensive research on the mechanistic links between caloric restriction and circadian rhythms.
Marmosets as a Translational Model for Aging Research
The proposed concept would support research using marmosets as a non-human primate intermediate between rodent and human studies. Marmosets are ideal because they are a short-lived species that exhibit some features of aging and neurodegeneration seen in humans. The Working Group expressed enthusiasm for the concept, but it discussed how the colony and aged marmoset cohorts would be maintained.
Microbiome and Aging: Impact on Health and Disease
The proposed FOA will support research characterizing the role of the microbiome in regulating the processes and diseases of aging, as well as the possible roles of age-related changes in the microbiome in the development of disease. The FOA will support both descriptive and hypothesis-driven research. The Working Group discussed the relevance of the rodent microbiome to the human microbiome and speculated on what principles can be learned. Research supported by the FOA will include studies of humans and other species.
- Statistical Package
Dr. Barr reported that NIA has seen a 50% to 60% growth in applications over the past 3 years. The NIA budget has grown by more than 100% over those years, so the budget is still outpacing the increase in applications. NIA is aggressively building its application base.
In response to questions about the makeup of study sections, Dr. Barr noted that the Center for Scientific Review (CSR) is reviewing that issue, because some study sections have a heavy load of applications as a result of the buildup. CSR is aiming first to redistribute content across panels to even the load. CSR will also consider building new study sections if necessary.
Dr. Hodes also noted that NIA has received permission to recruit for new staff to assist with review and grants management, although NIA is still constrained by the FTE limits set in the Institute's Congressional justification. NIA is using all available mechanisms to provide the staffing needed to address the increased application load.
The Council also discussed the number of AD-related applications going to the Division of Geriatrics and Clinical Gerontology, the role Council members can play in conducting outreach and recruiting other researchers into aging research, and the need to continue supporting young and new investigators as they transition to independent careers.
COUNCIL SPEAKER: ODP STRATEGIC PLANNING AND TRANS-NIH PREVENTION RESEARCH AND RELATED ACTIVITIES
Dr. David Murray, Office of Disease Prevention (ODP) Director, shared the Office's strategic plan for FY19 through FY23. The NIH ODP is one of several programmatic offices within the Division of Program Coordination, Planning, and Strategic Initiatives. Its mission is to improve public health by increasing the scope, quality, dissemination, and impact of prevention research supported by NIH and to provide leadership for the development, coordination, and implementation of such research across NIH and with other partners. Current ODP activities include management of the Tobacco Regulatory Science Program (TRSP), a joint venture between NIH and the U.S. Food and Drug Administration (FDA); serving as a liaison to other HHS activities such as the U.S. Preventive Services Task Force (USPSTF); an evidence-based assessment program; training and education; and cofunding of NIH research projects, meetings, and workshops that support prevention research.
The strategic plan outlines six priorities:
- Systematically monitor NIH investments in prevention research and the progress and results of that research. ODP has developed a taxonomy for prevention research; coded more than 5,000 R01 abstracts from FY10 through FY15; collaborated with the Office of Portfolio Analysis to develop machine-learning tools to automate coding processes; and coded more than 11,000 R, P, and U awards from FY12 through FY17. Findings will be published later in 2018. ODP aims to characterize the NIH prevention research portfolio and submitted applications, assess the impact of NIH investments in prevention research, and partner with colleagues to share data and tools.
- Identify prevention research areas for investment or expanded effort by NIH. ODP has improved coordination between NIH and the USPSTF, in part by using an annual survey of insufficient evidence statements to monitor progress and identify opportunities. ODP is now working with ICs to encourage the development of additional activities to address those gaps. ODP is also working to improve coordination with the Community Preventive Services Task Force, and it is working to support Healthy People 2020 and to develop Healthy People 2030. ODP hopes to sponsor two Pathways to Prevention workshops in 2018. It also plans to identify gaps and work with ICs to address them.
- Promote use of the best available methods in prevention research and support the development of better methods. ODP has created a course on Pragmatic and Group-Randomized Trials in Public Health and Medicine, added language to the Application Guide and Review Criteria for clinical trials applications, and used the Prevention Research Expertise Survey to help scientific review officers identify methods experts for study sections. Future plans include continuing to provide resources and training for review staff; identify methods experts for study sections; serving as a resource for ICs to incorporate prevention science methods as they develop new FOAs, workshops, and other activities; and developing metrics to monitor leading causes of, and risk factors for, premature death.
- Promote and facilitate coordination of collaborative prevention research projects across NIH and with other public and private entities. ODP is working with existing scientific interest groups and has created five new ones focused on screening in children; screening in adults; genetics of prevention; environmental-, policy-, and systems-level interventions; and interventions to prevent or delay the onset of comorbid disease. The Office aims to continue this work and to coordinate and support the development of collaborative prevention initiatives, including those to conduct larger and better-powered trials examining multiple outcomes.
- Promote and facilitate tobacco regulatory science and tobacco prevention research. TRSP has issued 27 trans-NIH FOAs and has supported more than 250 awards. Thirteen ICs have been involved. ODP will continue to serve as the liaison to the FDA Center for Tobacco Products and will ensure that projects funded under this program fall within the purview of the FDA's authority. Because TRSP is funded by FDA dollars and intended to support that agency's regulatory mission, NIH cannot fund studies on tobacco cessation or tobacco prevention trials. However, NIH can fund studies, for example, on the effects of advertising on tobacco purchasing patterns.
- Advance the understanding of prevention research, increase the availability of prevention research resources, and enhance stakeholder engagement. ODP has expanded its website from 4 pages to more than 250 pages and has created a presence on social media. ODP also has strengthened its partnerships with professional societies. ODP will continue this work. It will also build effective relationships and engage with stakeholders to enhance communication about prevention research and prevention-related activities conducted by NIH and other agencies.
ODP will submit its new strategic plan to Dr. Collins later this summer and expects to have it approved by the end of FY18. Dr. Murray asked the Council for comments, particularly with respect to advancing aging prevention research, potential cost-cutting themes, and other priorities ODP might consider.
Dr. Steve Kritchevsky noted that loss of independence concerns and the prospect of being a burden to others worries older adults the most. He suggested a larger emphasis on prevention of disability and loss of function, because the age-adjusted prevalence of physical impairments and disability have not changed much over the past 15 years. Dr. Murray noted that ODP's definition of prevention includes disability and that ODP is interested in prevention across the lifespan. ODP would like to work with NIA and others to develop new initiatives that would make it easier for older adults to live with more independence and greater satisfaction.
Dr. Sperling suggested that cognitive impairment and dementia be a high priority. She also noted that large prevention trials provide little information on cognition over time and asked whether ODP could play a role in gathering such data. Dr. Murray agreed on the need to prioritize cognitive impairment and dementia. Although much is known about risk factors and causes, more should be done to develop and evaluate interventions to reduce burden. Dr. Murray suggested that ODP and NIA encourage the attachment of cognitive measures to ongoing trials.
Dr. Mouton suggested that health disparities and minority issues be included as cross-cutting themes. He also noted that, although NIA does a good job in engaging communities, a trans-NIH initiative on community engagement is needed. Dr. Murray noted that health disparities is one of three cross-cutting themes under consideration and that ODP has worked with the National Institute of Minority Health and Health Disparities on several papers. These papers, which will be published in the American Journal of Public Health, will focus on the kind of research needed to address health disparities, moving beyond merely documenting health disparities and developing interventions to address them.
Dr. J. Taylor Harden applauded ODP's focus on the prevention or delay of comorbid conditions, which is a concern among individuals aged 65 and older. She also asked whether ODP staff included someone specifically focused on training and noted the NIA Summer Training program. Dr. Murray indicated that ODP staff members already participate in several training programs. ODP also makes presentations on prevention science methods and holds day-long workshops and 3-day courses. He noted that ODP would be happy to participate in the Summer Training program.
In response to questions from Dr. Maria Carrillo, Dr. Murray noted that it is not clear how much of the NIH prevention research portfolio focuses on aging and includes NIA-supported research. He reported that ODP presented its portfolio analysis to IC Directors in March 2018 and is now developing IC-specific reports. ODP will share its more detailed findings with NIA when they become available. Dr. Bernard noted that responding to statements from the USPSTF and work on Healthy People 2030 have helped NIA in thinking about research gaps, developing objectives, and translating evidence. She announced that a follow-up to the 2015 Healthy Aging Summit will be held on June 16–17, 2018, to assess dissemination and building on existing information regarding healthy aging.
Dr. Anne Newman asked about efforts to improve prevention guidelines, which often lack a life course perspective. For example, they often do not address when someone should initiate therapies or intervention or stop undergoing screening. Dr. Murray responded that as ODP conducts its insufficient evidence survey, it tries to identify areas for further research.
COUNCIL SPEAKER: TRANSLATION AND IMPLEMENTATION OF THE REACH II INTERVENTION
Dr. Leisa Easom, of the Rosalyn Carter Institute for Caregiving (RCI), described the Institute's Resources to Enhance Alzheimer's Caregiver Health (REACH) program. The REACH intervention began as a feasibility study funded by NIA and the National Institute of Nursing Research. It was based on a health stress model, which focused on identifying and alleviating or changing stressors. On the basis of this study, a randomized, controlled trial, REACH II, was conducted among an ethnically diverse group of participants. A U.S. Department of Veterans Affairs medical center was among the first to translate REACH from the clinical setting to the community. REACH-VA was implemented among veterans with great success.
With funding from the Administration for Community Living, RCI REACH implemented programs in rural and coastal Georgia. Based on the REACH-VA model, RCI REACH is a 6-month intervention program that involves educating the family about dementia as a disease, safety for the individual living with dementia, managing caregiver stress, promoting caregiver self-care, social support for both patient and caregiver, managing problem behaviors, and coping skills. The intervention is tailored to individual caregiver concerns and their top priorities. REACH involves nine face-to-face and three telephone interactions between coaches and caregivers. Caregivers are also given a resource guide for their reference.
Like REACH II and REACH-VA, RCI REACH is a rigorous, scripted, and organized program. Investigators from the original project trained the RCI teams and served as consultants for the first 4 years. RCI REACH uses all outcome assessment tools included in the original delivery program, and fidelity checklists are completed after each coach-caregiver interaction to ensure that coaches have followed protocol. Metrics include a burden scale, a revised memory/burden checklist, a revised caregiver self-efficacy checklist, and the desire to institutionalize the individual living with dementia.
Dr. Easom reported that RCI REACH has led to a statistically significant decrease in caregiver burden, caregiver depression, and desire to institutionalize the individual living with dementia. These effects are seen even after 12 months of follow-up. A cost-analysis has found that implementation of REACH costs about $7 per day in rural Georgia, or $210 per month, compared with an average cost of $5,000 per month for nursing home placement. Dr. Easom shared testimonials from families and a positive review of REACH published in the Annals of Internal Medicine, and she reported that 100% of caregivers in the program would recommend RCI REACH to other caregivers.
Dr. Easom noted that REACH is available in only 24 counties nationwide and that further scale-up is needed. Some REACH communities are considering intervention delivery through telehealth approaches such as FaceTime and Skype.
In response to questions from the Council, Dr. Easom noted that RCI REACH has not engaged in recruitment and retention efforts but that RCI itself can do so. She also pointed out that RCI also offers services to track caregivers' cognition, although this is not part of the REACH intervention itself. Dr. Terrie Moffitt suggested that RCI REACH incorporate measurement of stress hormones, which can be more effective than self-reports in assessing caregivers' physical health. In response to comments about the time-consuming nature of REACH, RCI REACH has extracted the component on managing troubling behaviors into a 4.5-hour workshop and developed a half-day "Train the Trainer" program to train coaches in working with families. Dr. Easom also noted that RCI works consistently with training and implementation scientists and provides intensive technical assistance to ensure fidelity between RCI REACH and the original REACH intervention.
The Council and guests also discussed financial aspects of REACH. Involving insurance companies and other payors in the scale-up of REACH was suggested. Ms. Peschin suggested that RCI reach out to the Centers for Medicare and Medicaid Services (CMS) Center for Medicare and Medicaid Innovation about new demonstration projects. Dr. Easom also noted that RCI REACH is free to families as long as they qualify for services from the community agencies. Dr. Jane Tilly pointed out that CMS allows Medicare Advantage plans to provide a wide range of services as long as those services aim to mitigate a health condition.
COUNCIL SPEAKER: IDEA CLINICAL AND TRANSLATIONAL RESEARCH AWARD
Dr. Clifford Rosen, Director of Clinical and Translational Research at the Maine Medical Research Institute (MMRI) spoke about the Institutional Development Award program (IDeA). IDeA was established in by Congressional mandate in 1993 to level the playing field by enhancing the geographic distribution of research infrastructure in the United States. Administered by the National Institute of General Medical Sciences (NIGMS), IDeA includes Centers of Biomedical Research Excellence (COBRE), the IDeA Networks of Biomedical Research Excellence (INBRE), and IDeA cofunding for meritorious applications that might not have met the cutoff for IC funding. Dr. Rosen described a fourth component, the IDeA Clinical and Translational Research Award program (CTR), and work within his own CTR.
CTR supports the development of infrastructure for human clinical research studies and enhances the ability of institutions to develop clinical and translational research projects. CTR applicants must reside in IDeA-eligible states, and only one CTR can be awarded per eligible state. Key components of the CTR program include faculty recruitment, enhancement of cyber infrastructure, clinical research resources and facilities, ethics and regulatory knowledge, biomedical informatics and support services, and research technologies and resources with cores in administration, professional development, community engagement, and biostatistics. NIGMS currently supports 10 CTRs.
Among these CTRs is the Northern New England Clinical and Translational Research Network, which collaborates with a Clinical and Translational Science Award (CTSA) center at Dartmouth College and serves Maine, New Hampshire, and Vermont. The Network focuses on rural health, particularly substance abuse, cardiovascular disease, cancer, and diabetes. It includes a Rural Practice and Clinical Research Core, which engages with rural practitioners to determine which community priorities to support. For example, the Network's external advisory committee includes community advisors from the Western Maine Health and Stephens Memorial Hospital to understand the needs of the community in Norway and Oxford Hills. The Northern New England Clinical and Translational Research Network also develops research catalysts or research navigators to serve as an interface between clinicians and basic scientists and to address core areas such as institutional review boards, biostatistics, and epidemiology. The Network has funded five pilot projects and plans to fund seven more. Among these projects is a pilot project to use telemedicine among small hospitals to reduce disparities in the time it takes to address neonatal anoxia.
Dr. Rosen highlighted ways in which CTR programs can integrate with NIA. He noted a project focused on connections between antipsychotic use and bone loss among older individuals. This project has studied these connections in mice and is now working to translate this work into humans, for example with a study assessing the effects of beta blockers in reducing or preventing antipsychotic-associated bone loss. The CTR is also examining combinations of opioids with other drugs and their effects on opioid-induced bone fractures.
In response to questions from the Council, Dr. Rosen noted that the CTR consortium, which comprises the principal investigators from the 10 CTS programs across the nation, is always looking for opportunities for collaboration. He noted that NIGMS considers offering supplements to support regional partnerships between CTRs and other NIH-supported programs such as CTSAs. A supplement to study opioids and substance abuse has just been issued for the CTR programs. Dr. Rosen also noted that CTRs and CTSAs are beginning to break down siloes, for example in a research program on rural primary care. In addition to partnering with Dartmouth, the Northern New England Clinical and Translational Research Network is also considering models from the Patient-Centered Outcomes Research Institute and identifying priorities among rural practitioners.
Division of Aging Biology (DAB): Mitochondrial Metabolic Checkpoint, Stem Cell Aging, and Rejuvenation
Dr. Danica Chen, of the University of California at Berkeley, noted that it is well accepted that aging is caused in general by cell damage arising from various processes. One such process, oxidative stress, increases with age, but why it increases and how that increase contributes to aging is poorly understood. The contribution of oxidative stress to aging could arise as an acute effect of elevated levels of reactive oxygen species, or it could result from a chronic accumulation of oxidative damage. A large body of evidence also shows that stem cell function declines with age, resulting in the degeneration and dysfunction of aging tissue. However, the impact of dysfunctional stem cells might be underestimated. Human studies have found that many older individuals have one stem cell clone that dominates 20% to 80% of blood cell production. Called clonal hematopoiesis, this dominance has been associated with higher risk for blood-related diseases and early mortality from myocardial infarction or stroke. Under stress conditions, stem cells become quiescent to prevent cell death and depletion of the stem cell pool. In this state, they contain few mitochondria.
Dr. Chen uses mouse models to understand age-associated physiologic and pathologic changes and to identify aspects of those changes that might be reversible. Using a combination of biochemistry and mouse genetics, she and her colleagues have studied sirtuins, a family of proteins whose genes are repressed in aged hematopoietic stem cells (HSCs). Under mitochondrial stress, the nuclear protein SIRT7 represses NRF1 expression in the mitochondrial ribosome, leading to reduced mitochondrial biogenesis and cell proliferation. Dr. Chen and colleagues have found that mice deficient in SIRT7 show the hallmarks of HSC aging and that the stem cells in these mice undergo increased proliferation and have a higher tendency toward cell death. Dr. Chen and her colleagues also looked at SIRT3, which resides in the mitochondria and reduces oxidative stress upon activation. Although SIRT3-knockout mice initially showed no phenotype in terms of HSC number or regenerative capacity, aged SIRT3-knockout mice showed reductions in both. The stem cells in these mice also underwent increased proliferation and had an increased tendency toward cell death. SIRT2-knockout mice showed similar defects, again only with older age, but they also showed increased activation of caspase 1. Dr. Chen further found that overexpression of SIRT2, SIRT3, or SIRT7 improved the regenerative capacity of aged HSCs.
On the basis of these findings, Dr. Chen proposes that the transition of HSCs from quiescence to proliferation results in increased mitochondrial biogenesis and is associated with both mitochondrial protein folding stress and oxidative stress. SIRT3 and SIRT7 likely monitor these events and help mitochondria become quiescent, while SIRT2 inactivates caspase 1 to reduce cell death. There may be some therapeutic potential in reversing age-related dysfunction in these sirtuins.
Council discussion centered on speculation about the implications of this work for stem cell progenitors, other cellular processes, laboratory testing, and behavior.
Division of Geriatrics and Clinical Gerontology (DGCG): Beyond Sarcopenia
Dr. Stephen Kritchevsky, Professor Internal Medicine-Gerontology and Geriatric Medicine at Wake Forest Baptist Medical Center, noted Health ABC and Women's Health Initiative data showing that obesity, as reflected by elevated body mass index, is strongly related to mobility impairment and disability. In the Health ABC study, body fat as assessed by CT imaging is associated not only with decreased strength, but also with disability risk, insulin resistance, coronary calcification, inflammation, functional impairment, and difficulties in blood pressure control. Work by Beavers and colleagues has found that gains in intramuscular fat in the thigh were linked to faster losses in gait speed. How to address these issues in older adults is not clear. One hypothesis suggests that obesity is bad overall and should be addressed to improve function and alleviate metabolic risk factors. On the other hand, the sarcopenia view suggests that obesity should not be addressed in older adults, who are already at risk for lower lean muscle mass. In addition, unexpected weight loss and underweight among older persons are associated with many poor outcomes.
Mobility limitation, which is common among older adults, occurs early in the disablement process and has a large impact on independence. Slow gait predicts several adverse outcomes; a study by Studenski and colleagues indicates that a 0.1 m/s difference in gait speed translates to a 12% difference in mortality. One hypothesis suggests that mobility impairment can be alleviated by addressing sarcopenia, defined as low muscle mass with or without weakness. However, attempts to operationalize this hypothesis among community-dwelling older adults have shown that sarcopenia is not necessarily a strong predictor of physical function, and interventions targeting muscle mass have shown little benefit. In fact, Goodpaster and colleagues used computed tomography (CT) data from the Health ABC study to show that lean muscle mass declines with age and that strength declines more severely with age, but that the correlation between changes in muscle mass and strength is modest.
Dr. Kritchevsky discussed studies addressing obesity and fat in older adults. These studies have shown that intentional weight loss among overweight or obese older adults is associated with positive outcomes such as improved chair rising and stair climbing, reduced lower-extremity pain, reduced inflammation and cardiovascular risk, and slower rates of diabetes complications. Studies have also found associations between changes in fat, particularly intramuscular fat in the leg, and improvements in peak VO2, fitness, and mobility. Resistance training can be used to address weight loss–associated losses in bone mineral density, and both resistance training and increased dietary protein can be used to address declines in lean muscle mass. A large, randomized trial is needed to determine the effects of long-term intentional weight loss on cognition and dementia, fracture risk, disability, and mood and quality of life. The randomized trial could also assess whether the risks and benefits of weight loss are the same across subgroups with different morbidities and how they are affected among individuals who regain the weight they have lost.
Dr. Kritchevsky closed his presentation by referencing ongoing work exploring the relationship between various processes and the "hallmarks of physical function": structure, energy, and information processing. Council discussion focused on the connection between amyloid deposition and weight loss, the influence of age on the connection between caloric restriction and bone loss, and how to best balance the high level of adherence typically required by clinical trials and levels of adherence that might be more practical in the community.
Division of Neuroscience (DN): CNS-Draining Lymphatics in Aging and AD
Dr. Jonathan Kipnis, of the Center for Brain Immunology and Glia at the University of Virginia, presented work done in mice. He and his colleagues have identified vessels along the sinus that carry immune cells and express lymphatic vessel markers, and they have found that brain lymph drains into these vessels. Ablation of meningeal vessels abrogates drainage from the brain into the periphery, whereas ablation of nasal vessels does not. Dr. Kipnis and colleagues have also shown that lymphatic vessel function is impaired with older age, but that treatment of meningeal lymphatic vessels with VEGF165 improves not only lymphatic vessel function, but also cognitive function. Dr. Kipnis also showed unpublished work exploring the connection between lymphatic vessel dysfunction and AD pathology.
The brain does not have lymphatic vessels, which carry waste away from other tissues. However, waste is removed from the brain through the glymphatic system: cerebrospinal fluid (CSF) flows between arteries and glia, and arteries force the CSF out, creating a convective flow that removes waste products such as amyloid beta. It is not clear how waste is then removed from the CSF, and previous publications have offered several ideas, but little data.
Council discussion focused on questions about lymphatic vessel dysfunction in head injuries, the anatomy of lymphatics in the neck, the effects of exercise on lymphatics, and the specific immune cells affected by amyloid accumulation.
Division of Behavioral and Social Research (DBSR): Cognitive Loss in a Nationally Representative Sample: Trends and Differences
Dr. Eileen Crimmins described trends and differences in dementia and cognitive impairment based on HRS data. She described a 2017 paper in which Langa and colleagues noted that the prevalence of dementia has declined over the past 10 years, but she also pointed out that the meaning of this trend remains unclear. Both the absolute and relative number of years with cognitive problems, including dementia, have declined, and life expectancy with healthy cognition has increased among both men and women. Although the increase in cognitively healthy life expectancy is higher among men, their overall life expectancy remains shorter than that for women. Among both men and women, years of cognitively healthy life have increased within all education groups, but particularly among individuals with the highest level of education. Whereas no consistent decline in years with dementia has been observed among men with respect to education groups, women have shown a decline in years with dementia across all education groups, and particularly among those with the highest levels of education.
The NIA-supported Health and Retirement Study (HRS) has been ongoing since 1992. Study participants are interviewed every 2 years, and new individuals are enrolled every 6 years so that the sample remains representative of the U.S. population aged 50 years and older. Individuals are categorized as having dementia through a series of cognitive tests if they self-report or through proxy responses from relatives. HRS has defined dementia within a large population by using extensive examinations, consensus diagnoses, and statistical methods.
Dr. Crimmins noted, however, that the enhancement of good cognition over the lifespan arose from a changing educational distribution and not from changes in health. She also described work in models and cautioned that the prevention of chronic disease, while increasing health and longevity, does not necessarily reduce the likelihood of developing future dementia or the burden of dementia. In fact, models suggest that chronic disease prevention might increase the burden of dementia and that only direct treatment of dementia will reduce that burden.
In response to questions from Council members, Dr. Crimmins noted that the models assume causal connections between hypertension and dementia and between diabetes and dementia. She also noted that the models for dementia do not include the effects of slowing the rate of aging. Dr. Crimmins cautioned that the United States exhibits worse disparities in dementia by socioeconomic status, compared with other countries, and that the trends associated with education might not reflect education per se; instead, they might be related to health and wealth over the lifetime and particularly in early life. She noted large effects when the ApoE gene is included in the model, but she added that the models have not addressed genes associated with educational attainment.
The open session of the 134th meeting of the National Advisory Council on Aging adjourned at 6:10 p.m. on January 19, 2018. The next meeting is scheduled for May 22–23, 2018.
I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete.2
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)
- These minutes will be approved formally by Council at the next meeting on May 22–23, 2018, and corrections or notations will be stated in the minutes of that meeting. (Back to text)
Attachment A: Roster of the National Advisory Council on Aging
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING
HODES, RICHARD J., MD
NATIONAL INSTITUTE ON AGING
NATIONAL INSTITUTES OF HEALTH
BETHESDA, MD 20892-2292
APPLEBY, JAMES MPH
EXECUTIVE DIRECTOR AND CEO
THE GERONTOLOGICAL SOCIETY OF AMERICA
WASHINGTON, DC 20005
BENNETT, DAVID ALAN, MD
RUSH ALZHEIMER'S DISEASE CENTER
RUSH UNIVERSITY MEDICAL CENTER
CHICAGO, IL 60612
CARRILLO, MARIA C., PHD
CHIEF SCIENCE OFFICER, MEDICAL & SCIENTIFIC RELATIONS
ALZHEIMER'S ASSOCIATION NATIONAL OFFICE
CHICAGO, IL 60601
PRESIDENT AND CEO
GEOFFREY BEENE FOUNDATION
WASHINGTON, DC 20895
CRIMMINS, EILEEN M., PHD
AARP PROFESSOR OF GERONTOLOGY
ANDRUS GERONTOLOGY CENTER
DAVIS SCHOOL OF GERONTOLOGY
UNIVERSITY OF SOUTHERN CALIFORNIA
LOS ANGELES, CA 90089-0191
GOODELL, MARGARET A, PHD
PROFESSOR AND DIRECTOR
STEMS CELLS AND REGENERATIVE MEDICINE CENTER
BAYLOR COLLEGE OF MEDICINE
HOUSTON, TX 77030
HARDEN, J. TAYLOR, PHD
NATIONAL HARTFORD CENTER OF GERONTOLOGICAL NURSING EXCELLENCE
RESTON, VA 20191
HOLTZMAN, DAVID M., MD
PROFESSOR AND CHAIRMAN
ANDREW B. AND GRETCHEN P. JONES PROFESSOR AND CHAIRMAN, DEPARTMENT OF NEUROLOGY
PROFESSOR, DEPARTMENT OF DEVELOPMENTAL BIOLOGY
WASHINGTON UNIVERSITY SCHOOL OF MEDICINE
ST. LOUIS, MO 63110
KIRKLAND, JAMES L., PHD, MD
DEPARTMENT OF GENERAL INTERNAL MEDICINE
ROCHESTER, MN 55905
KRITCHEVSKY, STEPHEN B., PHD
INTERNAL MEDICINE & TRANSLATIONAL SCIENCE
DIRECTOR, STICHT CENTER FOR HEALTHY AGING AND ALZHEIMER'S PREVENTION
WAKE FOREST SCHOOL OF MEDICINE
WINSTON-SALEM, NC 27157
MOFFITT, TERRIE E., PHD
NANNERL O. KEOHANE UNIVERSITY PROFESSOR
DEPARTMENTS OF PSYCHOLOGY & NEUROSCIENCE, PSYCHIATRY AND BEHAVIORAL SCIENCES, AND CENTER FOR GENOMIC AND COMPUTATIONAL BIOLOGY DUKE UNIVERSITY
DURHAM, NC 27708
NEWMAN, ANNE B., MD
PROFESSOR DEPARTMENT OF EPIDEMIOLOGY
UNIVERSITY OF PITTSBURGH
PITTSBURGH, PA 15213
PESCHIN, SUSAN K., MHS
PRESIDENT AND CEO
ALLIANCE FOR AGING RESEARCH
WASHINGTON, DC 20006
REIMAN, ERIC MICHAEL, MD
BANNER ALZHEIMER'S INSTITUTE
PHOENIX, AZ 85006
ROSEN, CLIFFORD JAMES, MD
DIRECTOR OF CLINICAL AND TRANSLATIONAL RESEARCH
MAINE MEDICAL CENTER RESEARCH INSTITUTE
SCARBOROUGH, ME 04074
WAGERS, AMY JO, PHD
PROFESSOR DEPARTMENT OF STEM CELL
AND REGENERATIVE BIOLOGY
HARVARD UNIVERSITY MEDICAL SCHOOL
CAMBRIDGE, MA 02138
AZAR, ALEX II
THE US DEPARTMENT OF HEALTH AND HUMAN SERVICES
WASHINGTON, DC 20201
COLLINS, FRANCIS S., PHD, MD
NATIONAL INSTITUTES OF HEALTH
BETHESDA, MD 20892
IYENGAR, VIJETH, PHD
PRESIDENTIAL MANAGEMENT FELLOW (STEM)
ADMINISTRATION FOR COMMUNITY LIVING/AOA
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
WASHINGTON, DC 20005
PUGH, KENNETH G. LCDR, MC
DEPARTMENT OF MEDICINE
NATIONAL NAVAL MEDICAL CENTER
BETHESDA, MD 20889-5600
TILLY, JANE A., DRPH
SENIOR POLICY ADVISOR,
AGING ADMINSTRATION FOR COMMUNITY LIVING
CENTER FOR POLICY AND EVALUATION
WASHINGTON, DC 20001
BARR, ROBIN DPHIL
DIVISION OF EXTRAMURAL ACTIVITES
NATIONAL INSTITUTE ON AGING
BETHESDA, MD 20814
GOATE, ALISON M, PHD
PROFESSOR AND DIRECTOR
ICAHN SCHOOL OF MEDICINE
ALZHEIMER'S DISEASE RESEARCH CENTER
NEW YORK, NY 10029