Council Minutes -- January 2017
The 130th Meeting
January 17–18, 2017
- REVIEW OF APPLICATIONS
- CALL TO ORDER
- REPORT: TASK FORCE ON MINORITY AGING RESEARCH
- REPORT: WORKING GROUP ON PROGRAM
- COUNCIL SPEAKER: TOWARD PRECISION HEALTH FOR ALL: THE ALL OF US RESEARCH PROGRAM
- PROGRAM HIGHLIGHTS
- INTRAMURAL PROGRAM REPORT
The 130th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, January 17, 2017, at 3:00 p.m. in Building 31, Conference Room 10, National Institutes of Health (NIH), Bethesda, Maryland. Dr. Marie Bernard, Deputy Director, National Institute on Aging (NIA), presided.
In accordance with the provisions of Public Law 92–463, the meeting was closed to the public on Tuesday, January 17, from 3:00 p.m. to 5:00 p.m. for the review, discussion, and evaluation of grant applications in accordance with the provisions set forth in Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code and Section 10(d) of the Public Law 92–463.1The meeting was open to the public on Wednesday, January 18, from 8:00 a.m. to 1:00 p.m.
Dr. Maria Carrillo
Dr. Eileen M. Crimmins
Dr. Steven R. Cummings
Dr. Raynard S. Kington
Dr. James L. Kirkland
Dr. Richard Mayeux
Dr. Terrie E. Moffitt
Dr. Charles P. Mouton
Dr. Anne B. Newman
Dr. Thomas A. Rando
Dr. Norman E. Sharpless
Dr. Reisa A. Sperling
Dr. Debra Bailey Whitman
Ex Officio Participants:
Dr. Richard M. Allman, Veterans Health Administration
Dr. Jane Tilly, Administration for Community Living
Absent Ex Officio Participants:
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:
Dr. Aurea Denise De Sousa, Center for Scientific Review (CSR), NIH
Dr. Eric Dishman, All of Us Research Program, Office of the Director (OD), NIH
Dr. Vijeth Iyengar, Administration for Community Living
Dr. Luci Roberts, OD, NIH
Dr. Elyse Schauwecker, CSR
Dr. Afia Sultana, CSR
Members of the Public Present:
Ms. Patricia D'Antonio, Gerontological Society of America
Dr. David A. Bennett, Rush University Medical Center
Mr. Ryne Carney, Alliance for Aging Research
Dr. Malene Hansen, Sanford-Burnham-Prebys Medical Discovery Institute
Dr. J. Taylor Harden, National Hartford Center of Gerontological Nursing Excellence
Dr. David M. Holtzman, Washington University of St. Louis
Mr. Todd Kluss, Gerontological Society of America
Dr. Stephen B. Kritchevsky, Wake Forest School of Medicine
Dr. Kenneth Langa, Ann Arbor VA HSR&D and University of Michigan
Dr. Rose Maria Li, Rose Li and Associates, Inc.
Dr. Frances McFarland, Rose Li and Associates, Inc.
Ms. Susan K. Peschin, Alliance for Aging Research
REVIEW OF APPLICATIONS
This portion of the meeting was closed to the public, in accordance with the determination that it concerned matters exempt from mandatory disclosure under Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix).
A total of 1207 applications requesting $2,228,143,640 for all years underwent initial review. The Council recommended 671 awards for a total of $1,429,158,117 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. Bernard welcomed members to the open session of the 130th NACA meeting and called the meeting to order at 8:00 a.m. on Wednesday, January 18, 2017.
Director’s Status Report
Dr. Bernard opened the meeting by passing on regards from Dr. Richard Hodes, NIA Director, who was attending the World Economic Forum in Davos, Switzerland.
Dr. Bernard reported that the federal government is operating under a continuing resolution through April 28 and that President Obama had proposed an FY2017 budget that was equal to FY2016 in nominal terms. She reminded the Council that under continuing resolutions, the NIA usually spends up to 90 percent of what had been authorized for the previous year. However, she also noted that allocations will depend on the incoming administration.
The continuing resolution contains funding authorized by Congress through the 21st Century Cures Act, which Congress passed in November (House) and December (Senate) and President Obama signed into law on December 13, 2016. Funding for the Act will be drawn from the Prevention Fund and the Strategic Oil Fund and will vary from year to year. The 21st Century Cures Act:
- Provides funding for several ongoing initiatives, including the Precision Medicine Initiative (PMI), the Beau Biden Cancer Initiative (formerly the Cancer Moonshot Initiative), the Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) initiative, and the Regenerative Medicine Initiative.
- Raises the NIH Loan Repayment Program cap from $35,000 to $50,000.
- Relieves administrative burdens by exempting NIH from the Paperwork Reduction Act and from restrictions on conference travel.
- Requires the Office of Management and Budget (OMB) to establish a Research Policy Board to review regulations across federal science agencies, HHS to review financial conflicts of interest, and NIH to reduce burdens related to subcontracts within grants.
- Addresses data access and privacy by exempting certain genomic information from Freedom of Information Act requests, requiring the issuance of certificates of confidentiality, enhancing protections, and authorizing the NIH Director to require funding recipients to share data.
Dr. Bernard further reported that the 21st Century Cures Act requires that NIH ensure the inclusion of women, children, and racial and ethnic minorities in clinical research; improve research related to sex and gender minority populations; and assemble data on women, minorities, and age in clinical study populations. In anticipation of this legislation, an Inclusion Governance Committee has been assessing these issues, for example by analyzing the inclusion of older adults in Phase III clinical trials of conditions affecting that population. The provision on inclusion requires the NIH Director to convene a workshop on appropriate age groups, within 180 days of the Act being signed into law, and to update policies as appropriate. The workshop, co-chaired by Dr. Samir Sauma, Director of NIA's Office of Planning, Analysis, and Evaluation, will likely take place on June 1–2, 2017, at Natcher Conference Center. It will focus on the impact of exclusion, issues in study design, ethical considerations, the types of expertise needed, NIH reporting, and the intersection of age with other demographic variables. Dr. Bernard added that NIH is interested in the barriers that scientists face in including these populations and opportunities for enhancement of future research.
A Legislation Implementation Working Group consisting of representatives from Offices within the Office of the Director (OD) and the Institutes and Centers (ICs) is reviewing the statute and will provide final plans to the NIH Director.
Dr. Bernard then presented updates from NIA, NIH, and HHS. She noted that three NIA-supported findings—an association between income and life expectancy, effects of cranberry capsules on bacteruria plus pyuria among older women in nursing homes, and sex and race differences in the association between statin use and the incidence of Alzheimer's disease (AD)—were among the most talked-about articles in JAMA and JAMA Neurology. She also noted changes in clinical trials policy, including a requirement for good clinical practice training for all personnel involved in a clinical trial, the establishment of funding opportunity announcements (FOAs) specific to clinical trials, a new provision for a single institutional review board (IRB) to review projects with multiple sites in the United States, and a requirement that trials be registered with ClinicalTrials.gov within 21 days of the first enrollment and deposit of study results at ClinicalTrials.gov. Dr. Bernard noted that all the concepts cleared by NACA in anticipation of FY2017 have become FOAs and that concept approvals will be posted on the NIA website immediately following Council meetings. She noted that the Third AD Research Summit will be held on March 1–2, 2018, and that the AD Care and Services Research Summit will be held on October 16–17, 2017, both on the NIH campus. Dr. Bernard closed her presentation by noting the President-Elect's nominations of Representative Tom Price, MD, for HHS Secretary and Ms. Seema Verma for Director of the Centers for Medicare and Medicaid Services.
Dr. Bernard, Dr. Robin Barr, and NIA Division Directors introduced several new staff. Dr. Barr also announced that Priscilla Garner, Council Manager, will take a new job as a grants specialist and that Diane Zwinak will assume the role of Council Manager.
Future Meeting Dates
May 16–17, 2017 (Tuesday and Wednesday, Building 31)
September 26–27, 2017 (Tuesday and Wednesday, Building 31)
January 23–24, 2018 (Tuesday and Wednesday, location TBD)
May 22–23, 2018 (Tuesday and Wednesday, location TBD)
September 19–20, 2018 (Tuesday and Wednesday, location TBD)
Consideration of Minutes of the Last Meeting
The minutes of the September 2016 meeting were considered. A motion was made, seconded, and passed to approve the minutes.
REPORT: TASK FORCE ON MINORITY AGING RESEARCH
Dr. Maria Carrillo reported that the Task Force on Minority Aging Research heard two presentations. The first, given by Dr. Deborah Guadalupe Duran, Chief of the Office of Strategic Planning, Legislation, and Science Policy at the National Institute on Minority Health and Health Disparities (NIMHD), focused on minority health and health disparities research across NIH and on changes in definitions and reporting rules. At first glance, research on minority health and health disparities totals about $2.8 billion across all ICs. However, there has been no official definition of minority health or health disparities. In addition, examination of ongoing clinical trials has revealed that these studies have reached the required goals for inclusion but have not conducted analyses on these subpopulations. When these factors are considered, NIH invests approximately $500 million in minority health research and $500 million in health disparities research.
NIH now defines "minority health" as distinct health characteristics and attributes of racial or ethnic groups that are socially disadvantaged and subject to potential discriminatory acts. Research in minority health aims to increase understanding of health outcomes among groups that typically have been underrepresented in biomedical research. These groups are described by OMB. "Health disparities" are defined as health differences that adversely affect disadvantaged populations, and research in health disparities focuses on developing interventions to reduce or eliminate these disparities. Dr. Duran noted that the two terms are linked but represent different aspects of minority health. Although most principal investigators (PIs) now understand the difference, more education is needed. NIMHD has also created a registry that lists health disparities research by IC. So far 16 (of 27) ICs have contributed information on 104 diseases and conditions.
The second presentation, given by Dr. Thomas Obisesan of Howard University, focused on cardiovascular disease (CVD) risk factors and dementia and AD. Dr. Obisesan noted that AD rates are higher among African American and Hispanic individuals and that the rate of occurrence for the ApoE4 allele is higher among these populations. However, he also noted that the risk associated with that allele is lower than that in Caucasians. Dr. Obisesan has focused his research on CVD risk factors that might influence the higher AD rates. He reported that a small, 6-month exercise trial among African American patients with mild cognitive impairment (MCI) found no differences in cognition between those assigned to aerobic exercise and those assigned to stretching exercises. Although both groups showed decline in magnetic resonance image brain volume, the decline was less severe among the aerobics group. In addition, more changes in gene expression were apparent in the aerobics group. A larger trial is needed to explore these differences further. Dr. Obisesan also noted the support he had received from NIA and the importance of that support in his career.
Dr. Carillo closed her report by reminding Council members about an FOA supporting administrative supplements for research on sexual and gender minority populations. She also encouraged the Council to spread the word about the Butler-Williams Scholars program.
In response to questions about the emphasis on age categories in the 21st Century Cures Act, Dr. Carillo reported that Dr. Duran had discussed plans focused on the intersection between minority health and health disparities research and the AD National Plan. There has been some focus on the inclusion of subjects across the lifespan and on the issue of the impact of inclusion or exclusion of older adults on underrepresented minorities. Some analyses are under way, and opportunities for improved reporting exist. This intersectionality will also be a point of discussion at the June workshop.
REPORT: WORKING GROUP ON PROGRAM
Clinical Trials Advisory Panel (CTAP)
Dr. Robin Barr reported that CTAP reviewed a proposal for a trial investigating valid approaches to reduce infections and secondary hospitalizations among residents in nursing homes. Although a CTAP subcommittee noted that the proposal focused on an important topic, it believed that the proposal needed more development. The subcommittee recommended that the proposal be revised and resubmitted with additional preliminary data. CTAP concurred with this recommendation.
RFA/RFP Concept Clearances
The Working Group reviewed seven concept proposals. A motion to approve these concepts en bloc was forwarded and seconded. The motion passed unanimously.
Novel Mechanisms of Non-Cell-Autonomous Signaling in Aging and Longevity
This concept proposes a set-aside to support research examining mediators, tissues of origin, cellular effects, and common mechanisms among secreted factors that might drive the biology of aging. The Working Group supported this concept unanimously.
Development and Commercial Availability for Cell-based Tests for Changes in Resiliencies to Aging-Related Physical Stressors
This concept calls for applications from small companies or academic institutions working with those companies to develop cell- or biospecimen-based assays of the ability to respond to perturbations. Such assays would be useful as measures in clinical trials or in assessing responses to interventions. The Working Group supported this concept and endorsed it unanimously, but some members expressed concern that the applicant pool might be too small.
Competitive Renewal of AMP AD Targets Discovery and Preclinical Validation Project
This concept aims to enhance the Accelerating Medicines Partnership (AMP)-AD target discovery program by shortening the intervals between discovery; genomic, proteomic, or metabolomic findings; and identification of therapeutic targets. AMP AD has postmortem tissue and has conducted genomic sequencing, but additional time is needed for annotation and combination with additional datasets. The Working Group enthusiastically supported the concept.
Characteristics, Causes, Context, and Consequences of Elder Mistreatment
This concept will support new research and team science on elder abuse. The concept is based on the premise that such research will advance more rapidly if experts in elder health are brought together with those in child health and focus both on victims and perpetrators of such abuse. The Working Group believed this concept is important because it addresses sections of the NIA plan focused on maintaining the dignity, rights, and safety of older persons with AD.
Socioeconomic Disparities in Health at Older Ages
The goal of this concept, which builds on a 2016 workshop, is to focus on the influence of income, educational attainment, and geographic region on health disparities among older adults. The Working Group unanimously endorsed this concept.
Coordinating Center for the Claude D. Pepper Older American Independence Centers
The concept supports competition for a new coordinating center for the Pepper Centers. A coordinating center has been funded for the past 10 years, but that funding will end in 2018. Support from the concept will continue the current functions of the coordinating center while adding techniques to enhance data sharing, an interactive Web interface, and support for trainees. The Council unanimously approved this concept.
HIV and Aging
This concept supports a set-aside for research on HIV and aging. Patients with HIV are aging, and by 2020 approximately half of patients with HIV will be older than 50 years. In addition, evidence suggests HIV infection as a model for accelerated aging, and treatments for HIV have increased patients' risk for CVD and neurodegenerative diseases. The Council unanimously approved this concept.
- External Program Review
Dr. Richard Mayeux reported on a review by a committee charged with assessing internal and external interactions at NIA and with addressing new opportunities and challenges posed by trends in biomedical research and advances in aging research. The committee noted considerable strengths, including outstanding leadership, increased funding for AD research, and the development of joint projects. However, the group also identified weaknesses, including a small workforce , a grants coding system that hampers collaboration among Divisions, limited external communication with respect to paylines, and limited communication across Divisions. The committee thus recommended that NIA:
- Consider phenotypic harmonization for existing and future cohorts.
- Establish discussions on translation across all Divisions and with the Intramural Program.
- Increase collaboration.
- Establish cross-Division officers.
- Increase crosstalk with other stakeholders in aging and AD, such as the Centers for Medicare and Medicaid Services, the Patient-Centered Outcomes Research Institute, and medical foundations.
- Inform stakeholders in the lay community about NIA efforts and their impact on older adults.
- Increase research training in aging.
- Reconsider funding constraints placed on the Geroscience Initiative.
- Continue to develop portfolios relevant to aging and health and have well-trained individuals work with NIA staff.
- Work with the Center for Scientific Review to develop a review mechanism for transdisciplinary sciences.
COUNCIL SPEAKER: TOWARD PRECISION HEALTH FOR ALL: THE ALL OF US RESEARCH PROGRAM
Dr. Eric Dishman, Director of the All of Us Research Program, provided an overview of the Precision Medicine Initiative (PMI). The mission is to accelerate scientific discovery and breakthroughs in precision medicine by building a national resource of clinical, environmental, lifestyle, and genetic data from one million participants. Participants will consent to provide data on a longitudinal basis. A major priority of PMI is to reflect the broad diversity in age, race and ethnicity, gender, socioeconomic status, geography, and health status in the United States. Other priorities include building the tools and capabilities needed to enable researchers, ranging from citizen scientists to premier academic research laboratories, to access data and biospecimens and conduct ancillary studies to make discoveries. The core values of the initiative focus on broad participation, reflecting diversity, earning trust, opening access to data and information, and serving as a catalyst for innovative research programs and policies. For these reasons, PMI has been renamed the All of Us Research Program.
Dr. Dishman noted two primary methods for recruitment—direct volunteers and a nationwide network of health provider organizations—and briefly described the four major building blocks of All of Us: a data and research support center, a biobank, a participant technology center, and health care providers. The protocol will include an electronic, interactive consent process, with separate opt-in procedures for some survey modules. Survey modules will include participant-provided information, such as contact and sociodemographic information, personal habits, and personal health history; a simple physical evaluation and biospecimen collection; electronic health record data; and genetic information. All of Us plans to conduct several pilots that will inform secondary analyses, ancillary studies, and newer platform versions. Recruiting of more than one million participants will likely take 3.5 to 4 years.
Dr. Dishman reported that all major building blocks of the program are on target, that the awardee network has been constructed, and that the protocol was submitted to the program's IRB in December 2016. The program has also completed workshops to target partners and develop a plan for community outreach, and it has delivered and tested its new name, content, and brand. Development of the enrollment website, 800 number, smartphone apps, and data center is almost complete. Security systems and information technology interfaces for data and sample transfer are undergoing testing. Construction of the biobank is under way, with a target capacity of 35 million vials.
Dr. Dishman also reported that All of Us will conduct workshops with ICs in fall 2017 to explore research questions and resources of interest. Specifically, the workshops will focus on questions and measures that constitute near-term, low-hanging fruit; mid-term questions requiring additional work in selecting among measures and instruments; and questions that would be ripe for a program of this magnitude in the long-term.
In response to questions from the Council, Dr. Dishman noted that All of Us is talking with its partners about participant burden with respect to participation in other research and clinical studies. Recruiting will initially focus on participants aged 18 years and older, although plans are under way to add children and cognitively impaired individuals. Dr. Dishman also noted that All of Us is keeping its recruitment separate from that for other large-scale facilities, such as Department of Veterans Affairs (VA) facilities, to ensure its ability to protect its data.
Division of Aging Biology (DAB): Cellular Recycling: Role of Autophagy in Aging Disease
Dr. Malene Hansen, of the Sanford-Burnham-Prebys Medical Discovery Institute, described work in her laboratory to investigate the link between autophagy and longevity in C. elegans, using germline removal as a model for longevity. In autophagy, the cell sequesters cargo such as damaged organelles or old or aggregated proteins into double membrane-bound structures called autophagosomes. These structures then fuse with acidic lysosomes, where cargo is degraded and material recycled. Induced by stresses to the cell, autophagy is a complex process that is conserved across organisms. Autophagy has been linked to aging and several age-related diseases. In addition, conserved longevity pathways extend lifespan partly by boosting autophagy.
In worms carrying mutations in glp-1 and thus no germline, lifespan is extended and autophagic events are increased in the intestine. Increased autophagy is required for lifespan extension, as illustrated by a reduction in lifespan when autophagy genes are inhibited in glp-1 germline-less animals. Additional work has shown that the transcription factor HLH-30, a worm ortholog to TFEB (a known positive regulator of autophagy), localizes to the nucleus in glp-1 mutants, suggesting that HLH-30 regulates the increased gene expression seen with boosted autophagy. This evidence, along with similar lines of evidence in other laboratories, demonstrates increased autophagy as an emerging gero-protective mechanism.
Dr. Hansen's laboratory has also found several post-translational and transcriptional regulators of autophagy in C. elegans and mammalian cells. They are also looking for age-related cargo and have identified the lysosomal lipase LIPL-4 as an important component in lifespan. In addition, Dr. Hansen's laboratory is assessing the tissue requirements for autophagy to ensure longevity. Dr. Hansen described an unpublished study using two longer-lifespan mutants to examine spatial and temporal regulation of autophagy.
Council discussion focused on technical aspects and potential implications of Dr. Hansen's work.
- Division of Behavioral and Social Research (DBSR): A Comparison of the Prevalence of Dementia in the United States in 2000 and 2012
Dr. Kenneth Langa, of the Ann Arbor VA and the University of Michigan, discussed work, recently published in JAMA Internal Medicine, that has used data from the Health and Retirement Study (HRS) to assess changes in dementia prevalence between 2000 and 2012. Dementia is defined as at least two cognitive impairments that are severe enough to interfere with one's ability to function in usual activities but cannot be explained by delirium or a psychiatric disorder. Each year, dementia costs approximately $50,000 per case and $200 billion nationally, and it represents a major impact on families, with almost 50 percent of patients receiving primarily informal care. AD accounts for 60 to 70 percent of cases, whereas vascular dementia accounts for 20 to 30 percent of cases, and other causes account for approximately 10 percent of cases. Mixed dementia, in which AD overlaps with vascular pathology, is likely the most common cause of dementia, particularly in the oldest of older patients. Several cardiovascular risk factors, including hypertension, high cholesterol, and diabetes, have been implicated in dementia, and for a given level of AD pathology in the brain, an individual is more likely to have clinically significant dementia if he or she has a higher number of vascular lesions. Although the prevalence of obesity, diabetes, and hypertension has increased over the past 20 years, treatment has become more widespread and intensive, leading to decline in diabetic and cardiovascular complications. In addition, literacy and the proportion of 30- to 34-year-olds with college degrees has risen steadily, and more adults now reaching older age have had significantly more formal schooling early in life. Education appears to be protective against dementia.
This study specifically tracked brain health and collected information on protective and risk factors, and included a substudy—the Aging, Demographics, and Memory Study (ADAMS)—that conducted more in-depth neuropsychological assessments. Dr. Langa and colleagues have found that the prevalence of dementia declined from 11.6 percent of the HRS sample in 2000 to 8.8 percent in 2012. Declines in prevalence were significant across all age ranges among adults aged 65 years and older. This trend coincided with a slight increase in education and net worth. However, even after data were adjusted for age and net worth, African Americans and Hispanics were more likely to be diagnosed with dementia. After data were adjusted for cardiovascular risk and obesity, stroke and diabetes still appeared to increase the risk for dementia.
These findings are consistent with those of other population-based studies except for the Chicago Health and Aging Project, which did not find a significant change in dementia prevalence. Dr. Langa also noted the challenges in tracking dementia, including a "fuzzy" and drifting definition of dementia and changes in survey response rates, diagnostic coding in administrative data, and threshold of entry into nursing homes. He also noted a recent paper by Dr. Crimmins, who reported that the life expectancy at age 65 among patients with dementia dropped by 3.3 percentage points between 2000 and 2010.
Council discussion focused on additional considerations, including trends for dementia and stroke, the impact of extreme differences in access to and quality of education during the Jim Crow era, and autopsy series showing AD pathology and vascular disease in individuals who were clinically normal.
- Division of Neuroscience (DN): Understanding the Relationships between Sleep, Protein Aggregation, and Alzheimer's Disease
Dr. David Holtzman, of the Washington University at St. Louis, described work examining modifiers of these processes. The current model of AD brain pathology states that neurofibrillary tangles in the neuron lead to dystrophic neurites, the formation of amyloid plaques through amyloid beta (Ab) aggregation, and hyperphosphorylation of the tau protein. This pathology appears years before the onset symptoms: Ab aggregation can be seen 15 years beforehand, and the spread of hyperphosphorylated tau is apparent 5 years before.
Synaptic activity itself appears to drive accumulation of the Ab peptide in the brain. Amyloid deposition appears first in the default mode network, which is most active when individuals are not performing specific cognitive tasks. Regions of endogenous Ab levels correlate with regions of neuronal activity and predict the level of amyloid depositions. Moreover, Dr. Holtzman and his colleagues have found that Ab levels fluctuate with the sleep-wake cycle, with the highest levels appearing during periods of wakefulness. Administration of orexin, which promotes wakefulness, enhances increases in Ab levels, whereas administration of an orexin receptor antagonist attenuates this increase. Likewise, sleep deprivation markedly increases amyloid plaques in PS1/APPswe transgenic mice, but manipulations that cause these mice to sleep more result in less amyloid deposition. Amyloid deposition is also less apparent in mice deficient in orexin. Overexpression of orexin in the hippocampus of orexin-deficient mice has no effect on amyloid accumulation, but restoration of orexin in a small region of the hypothalamus restores amyloid pathology.
Dr. Holtzman also described preliminary work in mice with designer receptors exclusively activated by designer drugs (DREADDs) to rule out confounding factors in sleep-cycle manipulations. He discussed work in mice showing that amyloid deposition increases with age and increases wakefulness and that vaccination with Ab prevents amyloid deposition and attenuates poor sleep. Dr. Holtzman also described work showing that, among patients with normal cognition, sleep quality was worse among those with amyloid deposition. He noted another study showing that amyloid deposition disrupts non-REM sleep and that this disruption is associated with poor memory. Thus, Dr. Holtzman and his colleagues have identified a bidirectional relationship between Ab and the sleep-wake cycle. Similar findings have been observed in animals and patients with tauopathies.
Council discussion focused on additional research questions that Dr. Holtzman might consider, as well as implications for patients with Lewy bodies disorder.
INTRAMURAL PROGRAM REPORT
Laboratory of Clinical Investigation (LCI)
Dr. Richard Spencer, of the Magnetic Resonance Imaging and Spectroscopy Section (MRISS), described the Section's work dissecting magnetic resonance (MR) signal, using a Bayesian analysis approach, to detect different macromolecules. This approach has been used to map differences in brain myelination patterns among younger subjects, older subjects with no cognitive problems, and subjects with MCI. MRISS has also applied this approach to examine water pools associated with collagen and proteoglycans in cartilage and to map proteoglycan decreases seen with osteoarthritis.
Dr. Spencer also described recent work using the spectroscopic capabilities of MR to identify a correlation between the recovery rate of mitochondrial function and walking performance and to show that it is mediated by muscle strength. Dr. Spencer discussed collaborative work assessing the development of fatty liver, and reversal of fatty liver by leptin, in a mouse model with lipoatrophy and subcutaneous tissue inaccessible to fat. Imaging and spectroscopy have also been used to look at the human thigh, stroke in a rat model, and cardiac and respiratory-gated flash edema in mice.
Another LCI Section uses an integrated approach to study metabolic function, glucose homeostasis, and aging. Examples include studies of GLP-1 as a target for diabetes treatment and of peripheral endocannabinoid activity as a treatment for alcoholic liver disease, fatty liver, lipoatrophy, and specific causes of obesity. Other LCI Sections have developed techniques to identify a major ketamine metabolite that is essential for the antidepressant effects of ketamine and have used an interdisciplinary, translational approach to determine the clinical effectiveness of controlled alterations in dietary N-6 and N-3 fatty acids.
Council discussion focused on technical aspects of myelin mapping and how it compares with diffuse tensor imaging.
- Laboratory of Cardiovascular Sciences (LCS)
Dr. Edward Lakatta focused his presentation on the sinoatrial node (SAN) and SAN disease. Although SAN disease is the most common indication for implantation of a permanent pacemaker, the pacemaker treats only the symptoms. In addition, on the basis of data from the Baltimore Longitudinal Study of Aging, peak heart rate declines with age even in apparently healthy volunteers. This is consistent with an animal study showing that, even in longer-lived mice, SAN cell volume and the ability of the SAN to respond to sympathetic stimulation declines with age.
Dr. Lakatta discussed work examining the "calcium clock" in SAN cells and ventricular myocytes. He showed that the rhythmicity of this clock arises from the synchronization of oscillatory refractory periods and that links between the calcium clock and the action potential cycle, or "membrane clock," serve as brakes on the calcium clock. With age, the spontaneous beating rate and calcium transient amplitude decline, the expression of some proteins involved in calcium cycling is altered, the amount of calcium released is reduced, and the rhythmicity of the calcium clock declines. Dr. Lakatta concluded that the deterioration of mechanisms in SAN cells (and in ventricular myocytes) underlie age-associated deterioration in the initiation and execution of a heartbeat. He called for more study of clock molecules to identify ways to delay or prevent the transition from SAN decline to clinical disease.
Council discussion focused on potential sex differences in SAN decline and the potential translational implications of the LCS model.
The open session of the 130th meeting of the National Advisory Council on Aging adjourned at 1:00 p.m. on January 18, 2017. The next meeting is scheduled for May 16–17, 2017.
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)
- These minutes will be approved formally by Council at the next meeting on January 17-18, 2017, 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
CARRILLO, MARIA C, PHD
CHIEF SCIENCE OFFICER, MEDICAL & SCIENTIFIC RELATIONS
CHICAGO, IL 60601
CRIMMINS, EILEEN M, PHD
AARP PROFESSOR OF GERONTOLOGY
ANDRUS GERONTOLOGY CENTER
DAVIS SCHOOL OF GERONTOLOGY
UNIVERSITY OF SOUTHERN CALIFORNIA
LOS ANGELES, CA 90089-0191
CUMMINGS, STEVEN RON, MD
SAN FRANCISCO COORDINATING CENTER
SAN FRANCISCO, CA 94158-2549
KINGTON, RAYNARD S., PHD, MD, MBA
PRESIDENT AND PROFESSOR
GRINNELL, IA 50112
KIRKLAND, JAMES L., PHD, MD
DEPARTMENT OF GENERAL INTERNAL MEDICINE
ROCHESTER, MN 55905
MAYEUX, RICHARD P, MD
SERGIEVSKY PROFESSOR AND CHAIRMAN, DEPT OF NEUROLOGY
NEW YORK, NY 10032
MOFFITT, TERRIE E, PHD
NANNERL O. KEOHANE UNIVERSITY PROFESSOR
DEPARTMENTS OF PSYCHOLOGY & NEUROSCIENCE, PSYCHIATRY AND BEHAVIORAL SCIENCES, AND CENTER FOR GENOMIC AND COMPUTATIONAL BIOLOGY
DURHAM, NC 27708
MOUTON, CHARLES P., MD
DEPARTMENT OF FAMILY MEDICINE
MEHARRY MEDICAL COLLEGE
NASHVILLE, TN 37208
NEWMAN, ANNE B, MD
DEPARTMENT OF EPIDEMIOLOGY
UNIVERSITY OF PITTSBURGH
PITTSBURGH, PA 15213
RANDO, THOMAS A., MD, PHD
DEPARTMENT OF NEUROLOGY AND NEUROLOGICAL SCIENCES
STANFORD UNIVERSITY SCHOOL OF MEDICINE
STANFORD, CA 94304-5235
SHARPLESS, NORMAN E, MD
LINEBERGER COMPREHENSIVE CANCER CENTER
SCHOOL OF MEDICINE
UNIVERSITY OF NORTH CAROLINA
CHAPEL HILL, NC 27599
SPERLING, REISA A., MD
PROFESSOR OF NEUROLOGY
HARVARD MEDICAL SCHOOL
CENTER FOR ALZHEIMER RESEARCH & TREATMENT
MEMORY DISORDERS UNIT
BRIGHAM AND WOMEN'S HOSPITAL
BOSTON, MA 02115
WHITMAN, DEBRA BAILEY, PHD
EXECUTIVE VICE PRESIDENT, POLICY, RESEARCH, AND INTERNATIONAL
WASHINGTON, DC 20049
BENNETT, DAVID ALAN MD, MD
ALZHEIMER'S DISEASE CENTER
RUSH UNIVERSITY MEDICAL CENTER
CHICAGO, IL 60612
HARDEN, J TAYLOR, PHD
NATIONAL HARTFORD CENTER OF GERONTOLOGIC
NURSING EXCELLENCE COORDINATING CENTER
WASHINGTON, DC 20005
HOLTZMAN, DAVID M., MD
PROFESSOR AND CHAIRMAN
PROFESSOR, DEPARTMENT OF DEVELOPMENTAL BIOLOGY
ALZHEIMER'S DISEASE RESEARCH CENTER
MEMBER, HOPE CENTER FOR NEUROLOGICAL DISORDERS
WASHINGTON UNIVERSITY SCHOOL OF MEDICINE
ST. LOUIS, MO 63110
KRITCHEVSKY, STEPHEN B., PHD
STRICHT CENTER ON AGING
DEPARTMENT OF INTERNAL MEDICINE
WAKE FOREST UNIVERSITY
WINSTON-SALEM, NC 27157
PESCHIN, SUSAN K MHS
PRESIDENT AND CEO
ALLIANCE FOR AGING RESEARCH
WASHINGTON, DC 20006
BARR, ROBIN, PHD
OFFICE OF EXTRAMURAL ACTIVITIES
NATIONAL INSTITUTE ON AGING
BETHESDA, MD 20814
ALLMAN, RICHARD M., MD
GERIATRICS AND EXTENDED CARE SERVICES
DEPARTMENT OF VETERANS AFFAIRS
WASHINGTON, DC 22150
BURWELL, SYLVIA M.
DEPARTMENT OF HEALTH AND HUMAN SERVICES
WASHINGTON, DC 20201
COLLINS, FRANCIS S., MD, PHD
NATIONAL INSTITUTES OF HEALTH
BETHESDA, MD 20892
HODES, RICHARD J., MD
NATIONAL INSTITUTE ON AGING
NATIONAL INSTITUTES OF HEALTH
BETHESDA, MD 20892-2292
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.
DEPARTMENT OF MEDICINE
NATIONAL NAVAL MEDICAL CENTER
BETHESDA, MD 20889-5600
TILLY, JANE A, DRPH
SENIOR POLICY ADVISOR, AGING
ADMINISTRATION FOR COMMUNITY LIVING/
AOA CENTER FOR POLICY AND EVALUATION
WASHINGTON, DC 20001
TILLY, JANE A, DRPH
AGING PROGRAM SERVICES SPECIALIST
TEAM LEADER, BRAIN HEALTH AND DEMENTIA
OFFICE OF SUPPORTIVE AND CAREGIVER SERVICES
ADMINISTRATION FOR COMMUNITY LIVING/ADMINISTRATION ON AGING
WASHINGTON, DC 20001