Council Minutes -- September 2018
The 135th Meeting
September 13-14, 2018
- REVIEW OF APPLICATIONS
- CALL TO ORDER
- REPORT: Task Force on Minority Aging Research
- REPORT: Working Group on Program
- PROGRAM HIGHLIGHTS
The 135th meeting of the National Advisory Council on Aging (NACA) was convened on Thursday, September 13, 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 Thursday, September 13, 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 Friday, September 14, from 8:00 a.m. to 2:15 p.m.
Mr. James Appleby
Dr. David A. Bennett
Dr. Maria Carrillo
Ms. Meryl Comer
Dr. Eileen M. Crimmins (by phone)
Dr. Alison Goate
Dr. J. Taylor Harden
Dr. David M. Holtzman (by phone)
Dr. James L. Kirkland
Dr. Stephen B. Kritchevsky
Dr. Terrie E. Moffitt
Dr. Anne B. Newman
Ms. Susan K. Peschin
Dr. Eric Michael Reiman
Dr. Clifford James Rosen
Dr. Amy Wagers
Dr. Margaret Goodell
Dr. Raynard S. Kington
Ex Officio Participants:
Dr. Vijeth Iyengar, Administration for Community Living
Dr. Jane Tilly, Administration for Community Living (by phone)
Absent Ex Officio Participants:
Dr. Alex Azar II, Department of Health and Human Services
Dr. Francis S. Collins, National Institutes of Health
LCDR 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:
Ms. Valerie Cosby, National Institute of Diabetes and Digestive and Kidney Diseases
Members of the Public Present:
Dr. Satyajit Ambika, Purdue University
Mr. Patrick Hein, Purdue University
Dr. Bruce Lamb, Indiana University
Dr. Rose Maria Li, Rose Li and Associates, Inc.
Dr. Seema Mattoo, Purdue University
Dr. Daniel Promislow, University of Washington Medicine Pathology
Dr. Elizabeth (Libby) Richards, Purdue University
Dr. Vicki Simpson, Purdue University
Dr. Elena Volpi, University of Texas Medical Branch
Dr. Jiayun Xu, Purdue University
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 1936 application requesting $4,304,229,897 for all years underwent initial review. The Council recommended 1141 awards for a total of $2,761,988,372 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.
Dr. Hodes welcomed members to the open session of the 135th NACA meeting and called the meeting to order at 8:00 a.m. on Friday, September 14, 2018.
Director's Status Report
Dr. Hodes reported that, although the outcome remains uncertain, the House and Senate have compatible budgetary language and that there is a chance that HHS will have a budget or appropriation before the beginning of the new fiscal year. Dr. Hodes noted that this would improve the Institute's ability to plan how it supports research. The proposed 2019 minibus appropriation includes $39.08 billion for NIH, an increase of $2 billion from the current fiscal year. The NIA budget would increase by more than $500 million to $3.08 billion. Of that increase, $425 million would target Alzheimer's disease (AD) and related dementias (ADRD).
With the overall budgetary increases in the current fiscal year, the paylines offered by NIA are at historic highs. Dr. Hodes reported paylines of the 23rd percentile for general applications requesting less than $500,000, the 28th percentile for AD and ADRD-related applications, a payline of 33 for general program projects, a payline of 38 for AD and ADRD-related applications, a score of 21 for general training and career development grants, and a score of 35 for AD and ADRD-related training grants. As usual, there were special considerations for new and early-stage investigators, and the paylines were slightly lower for applications requesting more than $500,000. Dr. Hodes expressed appreciation for this level of support from Congress and hoped that these levels would be maintained in FY19.
Dr. Hodes also reported that 13 Institutes and Centers (ICs) participated this year in the development of the FY20 bypass budget for AD. This budget calls for an additional $477.7 million above current levels to sustain the existing pace toward meeting the goals in the National Plan. Dr. Hodes also clarified that this sum would be in addition to the funds needed to cover the gap in the President's proposed budget, which calls for a cut of $399 million from the NIA AD/ADRD research budget. The bypass budget estimates $2.39 billion in total resources needed for Alzheimer's and Alzheimer's related dementia research for FY20.
Dr. Hodes then reported on recent events. NIA leadership participated in the Alzheimer's Association International Conference (AAIC) in Chicago and accompanied Dr. Francis Collins, NIH Director, to testify at the Congressional appropriations hearings. Dr. Hodes also noted that the 2018 NIA Directors Regional Meeting will take place on November 1 at the University of Kansas. This meeting will offer opportunities to provide outreach to nontraditional institutions and to involve them in aging research. Dr. Hodes expressed the hope that Congressional representatives would attend. The third ADRD Summit will be held in Bethesda on March 14– 15, 2019, and the Research Summit on Dementia Care will be held on March 24–25, 2020.
Dr. Hodes closed his report by announcing the appointment of two new IC Directors: Dr. Helene Langevin has joined NIH as the Director of the National Center for Complementary and Integrative Health, and Dr. Bruce Tromberg has joined as Director of the National Institute of Biomedical Imaging and Bioengineering.
In response to questions, Dr. Hodes noted the laudable efforts of NIA staff in making decisions and awarding grants under a tight timeline. He reiterated that having a budget in place before the new fiscal year would allow NIA to disburse awards in a timelier manner. Dr. Hodes also noted the high level of bipartisan support for NIH, which has led to the recent budgetary increases and helped to sustain a healthy research environment.
Future Meeting Dates
- 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 May 2018 meeting were considered. A motion to approve the minutes was made, seconded, and passed unanimously to approve the minutes.
Comments from Retiring Council Members
Dr. Hodes recognized four retiring members: Drs. Maria Carillo, Raynard Kington, James Kirkland, and Anne Newman. Dr. Kington was absent from the meeting.
Dr. Maria Carrillo noted that serving on the Council had been a great opportunity and honor. She commended the NIA leadership and staff on their hard work and their careful planning of how AD dollars are disbursed. Dr. Carrillo noted that this is an historic moment in funding of and support for research into aging, AD, and ADRD, and she highlighted the privilege of serving on the Council and of being a part of that moment.
Dr. James Kirkland echoed Dr. Carrillo's comments and noted that he had learned a lot while serving on the Council. He noted the remarkable transformation in the field of aging over recent years and pointed out that this has attracted many talented trainees and new investigators The best and the brightest are now interested in geriatrics and in research on the basic biology of aging and neurocognitive disorders. Thus, Dr. Kirkland cautioned that the additional dollars NIA receives for research on AD and ADRD will be used quickly. He further indicated that investigators are also moving into the field because it has reached the point of developing interventions that can delay or prevent whole groups of age-related diseases (rather than merely one disease at a time).
Dr. Anne Newman expressed appreciation for the opportunity to work with the excellent staff at NIA, to help address important issues, and to learn about the importance of advocating for the participation of older adults in clinical trials. She noted that those opportunities, which have included reviewing AD programs and the Division of Geriatrics and Clinical Gerontology (DGCG), have given her a multifaceted perspective of NIA. Like Dr. Carrillo, Dr. Newman viewed Council as engaging in a partnership with NIA. She noted the energy, creativity, and enthusiasm shown by NIA leadership and staff in making optimal use of increased AD funding, including co-funding research at other ICs that has heightened interest across the NIH to focus on AD-relevant research. Dr. Newman closed her remarks by noting that aging processes are changing over time, suggesting that the knowledge gained from previous aging populations in the United States will not necessarily apply exactly to present and future populations as they age.
Dr. Carrillo began by thanking Dr. Carl Hill for his work with the Task Force and Dr. J. Taylor Harden for agreeing to serve as Task Force Chair after Dr. Carrillo leaves the Council. Dr. Carrillo then reported on the two presentations that the Task Force heard the day before. The first, from Dr. Marie Bernard, NIA Deputy Director, focused on steps taken by NIH to implement 21st Century Cures Act requirements regarding the age of participants in clinical research. In response to such requirements, NIH convened a workshop on Inclusion Across the Lifespan on June 1–2, 2017 to explore challenges and barriers to including children and older adults in clinical studies. NIH also has conducted a baseline analysis on participants' ages in NIH-supported studies (including in pediatrics). As noted by Dr. Bernard, the analysis revealed that many trials excluded older participants. About 27% of the studies had arbitrary upper-age limits, and many studies also had indirect exclusion criteria, such as comorbidities or polypharmacy, that exclude older adults. Consequently, the study populations in these trials may not represent the corresponding real-world disease populations. NIH formed four working groups focused on study populations, ethical issues, study design, and data collection and reporting. It then issued a request for information (RFI) on inclusion across the lifespan. These efforts resulted in a revision of NIH policy, such that applicants are now required to submit a plan for inclusion of individuals across the lifespan, or a justification for any age-based exclusion.
The second presentation, by Dr. Hector Gonzalez, of the University of California, San Diego, focused on a research framework for resolving Latino ADRD disparities. Dr. Gonzalez noted the growing Latino population in the United States and the unique issues this population faces. For example, although Latino individuals have a 3-year longer life expectancy at birth, a disproportionate number of them will be affected by dementia and comorbidities (e.g., cardiovascular disease). Some studies, such as WHI-CAP and SALSA, have reported differences in prevalence of dementia. However, such differences also appear within the Latino population, reflecting this population's heterogeneity. In addition, some studies, including one conducted by Kaiser Permanente, have excluded uninsured individuals, suggesting that Latino individuals may be underrepresented in administrative cohorts. Dr. Gonzalez presented data from the Hispanic Community Health Study/Study of Latinos (SOL), which showed distinctions between comorbidity trajectories among mainland and island Latino populations. He also presented preliminary data from the SOL-Investigation of Neurocognitive Aging (INCA), which includes 6,500 individuals from the initial SOL study.
Dr. Carrillo reported that AAIC held a health disparities panel featuring R03-funded early investigators, as well as sessions on inclusion, the National Recruiting Strategy, and the R24 (PAR-18-749) funding opportunity related to Examining Diversity, Recruitment and Retention in Aging Research. She also noted participation by the Gerontological Society of America (GSA) in an NIA workshop on recruitment and retention, an NIA symposium on health disparities and the social determinants of health and aging, and in the NIA Health Disparities Research Network.
She reported that Washington University (Principal Investigator: Dr. John Morris) has received an R13 grant from NIA to host a workshop on African American participation in AD research, for which the Alzheimer's Association provided 11 travel scholarships. Dr. Carrillo closed her presentation by noting the increased awareness of the need for diversity.
In response to questions from the Council, Dr. Bernard noted that, as of January 25, 2019, any grant application submitted must address the ages of study participants, and funded investigators must include information in their progress reports about the age, sex/gender, race, and ethnicity of study participants at the time of enrollment. She also noted that the 21st Century Cures Act mandates that study participation be reported by disease category based on sex/ gender, race, and ethnicity. Dr. Bernard noted related efforts by other organizations, such as the American Geriatrics Society, which plans to publish a special issue or articles about inclusion across the lifespan, and GSA, which has held a workshop on inclusion across the lifespan. Dr. Susan Peschin referenced a similar meeting that occurred between the U.S. Food and Drug Administration (FDA) and the American Society of Clinical Oncology. She suggested that NIA work with FDA and with the European Medicines Agency, which has developed a related strategy for geriatric medicine.
Dr. Eileen Crimmins reported that the Working Group was not presented with any funding opportunity concepts during this cycle.
Review of the Division of Neuroscience (DN)
Dr. Eric Reiman reported that the Working Group had heard preliminary findings and recommendations from the initial review of DN, presented by Dr. Reisa Sperling. The review panel congratulated DN for the extraordinary progress, productivity, and responsiveness of the Division in advancing work in AD. The review panel also noted the substantial impact that Dr. Eliezer Masliah, Division Director, has had on productivity, communication, and morale in the division.
The review panel issued the following recommendations:
- Increase staff strategically to advance the Division's goals.
- Identify opportunities to leverage support for research on normal brain aging to help advance knowledge of AD.
- Identify additional opportunities to attract and retain trainees as well as new and senior investigators from other fields.
- Increase awareness among potential applicants of increased funding support.
- When possible, review grant applications that are close to a fundable score and allow applicants to strengthen those applications to qualify for funding approval.
- Increase the diversity of researchers, not only with respect to background, but also with respect to areas of expertise.
- Dramatically improve the value of existing cohorts and other studies, for example by identifying ways to embed more AD-association biomarkers.
- Develop more scalable and less invasive biomarkers for AD, as well as for comorbidities and other conditions, and develop the infrastructure to support such efforts.
- Incorporate expertise in mobile technologies within the Division to advance its overall agenda.
The review panel also commended NIA in general on the partnerships it has formed with other agencies and the number of funding opportunity announcements (FOAs) it has generated to advance its priorities. The panel suggested that NIA continue to identify ways to balance directed FOAs with other strategies for supporting research. It also suggested continued efforts to increase diversity among the research workforce and in study participation.
A formal report will be presented to the Council at its January 2019 meeting.
National Recruitment Strategy for Participation in ADRD Studies
Ms. Melissa McGowan, NIA Office of Communications and Public Liaison (OCPL), discussed the National Recruitment Strategy for Participation in ADRD Studies, an initiative NIA has undertaken in partnership with the Alzheimer's Association. This initiative has brought together researchers, academic experts, and federal officials to explore challenges in clinical trials recruitment and to identify ways to expand the study participant pool and ensure that it is inclusive. The National Strategy initiative includes working groups focused on three components:
- Increasing awareness and engagement at the national level.
- Expanding capacity and diversity at the site level.
- Collective efforts at the community and local levels to enhance diverse enrollment.
The working groups presented their ideas and strategies to the public for comment: hundreds of comments were received (including 240 additional ideas) from more than 1,000 participants. A document incorporating these and the working groups' ideas is currently in the final stages of review. The National Strategy is expected to launch at the National Alzheimer's Project Act Advisory Council meeting in October.
Another part of the National Strategy involves R24 Resource Related Research Projects FOA (PAR-18-749) directed by Dr. Cerise Elliott (DN) to develop the science of clinical trials recruitment. In addition, NIA is developing a recruitment repository, an online database of resources to enhance study recruitment. NIA sees the National Strategy as an ongoing, iterative process and expects to incorporate new and better-tested strategies as they are developed.
Outreach in Promoting AD and ADRD Funding Opportunities
Dr. Dawn Beraud, of the NIA Office of the Director, summarized outreach efforts to increase awareness about the many FOAs issued by NIA. The OCPL has developed several web pages to inform the community, websites to aggregate information about all AD- and ADRD-focused FOAs, and blogs to promote discussion of specific FOAs as they are launched. NIA also has an FOA email list that sends information periodically and has developed a presence on social media to draw attention to these FOAs. OCPL also has worked to raise awareness about an NIA pilot program that has proven popular with other NIH Institutes, Centers, and Offices (ICOs) to award AD or ADRD supplements to non-AD-associated grants. Other efforts include meetings with advocacy groups and professional societies, that share NIA's communications with their stakeholders. Within the past 2 years, NIA also has more than doubled its support for other ICs: in 2017, NIA provided almost $58 million to other ICs to fund meritorious applications relevant to NIA priorities. Dr. Beraud noted the efforts of each Division to increase awareness among researchers about various FOAs (e.g., many program staff have attended meetings and workshops to promote various opportunities).
Strategic Directions for 2019
Ms. Kate Nagy, NIA Office of Planning, Analysis, and Evaluation (OPAE), noted that the NIA Strategic Directions document needed updating, particularly to incorporate requirements from the 21st Century Cures Act. NIA has been developing its new strategic plan since April. OPAE is part of a trans-NIH effort to develop a common template for strategic plans. As part of this effort, it has surveyed researchers about how they use the NIA Strategic Plan and is currently conducting an internal analysis of FOAs and new program projects awarded since the release of the previous Strategic Plan. It is also currently interviewing Division Directors and staff for their perspectives. Ms. Nagy reported that the Institute's scientific goals and objectives have not changed much since the 2014–2015 Strategic Plan. She also noted the need for increased visibility of AD and ADRD within the new document, and in a way that does not conflict with the National Plan. The NIA will release an RFI in November to seek feedback from the scientific community and the public, and to present an update at the meeting of the Gerontological Society of America. OPAE expects to revise the Strategic Plan through April, make a final presentation to the Council at its May 2019 meeting, and release the final document on June 15, 2019. In response to questions from the Council during the closed session on September 13, Ms. Nagy noted that the Council will have opportunities to be involved before the presentation of the document in May 2019.
Dr. Barr reported that the Institute has seen considerable growth in the number of applications submitted to NIA, more than 50% of which are focused on AD and ADRD. NIA has also received a substantial number of applications in response to its FOAs: approximately 500 applications were received for the August round. Thus, the growth reflects a combination of increases in investigator-initiated applications and applications submitted in response to directed initiatives. Dr. Barr also noted that many of the new applications face difficulties in review, primarily because of insufficient preliminary data. NIA is therefore identifying ways to help investigators obtain more preliminary data before submitting R01 applications.
Division of Neuroscience (DN): New In Vivo Models for AD: Update from the MODEL-AD Consortium
Dr. Bruce Lamb, of Indiana University, discussed the Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease (MODEL-AD) Consortium. Despite the many insights gained about the pathology of AD, many clinical trials, which have focused primarily on anti-amyloid and anti-tau therapies, have ended in failure. Possible explanations for such failures include the targeted disease stage, the mechanism of therapy delivery, the suitability of the patient population, and the therapeutic target. Yet another is the face and construct validity of the animal models used in preclinical studies. Many of these models are maintained on different genetic backgrounds (making it difficult to understand their biology) and tend to be based on large transgenes. Most are mice, and most are focused on mechanisms underlying early-onset AD. In addition, legal restrictions make it difficult for investigators to obtain animal models to conduct new and reproduce previous work. Thus, there is no way to explore the reproducibility of findings with respect to biomarkers relevant to humans. Several recommendations from the 2015 AD Summit focused on animal models (particularly on next-generation models), standardization and scientific rigor, translatable biomarkers, and rigorous preclinical testing.
The MODEL-AD Consortium is an initiative to expand animal model resources for basic research and preclinical testing of candidate therapeutics. The initiative is undertaking the challenge of modeling late-onset disease, which is more diverse in terms of genetics and comorbidities than is early onset Alzheimer's Disease. Overall goals include using CRISPR to generate new mouse models, piloting rat models, deep phenotyping and high-capacity screening of all models, aligning mouse and human phenotypes, and preclinical testing of the most promising models and therapeutics.
MODEL-AD encompasses three cores. The Bioinformatics and Data Management Core (BDMC) uses information from existing resources to identify and prioritize genes and variants for further development. BDMC is systematically assessing genes and variants across several biologic mechanisms, including lipid homeostasis, synaptic signaling, immunity, and mitochondrial function. The Disease Modeling Project (DMP) has generated several models, including two humanized APPmodels, a new ApoE allelic series, a model combining ApoE variants with the TREM2 R47H variant, and a human tau knock-in mouse model. Dr. Lamb reviewed the DMP's efforts to assess how closely these model phenotypes mimic human late- onset AD and how reproducible findings have been across sites. The Preclinical Testing Core (PTC) triages the most promising models with the help of the Consortium's Steering Committee and Advisory Board and uses these models to explore up to two therapies per year. Its primary screen for efficacy focuses on pharmacokinetics and translational pharmacodynamics. The PTC has developed standard operating procedures for its screening process—procedures and data will be available at SAGE Synapse—and a web-based portal to help the Consortium prioritize therapies.
All models, data, genetics, phenotypes, and preclinical findings will be available to investigators without restrictions. Members of the MODEL-AD Consortium have made presentations at a meeting hosted by the Alzheimer's Association and a symposium at the Society for Neuroscience conference. Future directions include funding supplements to explore genetic diversity among existing models, developing rat models of late-onset AD, and interacting with NIA-supported Alzheimer's Disease Centers for discovery of new therapeutics.
Questions from the Council focused on technical aspects of MODEL-AD's work.
Division of Geriatrics and Clinical Gerontology (DGCG): Identifying Therapeutic Targets of Sarcopenia
Dr. Elena Volpi, of the University of Texas Medical Branch, described work exploring the metabolic control of muscle mass as a way to assess the balance between muscle growth and atrophy and identify potential therapeutic targets for sarcopenia. She explained that muscle homeostasis is controlled by balance between muscle protein synthesis (muscle growth) and degradation (muscle atrophy). This balance is controlled first by nutritive factors: nutrition activates protein synthesis and growth, whereas starvation induces atrophy. The balance is also controlled by exercise: exercise stimulates growth, whereas inactivity leads to atrophy.
In younger adults, the net balance of muscle protein fluctuates daily. During rest, the net balance is negative, and the muscle releases amino acids for the rest of the body to use. When food is introduced, the net balance becomes positive, and the muscle can replenish the amino acids that have been lost. If the younger adult exercises during the fasting period, the balance might improve, but it never becomes positive. If that exercise is followed by feeding, particularly with a protein meal, the synergy between exercise and feeding promotes muscle protein synthesis and accumulation. Although studies have found no evidence of alterations in net protein balance in healthy, independent older adults, they do show a significant increase in mechanistic target of rapamycin (mTOR) phosphorylation. In addition, unlike younger adults, who show significant increases in muscle protein synthesis in response to a meal, older adults show no such increases. Additional work has shown two mechanisms that promote muscle growth: direct stimulation of mTOR signaling by dietary protein, and indirect stimulation by carbohydrates via vasodilation within the muscle. Infusion of insulin alone increases muscle protein synthesis and blood flow in younger adults, but superphysiologic doses of insulin are needed to induce these increases in healthy older adults, indicating that muscles are resistant to the anabolic effects of insulin even in nondiabetic older adults. Amino acid dose appears to be important. Dr. Volpi reported that a dose corresponding to 15 g of high-quality protein increases protein synthesis in younger, but not in older, adults. An increased dose of protein can stimulate protein synthesis in older adults, but there is also a maximum effective dose. Anabolic resistance to amino acids, even at larger doses, increases when older adults are placed on bed rest for seven days. This resistance is associated with reduced expression of amino acid transporters. Thus, endothelial function, amino acid transport, and mTOR signaling are key regulators of skeletal muscle protein anabolism and therefore are potential therapeutic targets for sarcopenia.
The administration of essential amino acids, which hyperactivates mTOR1C (a protein complex associated with mTOR) signaling, may be one way to target these elements. The addition of excess amino acids leads to the recovery of normal muscle responses to resistance training among healthy, older adults. However, in an interventional study among older adults, amino acid supplementation not only had no significant effect on total lean mass; it also appeared to increase total fat mass. Aerobic exercise can restore vasodilation and the anabolic response to insulin in older adults, and aerobic exercise before a meal can restore the muscle response to feeding. In the interventional study, aerobic exercise led to significant loss in fat mass, and this exercise combined with amino acid supplementation increased walk speed and leg strength. This and other interventions may be particularly helpful among malnourished and/or frail older adults.
Council discussion focused on speculations regarding caloric restriction interventions, sex and gender differences, research on general functional impairment, and the timing of protein meals.
Division of Behavioral and Social Research (DBSR): Studying Aging in Young People: An Opportunity for Prevention
Council Member, Dr. Terrie Moffitt, Duke University, introduced Council to the Dunedin Multidisciplinary Health and Development Study (The Dunedin Study). The prevailing model of aging and disease has evolved. Historically, the prevailing model has proposed that age-related diseases begin late in life, leading to frailty and death. An alternative model suggests that diseases of older age have their origins in the earliest periods of life; this model has sparked a surge of research on genetic effects and childhood risk factors, but has not yet specified the causal pathway or intervening variables. A more innovative model posits that risk factors from early life accelerate aging during the third, fourth, fifth, and sixth decades of life.
The study enrolled more than 1,000 babies born in 1972 and 1973 in Dunedin, New Zealand. This cohort has undergone 14 assessments, the latest occurring when participants were 38 years old. Data collection is currently under way for participants who are now 45 years old. With support from NIA, Dr. Moffit and colleagues have added age-related assessments to the study and have therefore been able to measure several age-related constructs even in younger patients. They have found that brain health at age 3 can predict gerontologic measures at age 45. They also have modeled the pace of aging, based on biomarkers across several systems, and found that the pace of aging can be measured in younger adults and can predict physical limitations, cognitive decline, and facial aging. In addition, Dr. Moffitt and her colleagues have reported how other aging measures, such as epigenetic clocks, are related to their pace-of-aging model. Future opportunities for such work include randomized controlled trials to measure the pace of aging and predict outcomes; basic science studies on individual differences among healthy younger adults; and studies to identify which demographics are most in need of anti-aging prevention and which are most likely to respond to anti-aging interventions.
In response to questions from Council, Dr. Moffitt reported that most of her research group's analyses control for socioeconomic status. However, they have looked at associations between brain health and family social class, and have reported that study participants who began life in a lower social class show negative effects on their health, even if they have subsequently moved into a higher social class. Dr. Moffitt also noted the substantial amount of cooperation from colleagues and the public in New Zealand, at all levels, to help minimize study attrition.
Division of Aging Biology (DAB): Geroscience and the Dog Aging Project: Can Old Dogs Teach Us New Tricks?
Dr. Daniel Promislow, of the University of Washington Medicine Pathology, discussed the Dog Aging Project. The field of geroscience is built on three broad questions: (1) why organisms age, (2) why variations exist within a population, and (3) what, if anything, can be done about it. The foundation of understanding variation depends largely on an understanding of both genetic and environmental variation. Dogs can serve as a model of aging for several reasons. Aging and lifespan vary across breeds. There is a large amount of genetic variation underlying phenotypes such as size or behavior, and genetic variation has been used to map age-related diseases in dogs. Dogs also experience environmental variation, as dog owners are diverse and live across various socioeconomic levels. Dogs experience the same spectrum of diseases that humans do. However, their shorter lifespan allows researchers to learn about these diseases in a more compressed timeframe. In addition, the health care system for dogs is second only to that for humans. However, although there has been veterinary interest in biomarkers, typical veterinary studies have had small sample sizes.
The Dog Aging Project includes four separate subprojects. The first will identify measures to aid in defining healthy aging among dogs. The second will identify genetic factors that shape aging and age-related diseases. The third will explore mechanisms tying genotype to phenotype and identify biomarkers of healthy aging. The fourth will be an interventional study to assess the use of rapamycin to increase left ventricular heart function and general health span in aging dogs. The Dog Aging Project also has four organizational cores: an administrative core, a data core, a recruitment and retention core, and a core focused on collecting environmental data. The Project will enroll 10,000 dogs of all breeds and sizes. Within that sample will be a precision cohort of 1,200 dogs, for which systems biology and -omics data will be collected. Overlapping the precision cohort will be an intervention cohort for the rapamycin study. In-depth assessments, including targeted DNA sequencing, clinical chemistry, epigenomics, metabolomics, activity monitoring, and a survey of owners will be carried out for a subset of especially old dogs. The Dog Aging Project will engage owners as data collectors, using surveys and a smartphone app. Data will be made available not only to researchers, but also to the general public. The Dog Aging Project team has engaged with several human cohort studies, and it welcomes ancillary studies. Infrastructure for the project is under development, and recruitment is expected to begin in early 2019.
Council discussion focused on how dog owners would be engaged as data collectors (e.g., what can be learned in terms of social class, particularly with dogs as sentinels for human diseases?), and on the power of dog genetics in studying aging and variation. Dr. Promislow also referred to the Golden Retriever Lifetime Study (which was established in 2013) and the opportunities it has presented in building this research community.
The open session of the 135th meeting of the National Advisory Council on Aging adjourned at 12:45 p.m. on September 14, 2018. The next meeting is scheduled for January 29-30, 2019.
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 January 29-30, 2019, and corrections or notations will be stated in the minutes of that meeting. (Back to text)
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING
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
DIRECTOR 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 EMERITUS DIRECTOR
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 MAYO CLINIC
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 MAIN MEDICAL CENTER RESEARCH INSTITITE
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