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Council Minutes - May 2015

The 125th Meeting
May 12–13, 2015

CONTENTS

  1. REVIEW OF APPLICATIONS
  2. CALL TO ORDER
  3. REPORT: Task Force on Minority Aging Research
  4. REPORT: COUNCIL OF COUNCILS
  5. NACA PHYSICIAN-SCIENTIST WORKING GROUP
  6. PRELIMINARY REPORT: DGCG REVIEW
  7. REPORT: WORKING GROUP ON PROGRAM
  8. PROGRAM HIGHLIGHTS
  9. ADJOURNMENT
  10. REVIEW OF INTRAMURAL RESEARCH PROGRAM
  11. CERTIFICATION

Attachment A: Roster of the National Advisory Council on Aging
Attachment B: Director's Status Report to Council
Attachment C: May 2015 minutes in PDF format (4.7M)

The 125th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, May 12, 2015, at 3 p.m. in Building 45, Conference Room E1/E2, National Institutes of Health (NIH), Bethesda, MD. Richard J. Hodes, M.D., Director, National Institute on Aging (NIA), presided.

In accordance with the provisions of Public Law 92–463, the meeting was closed to the public on Tuesday, May 12, from 3 to 5 p.m. for the review, discussion, and evaluation of grant applications in accordance with the provisions set forth in Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code and Section 10(d) of the Public Law 92–463.1The meeting was open to the public on Wednesday, May 13, from 8 a.m. to 1 p.m.

Council Participants:

Dr. Kimberly D. Acquaviva
Dr. Maria C. Carrillo
Dr. Laura L. Carstensen
Dr. Ana M. Cuervo
Dr. Steven R. Cummings
Jennie C. Hansen
Dr. Kevin P. High
Dr. Bradley T. Hyman
Dr. James L. Kirkland
Dr. Eliezer Masliah
Dr. Richard Mayeux
Dr. Charles P. Mouton
Dr. Anne B. Newman
Dr. Thomas A. Rando
Dr. Jonathan S. Skinner

Absent Council Members:

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
Edwin L. 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. Anne Batam, Center for Scientific Review (CSR), NIH
Dr. Valerie Durrant, CSR, NIH
Dr. Samuel Edwards, CSR, NIH
Dr. Alexei Kondratyev, CSR, NIH

Members of the Public Present:

Dr. Elissa S. Epel, University of California, San Francisco
Dr. J. Taylor Harden, National Hartford Centers of Gerontological Nursing Excellence
Dr. Rose Maria Li, Rose Li and Associates, Inc.
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.

  1. 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 2838 applications requesting $4,694,179,967 for all years underwent initial review. The Council recommended 1631 awards for a total of $2,978,086,567 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.

  1. CALL TO ORDER

Dr. Hodes welcomed members to the open session of the 125th NACA meeting and called the meeting to order at 8 a.m. on Wednesday, May 13, 2015.

  1. Director’s Status Report

Dr. Hodes began his report by recognizing Richard Suzman, Ph.D., director of the Division of Behavioral and Social Research (DBSR), who passed away on April 16, 2015. Dr. Hodes noted the many articles that captured Dr. Suzman’s unique contributions and he commended the DBSR staff for maintaining Division operations while grieving. John Haaga, Ph.D., is serving as acting director for the Division and a search for a new director is under way.

In his budget update, Dr. Hodes reminded the Council that the budgets for NIH and NIA remain flat and have not recovered to pre-sequestration levels. Despite increases since the sequestration, annual budgets declined in purchasing power since 2005. In fiscal years 2013 and 2014, the percentage increase allocated to NIA was higher than that allocated to NIH overall, but the bulk of that increase reflects a substantial increase in research dollars for Alzheimer’s Disease (AD).

As the table below shows, the general payline was low this year and much lower than the payline of Alzheimer’s research. Dr. Hodes said that the lower general payline resulted from both an increase in the number of applications received by NIA and an increase in the number of NIA applications that fared well in review.

Payline: General/Alzheimer's
  <500 K: General <500 K: AD >500 K: General >500 K: AD
Payline
8
14
5
11
New Investigators (R01)
12
18
9
15
Early Stage Investigators (R01)
14
20
11
17

Dr. Hodes reminded the Council that language in the 2015 appropriations legislation requires NIH to submit an annual bypass budget for AD research. In this budget, NIH will state the resources needed to achieve the milestones detailed in The National Plan to Address Alzheimer’s Disease. With a large amount of scientific input, NIH led the development of specific milestones and related goals, objectives, and priorities. Currently, NIH is developing budget estimates and plans to submit the AD bypass budget for review by the HHS secretary in July. Although the HHS secretary and the Advisory Council on Alzheimer’s Research, Care, and Services will have opportunities to review and comment on the budget, they cannot alter it.

Dr. Hodes also reported that the NCATS Repurposing Program, which supports a range of activities to make FDA-approved drugs available for new uses, has generated preliminary data suggesting that an approved cancer therapy may also benefit AD. NIA was involved in this research. Dr. Hodes also noted the President’s Precision Medicine Initiative, which will apply sequencing and other information to precision medicine for cancer in the near term and generate a knowledge base to move precision medicine into all areas of health and disease in the long term. Part of this initiative will involve developing a national cohort of 1 million participants, along with a database and repository containing genomic data, lifestyle information, and biologic samples linked to electronic health records.

Dr. Hodes closed his report by highlighting the AD Summit, which was held on February 9–10, 2015. Several overarching themes emerged from this Summit:

  • Understanding all aspects of healthy brain aging and cognitive resilience to inform strategies for AD prevention
  • Integrative, data-driven research approaches such as systems biology and systems pharmacology
  • Computational tools and infrastructure
  • Leveraging use of wearable sensors and other mobile health technologies to analyze behaviors related to dementia progression
  • Enabling open science in basic, translational, and clinical research
  • Changing academic, publishing, and funding incentives to promote collaboration, transparency, and reproducible research
  • Investing in the development of a new translational and data science workforce
  • Engaging citizens, caregivers, and patients as equal partners in AD research

Summit recommendations have been finalized and will be presented to Council at a later date.

In response to questions from James Kirkland, Ph.D., Dr. Hodes noted the difficulty in predicting future paylines. He acknowledged concerns, among the scientific community, regarding smaller, investigator-initiated research projects, and he concurred with Dr. Kirkland’s comment that many of the greatest scientific advances have emerged from such projects. Dr. Hodes reminded the Council that NIA seeks to balance funding for smaller projects with larger, more expensive ones, while considering the need for new programs, such as those for new and early-stage investigators and differential paylines for various mechanisms.

The Council also discussed 21st Century Cures, a Congressional initiative to accelerate the process of treatment discovery, development, and delivery.

  1. Future Meeting Dates

September 16–17, 2015 (Wednesday and Thursday, Building 31)
January 19–20, 2016 (Tuesday and Wednesday, Building 31)
May 10–11, 2016 (Tuesday and Wednesday, Building 31)
September 27–28 (Tuesday and Wednesday, Building 31)

  1. Consideration of Minutes of the Last Meeting

The minutes of the January 2015 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.

  1. REPORT: TASK FORCE ON MINORITY AGING RESEARCH

Charles Mouton, M.D., summarized two presentations given to the Task Force during the previous day’s meeting. The first, by Kenneth Gibbs, Ph.D., described work exploring career interests and training experiences among recent Ph.D. graduates in science, technology, engineering, and mathematics. Through focus groups, a national survey, and in-depth interviews, Dr. Gibbs and his colleagues received 1,500 responses representing 5% of all American biomedical Ph.D. graduates and 10% of those from underrepresented minority groups. Responses indicated an overall decline in interest in faculty research careers, particularly among individuals at research-intensive institutions and particularly among underrepresented minority populations. Men cited low postdoctoral pay and difficulties in the job market and grant environment as reasons for their loss of interest, whereas women more often cited life balance and the general research climate as reasons. Despite similarities in initial interest, productivity, advisory investment, and research self-sufficiency, responses also showed disparate interest in Ph.D. completion. Dr. Gibbs and his colleagues concluded that interest in research careers was shaped both by personal values and structural dynamics and that new or revised institutional-level policies are needed to address these concerns. The second talk, given by Janet Paluh, Ph.D., focused on pluripotency and ethnic diversity in neural and cardiac stem cell tissue engineering. Dr. Paluh discussed a cluster analysis of stem cells, using international reference genotypes obtained primarily from samples of Northern European, Western European, and Middle Eastern origin. Ultimately, the analysis demonstrated how stem cells may contribute to health disparities. Dr. Paluh described the need to follow stem cells and gene expression over longer periods of time and how nanotechnology can be used to better understand such topics as neural connectivity. Following this presentation, the Task Force discussed within-group diversity in self-reported race and ethnicity, how specific single nucleotide polymorphisms in pluripotent cells might indicate differential disease expression, and the need to include a broader base of team members to enhance collaborative research.

Dr. Mouton concluded his report by noting a concept clearance reviewed by the Task Force: Aging Research on Stress and Resilience to Address Health Disparities in the United States. This concept was described further during the report from the Working Group on Program.

  1. REPORT: COUNCIL OF COUNCILS

Ana M. Cuervo. Ph.D., reported on the January 2015 meeting of the Council of Councils (CoC), which took place after the January NACA meeting. One discussion item at this meeting involved centralized non-human primate (NHP) resources supported by the Office of Research Infrastructure Programs. The Primate Centers provide infrastructure, animals, and expertise; collaborate with NIH-funded grantees; and provide a home base for researchers conducting cutting-edge science involving NHPs. The program, funded at $94 million, comprises seven large centers, six specialized centers, and specific pathogen-free colonies, employing 300 core scientists and 2,000 affiliates. Rhesus macaques represent 60% of the total NHP population at these centers. The program has supported approximately 1,000 individual projects, 30% of which focus on HIV/AIDS. Dr. Cuervo also noted that the Simian Immunodeficiency Virus could not be used as a model to produce potential AIDS vaccines had NHPs not been available.

The CoC also heard an update from Lawrence Tabak, Ph.D., principal deputy director of NIH, who discussed support for biomedical research, the biomedical research workforce, and exceptional opportunities such as the NIH BRAIN Initiative, Ebola research, and precision medicine. Dr. Cuervo highlighted Dr. Tabak’s comments concerning international changes in the biomedical workforce. For example, Dr. Tabak noted that while the U.S. biomedical workforce continues to grow, the biomedical workforce in countries such as China is growing more rapidly. In the past, China and other countries have provided many U.S. trainees. Dr. Tabak noted that the United States might not continue to have the luxury of recruiting its workforce from other countries and emphasized the need to engage more American individuals in science.

Dr. Cuervo also reported on recent activities related to the NIH Common Fund. She highlighted a task force established by the CoC to evaluate the principles and procedures in Common Fund management, assess the impact of science supported by the Common Fund, and provide recommendations to optimize the success and impact of the Common Fund. The task force has generated 47 recommendations. Dr. Cuervo highlighted some of these recommendations:

Strategic Planning
  • Engage a broad group of stakeholders to gather and shape ideas.
  • Clarify criteria for new Common Fund programs.
  • Engage Institute and Center (IC) directors and identify potential skeptics of specific proposals.
Program Management
  • Increase communication and publicity.
  • Ensure evaluation plans are developed early in the program life-cycle.
  • Familiarize everyone with the Common Fund process.
  • Establish kickoff and annual grantee meetings.
  • Include an evaluation at the midpoint of the funding term.

In response to this evaluation, the CoC now provides a second level of review to all applications for high-risk, high-reward initiatives, not just the Early Independence and Transformative Research Awards. That means that the CoC also provides second-level review for the Pioneer and New Innovator Awards. In addition, the concept clearance process has changed such that a small group of IC directors vet concepts before the CoC reviews the proposals. This allows the IC directors to give more targeted input and for clearer concepts to be presented to the CoC. Although these changes have reduced the number of concepts seen by the CoC, the concepts are better developed, allowing for richer input from the Council. In response to questions from Richard Mayeux, M.D., about the general decline in the number of individuals entering the biomedical workforce, Dr. Cuervo noted that the issues presented to the Task Force on Minority Aging Research in Dr. Gibb’s presentation highlighting decline in interest on faculty positions for URM were applicable in general. However, the CoC did not discuss issues with recruitment and retention. In response to questions from Eliezer Masliah, M.D., regarding the future of NHP centers, Dr. Cuervo pointed out that centralized NHP centers were created because NIH remains aware of the unique contribution of such research. She noted the need to ensure access to these centers and increase publicity to increase awareness.

  1. NACA PHYSICIAN-SCIENTIST WORKING GROUP

Although the number of K award applications from Ph.D.s has increased by approximately 50%, the number of applications from M.D.s and M.D./Ph.D.s has decreased. Kevin High, M.D., Chair of the Working Group updated the Council on the activities of a working group assessing reasons for decline.

The Working Group met with Dr. Sherry Mills, Director NIH Office of Science Policy and co-chair of the NIH Physician-Scientist Working Committee and discussed NIA Physician Scientist Awards. The NACA Physician-Scientist Working Group found the number of applications from physician-scientists, particularly for K08 awards, has declined from 50% of all K applications in 2002–2003 to 5% in 2012. The major reasons for this decline include uncertainty about grant-funded research careers for young physician-scientists, salaries outpacing K awards, the decreased ability of departments and institutions to fill pay gaps, and the inability to fulfill the requirement for 25% protected time. The data suggest that during the past 5 years, only half of physician-scientists receiving an R01 had a K award first. However, the average amount of time from degree to the first R01 is on average 2 years shorter with the K award than without it. Therefore, the NACA working group concludes that the K award is a strong mechanism that is underused.

Dr. High highlighted the working group’s recommendations for physician-scientists:

  • Increase the dollar amount for each K award, commensurate with covering the same percentage of salary in 2015 as was covered when the award program was first established.
  • Establish a “step-down” K award that would allow less than a 75% effort and allow physician-scientists to receive concomitant funding from other sources.
  • Foster creative ways to continue K research mechanisms, such as the K99/R00, and make them friendlier toward physician-scientists.
  • Continue expanding related mechanisms such as the Grants for Early Medical/Surgical Specialists Transition to Aging Research (GEMSSTAR) and the Paul B. Beeson Career Development Awards in Aging Research.
  • Implement periodic reporting to NACA on these funding mechanisms and their success.

The NACA working group is refining its report based on feedback from junior and senior faculty. The final recommendations will be presented at the September NACA meeting.

  1. PRELIMINARY REPORT: DGCG REVIEW

Dr. High reported on a meeting of the working group tasked with reviewing the Division of Geriatrics and Clinical Gerontology (DGCG). The reports under development by the working group emphasize five general themes:

  • Translation. The Division’s efforts toward translation should be accelerated as much as possible and collaboration across NIA Divisions should be promoted. A meeting of directors from NIA-supported centers and the development of a phenotypic dataset were specific suggestions under this theme.
  • Training. Several programs, such as the GEMSSTAR and Beeson awards, have been highly successful, not only because of the money they have granted but also because of the communities they have helped to establish. The working group suggested expanding T35 and M.D./Ph.D.-focused award mechanisms.
  • Leveraging partners by developing knitted cohorts. The working group suggests building a network that emphasizes clinical research. Such a network could include international partners and be modeled after the NIH Geroscience Group.
  • Developing additional strengths in new research paradigms. These efforts include focusing on other –omics, such as epigenomics and metabolomics; the growing partnership with the Patient-Centered Outcomes Research Institute; and increasing research based on big data and electronic medical records.
  • Review. As is the case for all applications in aging research, applications for DGCG address complex research questions and are a poor fit for traditional study sections, which focus on reductionist approaches. This is a particular problem for expensive clinical studies.
  1. REPORT: WORKING GROUP ON PROGRAM

The Working Group on Program considered one report and two concept clearances.

  1. Recommendations from Past Meetings

Dr. High briefly noted the final report from the meeting on the NIA Clinical Trials Advisory Panel. He then reported that the Working Group on Program has forwarded a motion to accept recommendations generated by the AD Summit. There were no amendments to the recommendations. The motion to accept the recommendations was seconded and passed unanimously by the Council.

  1. RFA/RFP Concept Clearances

Look AHEAD

The Look AHEAD study is a successful, randomized, controlled trial of intensive lifestyle modifications for the treatment of diabetes. The study now has an opportunity to add aging-related measures such as walking speed and functional performance. NIA is requesting approval to co-fund the aging-related components as other ICs sustain and continue Look AHEAD. The Working Group agreed that this was an enormous opportunity for aging research, in line with its recommendations to incorporate aging research components into trials supported by other ICs. Working Group members also believed that this is an exciting opportunity to understand how diabetes influences aging. The Working Group forwarded the motion that this request be approved. In response to questions from the Council, the Working Group confirmed that these components include measures of cognition. The motion to approve the request was seconded and passed unanimously by the Council.

Aging Research on Stress and Resilience to Address Health Disparities in the United States.

This initiative was developed in response to a review by the Task Force on Minority Aging Research and the finding of gaps in research related to aging-related health disparities. In 2014, the Council approved a framework to prioritize research to address health disparities in aging research and this initiative was designed to address a cross-cutting theme—stress and resilience—that appeared in this framework. The initiative will require specialized expertise and interdisciplinary collaboration, particularly in peer review. It also represents an opportunity for collaboration across the four NIA Divisions. The Working Group enthusiastically motioned that this initiative be approved. The motion was seconded and passed unanimously by the Council.

  1. Statement of Understanding

Robin Barr, D. Phil., reminded the Council that the Statement of Understanding is an agreement between NACA and NIA staff on routine business, such as small supplements or reinstatements, which can be done without Council action. A motion to renew the Statement of Understanding, with a modification removing a sentence regarding the reinstatement of funds to a grant application, was forwarded and seconded. The motion passed unanimously.

  1. Statistical Package

Dr. Barr noted two tables reflecting the number of applications received for this round and how well they fared in review.

  1. PROGRAM HIGHLIGHTS

  1. Division of Neuroscience (DN): Alpha-Synuclein as an Immunotherapy Target for AD and Synucleinopathies of the Aging

Dr. Eliezer Masliah, a new Council member, described his work exploring ways to manipulate α-synuclein to treat various aging associated neurodegenerative disorders. α-synuclein is a highly abundant amino acid molecule found in pre-synaptic terminals and plays a role in synaptic function and neurotransmission. Although initially cloned from patients with AD, it has since been associated with several other aging-associated neurodegenerative disorders. α-synuclein plays a role in accumulating proteins that damage synapses and interacts with other pathogenic proteins such as ApoE4, amyloid beta (Aβ), and tau. Approximately 75% of patients with AD display accumulations of α-synuclein in areas of the limbic system, including the amygdala. As with Aβ or tau, α-synuclein appears to drive pathogenesis by forming smaller molecular complexes, or oligomers, that lodge in neural membranes and propagate across neurons. Thus, α-synuclein may be an important therapeutic target in AD and other neurodegenerative disorders.

Dr. Masliah and his colleagues have shown that actively immunizing both younger and older transgenic mice, using CFA + α-synuclein decreases the pathogenic accumulation of α-synuclein and synaptic pathology while increasing lysosomal activity. Because of accumulating evidence that active immunization with antigens maybe problematic, the researchers also collaborated with a company to identify “Affitopes®” that mimic the immunogenicity of α-synuclein without eliciting autoimmune or nonspecific reactions. In doing so, they demonstrated that antibodies generated against these Affitopes® reduce α-synuclein accumulation and behavioral deficits in both young and aged mice. Further work showed that immunization targeting α-synuclein Affitopes® protects against the degeneration of choline and dopamine seen in mouse models that are transgenic for both α-synuclein accumulation and AD. The researchers also found that immunization targeting Aβ Affitopes® offers glutaminergic protection. These results indicate that Aβ and α-synuclein target different populations of neurons and might be modulated with different types of vaccines.

Dr. Masliah and his colleagues also have explored the use of passive immunization to target propagating α-synuclein. They found that transplanting neuronal stem cells protects against α-synuclein accumulation, as does injecting antibodies targeting various domains of α-synuclein. In addition, Dr. Masliah’s group demonstrated that single-chain antibodies against oligomers of α-synuclein and ApoB traffic at higher levels into the central nervous system, recognize propagating α-synuclein, and clear it via autophagy. Clinical trials of both active and passive immunization are under way.

Discussion focused on opportunities for collaboration and on ways to adapt Dr. Masliah’s assays for use in human studies.

  1. Division of Geriatrics and Clinical Gerontology (DGCG): Epidemiologic Insights into Human Aging

Dr. Anne Newman a new Council member described the work of her and her colleagues towards developing a physiological index of morbidity. Aging can be defined as an accumulation of damage and repair in cells, tissues, organs, and a person over time. This accumulation is universal, detrimental, and inevitable, resulting in loss of function and in vulnerability to disease. Traditional epidemiologic models have viewed disease as selective and preventable and focused on identifying modifiable targets. However, recent research on various biologic mechanisms has begun to identify an aging phenotype and develop a model with modifiable risk factors that may influence disability and vulnerability. By looking across specific causes of death, Anne Newman. M.D., and her colleagues have identified a pattern suggesting that organ systems vary in susceptibility to damage, with age. For example, cancer deaths occur earlier than cardiovascular deaths, which in turn occur earlier than dementia-associated deaths. This pattern persists even after controlling for external factors. Dr. Newman and her colleagues have used this pattern to categorize risk factors but found that age remains a strong, independent risk factor for mortality and disability.

To identify patterns and characteristics associated with longevity, Dr. Newman and her colleagues have focused on a cohort of 2,000 individuals from the Cardiovascular Health Study who lived to be 90 years or older. Although the observations suggest that human aging involves a collection of independent systems, the researchers have developed a physiologic index of comorbidity that can identify the small cohort of exceptionally healthy individuals. This index explained about 40% of age-associated mortality. To accommodate other population studies with less detailed phenotyping, Dr. Newman and colleagues have developed a healthy aging index that substitutes measures more readily available worldwide. This index allows them to assess the heritability of, and potential genetic loci associated with longer life. Both indexes link intrinsic factors and biomarkers to function, longevity, and healthy aging among unique populations.

Dr. Newman and her colleagues are conducting a meta-analysis of 19,500 study participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. The researchers are using their healthy aging index to assess frailty and model trajectories of age-associated decline.

Discussion focused on the technical aspects of Dr. Newman’s work and the applicability of the healthy aging index to animal models.

  1. Division of Aging Biology (DAB): The Epigenetics of Aging: In Search of a Definition of Cellular Age

Thomas Rando, Ph.D., Council member, discussed epigenetics and how to manipulate it with respect to tissue repair, particularly in skeletal muscle. Epigenetics is the study of cellular and physiologic trait variations that are not caused by changes in DNA sequence. Epigenetic changes are apparent, for example, in the vast differences between cell types despite them sharing the same DNA. Induced pluripotent cells, which are generated by exposing differentiated cells to factors that revert them to their pluripotent state, and fertilized eggs are other examples of epigenetic influences.

Fetuses and newborns display a remarkable regenerative capacity. Following injury, stem cells activate and proliferate, eventually differentiating into new muscle cells. This regenerative potential declines with age, partly as a result of declining function in stem cells and aged tissues. This is illustrated in mice, which show less regeneration and more scarring with older age. One study showed that when a molecule that activates the Notch signaling pathway is administered simultaneously with a small injury to muscle in an older mouse, the mouse displays a regenerative capacity similar to that seen in younger mice. This reversibility has also been shown in parabiosis experiments, in which two mice share a circulatory system. When an older mouse is paired with a younger one (heterochronic pairing), tissue repairs just as well in the older mouse as in the younger one. Similar results are seen when plasma from younger mice is transferred to older ones and in different tissues from the skin, liver, and brain. These findings suggest the presence of circulating factors that influence stem cells, and several of those factors have been identified. Dr. Rando also discussed how the events that occur at fertilization could be viewed as a form of epigenetic rejuvenation and whether there is an epigenetic signature that can reveal cellular age at the molecular level. To examine such an epigenetic signature and determine whether older cells can be epigenetically reprogrammed to a younger state, Dr. Rando and his colleagues conducted a transcriptional analysis of younger and older muscle stem cells. This analysis showed an axis of aging, with expression patterns of stem cells from heterochronic pairing falling in between those of older and younger cells. Cells from older and younger mice also showed differences in histone modifications. For example, with increasing age, differences appeared in the methylation of lysine 27 on histone 3 (H3K27me3) and in DNA methylation across the genome. With heterochronic parabiosis, older cells appeared to revert to a youthful phenotype. A clearer understanding of age-associated epigenetic states may provide insight into ways to repair muscles as they age or after injury. Dr. Rando and his colleagues also are investigating the relationship between circulatory factors that affect cell age and the health benefits of exercise. Work is under way in both mice and humans. For example, Dr. Rando’s group has found that exercise induced neurogenesis in mice and they are studying the effects of neurogenesis-associated factors when introduced into older mice. Learning, memory, and behavioral tests are also under study.

Council discussion focused on the technical aspects of Dr. Rando’s work.

  1. Division of Behavioral and Social Research (DBSR): Psychological Stress, Physiological Stress, and Cellular Aging Mechanisms

Elissa Epel, Ph.D., of the University of California—San Francisco, described her work exploring the risk between psychological stress and cellular aging, The model of allostatic load explains how the slow wear and tear of aging has a cumulative toll on regulatory systems, leading to damage. Traditionally, these phenomena have been measured as risk factors such as metabolic syndrome and stress hormone levels. However, measurement of cellular aging, which is the building block of tissue aging, may provide a more sensitive way to monitor the effects of allostatic load. Dr. Epel has focused on the telomere, a repeating DNA sequence at the ends of chromosomes. It is not fully replicated as cells divide because of the limitations of DNA polymerases and when the telomere becomes too short, the cell can become senescent and pro-inflammatory. Telomerase, which contains both a protein component and a reverse transcriptase component, adds back nucleotides to promote and rebuild the telomere. Increasing evidence suggests that telomerase is particularly sensitive to daily stress.

In a study comparing young, healthy mothers caring for children with special needs (high-stress mothers) with low-stress mothers, Dr. Epel and her colleagues found that high stress is associated with significantly shorter telomeres and higher levels of oxidative stress. This finding is consistent with several other population studies associating telomere shortening with caregiving, trauma, anxiety, lower education level, poor diet, and metal exposures. The findings also are consistent with animal studies, particularly in birds, showing associations among social isolation, telomere shortening, and mortality. In a cohort of 5,000 participants from the Health and Retirement Study, Dr. Epel and her colleagues found that the extent of childhood adversity is a strong, independent predictor of the extent of telomere shortening in older adults.

Dr. Epel and her colleagues are looking further at cellular phenotypes associated with stress. They found that chronic stress mimics chronologic age with respect to telomerase activity, particularly in CD28-negative lymphocytes, which display a senescent and pro-inflammatory phenotype. They also assessed mitochondrial health, which is driven in part by telomeres, and found that mitochondrial health is worse in high-stress women than in low-stress women with similar numbers of mitochondria. In addition, Dr. Epel and her colleagues have found that higher stress is associated with an accelerated decline in klotho, a hormone that is associated with longevity and better functioning and cognition and that normally declines with age. These studies provide cellular and molecular evidence that stress accelerates aging.

Dr. Epel closed her presentation by describing work suggesting that chronic stress, such as that associated with caregiving, is a syndrome that involves hyper-responsiveness to daily stress. She also noted ongoing work to develop validated measures of stress and partnerships with global, NIA-supported studies of aging. She pointed to cellular resistance to stress as an exciting model in aging biology, with significant opportunities for research using animal and human models. She also noted potential for future research in translational geroscience.

The Council discussed the technical aspects of Dr. Epel’s work and distinctions between threat and challenge stress.

  1. ADJOURNMENT

The open session of the 125th meeting of the National Advisory Council on Aging adjourned at 12:40 p.m. on May 13, 2015. The next meeting is scheduled for September 16–17, 2015.

  1. CERTIFICATION

I hereby certify that, to the best of my knowledge, the foregoing minutes and attachments are accurate and complete.4

 

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.

 

 

  1. 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)
  2. For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions or (b) in which a conflict of interest may have occurred. This procedure applied only to applications that were discussed individually, not to “en bloc” actions. (Back to text)
  3. For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions or (b) in which a conflict of interest may have occurred. This procedure applied only to applications that were discussed individually, not to “en bloc” actions. (Back to text)
  4. These minutes will be approved formally by Council at the next meeting on September 16–17, 2015, 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

MEMBERSHIP ROSTER
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING

CHAIRPERSON

Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
9000 Rockville Pike
Building 31, RM 5C35
Bethesda, MD 20892

COUNCIL MEMBERS

Kimberly D. Acquaviva, Ph.D., MSW (2016)
Associate Dean for Faculty Affairs
Associate Professor
School of Nursing
George Washington University
Washington, DC 20037

Maria C. Carrillo, Ph.D. (2018)
Chief Science Officer
Alzheimer’ Association
Chicago, IL 60601

Laura L. Carstensen, Ph.D. (2015)
Professor
Department of Psychology
Stanford University
Stanford, CA 94305

Ana M. Cuervo, Ph.D., M.D. (2015) (TFMAR Member)
Professor
Albert Einstein College of Medicine
Department of Development and Molecular Biology
Bronx, NY10461

Steven R. Cummings, M.D. (2017)
Professor
Department of Epidemiology & Biostatistics
University of California, San Francisco
San Francisco, CA 94107

Jennie C. Hansen, MS, RN, FAAN (2016)
Immediate Past Executive Director
American Geriatrics Society
New York, NY 10036

Kevin P. High, M.D. (2016) (WGoP Member)
Associate Dean for Clinical Research
Department of Internal Medicine
Section of Infectious Diseases
Wake Forest University School of Medicine
Winston-Salem, NC 27157

Bradley T. Hyman, M.D., Ph.D. (2016)
Professor and Director
Department of Neurology/Alzheimer’s Research
Massachusetts General Hospital
Charleston, MA 02129

James L. Kirkland, M.D., Ph.D. (2018)
Professor
Department of General Medicine
Mayo Clinic
Rochester, MN 55905

Eliezer Masliah, M.D. (2018)
Professor
Departments of Neurosciences and Pathology
University of California, San Diego
La Jolla, CA 92093

Richard Mayeux, MD, MS (2017)
Gerturde H. Sergievsky Professor of Neurology, Psychiatry, and Epidemiology
Columbia University
New York, NY 10032

Charles P. Mouton, MD, MS (2017) (TFMAR Member)
Senior Vice President for Health Affairs
Meharry Medical College
Nashville, TN 37208

Anne B. Newman, MPH, MD (2018)
Professor
Department of Epidemiology
University of Pittsburgh, PA 15213

Thomas A. Rando, MD, Ph.D. (2017)
Professor
Department of Neurology and Neurological Sciences
Stanford University School of Medicine
Stanford, CA 94304

Jonathan S. Skinner, Ph.D. (2015)
Professor of Community and Family Medicine
Dartmouth College
Department of Economics
Institute for Health Policy and Clinical
Lebanon, NH 03755

Reisa A. Sperling, MD (2017)
Professor of Neurology
Brigham and Women’s Health Hospital
Harvard Medical School
Boston, MA 02115

Debra Bailey Whitman, Ph.D. (2017)
Executive Vice President, Policy, Strategy and International Affairs
American Association of Retired Persons (AARP)
Washington, DC 20049

EX OFFICIO MEMBERS

Sylvia Mathews Burwell
Secretary
Department of Health and Human Services
Hubert H. Humphrey Building
Washington, DC 20202

Francis S. Collins, Ph.D., M.D.
Director
National Institutes of Health
Public Health Service
Building 1, Room 126
Bethesda, MD 20892

Richard M. Allman, M.D.
Chief Consultant
Geriatrics and Extended Care Services (10P4G)
Veterans Health Administration
Washington, DC 20420

Kenneth G. Pugh, LCDR, MC
Department of Medicine
National Naval Medical Center
Bethesda, MD 20889

Edwin L. Walker
Deputy Assistant Secretary for Aging
Administration on Aging
Administration for Community Living
U.S. Department of Health & Human Services
Washington, DC 20201

EXECUTIVE SECRETARY

Robin A. Barr, D.Phil.
Director, Division of Extramural Activities
National Institute on Aging
Bethesda, MD 20892