The 119th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, June 4, 2013, at 3 p.m. in Building 31, Conference Room 10, National Institutes of Health, 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, June 4, from 3 to 5 p.m. for the review, discussion, and evaluation of grant applications in accordance with the provisions set forth in Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code and Section 10(d) of the Public Law 92–463. 1 The meeting was open to the public on Wednesday, June 5, from 8 a.m. to 1 p.m.
Dr. Norman Anderson
Dr. Laura Carstensen
Dr. Ana Maria Cuervo
Dr. Richard Morimoto
Dr. Eliseo Perez-Stable
Mr. Daniel P. Perry
Dr. Ronald C. Petersen
Dr. Arlan G. Richardson
Dr. Jonathan Skinner
Dr. Stephanie Studenski
Dr. Terrie F. Wetle
Dr. Robert Califf
Dr. Dennis Choi
Dr. Hugh C. Hendrie
Dr. James F. Burris, Department of Veterans Affairs
Dr. Jon Fuller, Department of Veterans Affairs
Robert Hornyak, Administration on Aging
Dr. Kenneth G. Pugh, National Naval Medical Center
Edwin Walker, Administration on Aging
James Wren, Administration on Aging
The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as attachment A.
Judy Dulovich, Office of Human Resources (OHR), Office of the Director (OD), NIH
Dr. Rene Etcheberrigaray, Center for Scientific Review (CSR), NIH
Michelle Hazel-Cannon, OD, NIH
Stephanie Joseph, Food and Drug Administration
Dr. Yuan Luo, CSR, NIH
Caroline McCullough, OHR, OD, NIH
Dr. Michelle Washko, Administration for Community Living
Dr. Kimberly Acquaviva, George Washington University (Membership to NACA pending)
Dr. Marilyn Albert, Johns Hopkins University School of Medicine
James Appleby, Gerontological Society of America
Kay Farley, National Center for State Courts
Jennie Hansen, American Geriatrics Society (Membership to NACA pending)
Dr. J. Taylor Harden, Gerontological Society of America
Linda Harootyan, Gerontological Society of America
Dr. Kevin High, Wake Forest University School of Medicine (Membership to NACA pending)
Dr. Michael Hurd, RAND Corporation
Dr. Brad Hyman, Massachusetts General Hospital (Membership to NACA pending)
Dr. Rose Maria Li, Rose Li and Associates, Inc.
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Dr. Karen Mowrer, Association of Independent Research Institutes
Sue Peschin, Alliance for Aging Research
Michelle Rodrigues, SRI International
Dr. Amy J. Wagers, Harvard University Medical School
Dr. Jeremy Walston, Johns Hopkins University School of Medicine
This portion of the meeting was closed to the public, in accordance with the determination that it concerned matters exempt from mandatory disclosure under Sections 552(b)(c)(4) and 552(b)(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix).2
A total of 1449 applications requesting $499,175,556 for all years underwent initial review. The Council recommended 773 awards for a total of $289,190,354 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 119th NACA meeting and called the meeting to order at 8:00 a.m. on Wednesday, June 5, 2013.
Dr. Hodes began his report by announcing the retirement of Steven Snyder, Ph.D., who served NIA as the deputy director of neuroscience. Dr. Hodes acknowledged Dr. Snyder as a force in the neuroscience community and expressed appreciation for Dr. Snyder’s intelligence, mentorship, dedication, commitment, and humility.
Dr. Hodes noted that since the end of the NIH budget doubling in 2003, NIH has seen a 20% reduction in purchasing power, including this year’s sequester. The President’s budget request for FY 2014 seeks to support innovative research by providing $31 billion to NIH, including the fulfillment of the Administration’s commitment to Alzheimer’s Disease (AD) research. However, this budget was submitted before the reductions due to the sequester. Thus, if the President’s budget is enacted, the overall appropriation to NIH would mark a substantial increase, and most Institutes and Centers (ICs) would see funding levels equal to or slightly above those in FY 2012. The allocation to NIA’s base (long-term) budget would include the additional $80 million targeting AD research.
Planning for the $80 million investment in AD research began in 2012, based on recommendations from the May 2012 AD Research Summit and on expectations of the additional monies in the NIA budget. As a result, several requests for applications (RFAs) were issued, including one supporting interdisciplinary approaches to the identification and validation of novel therapeutic targets, an AD therapeutics program, an AD prevention trials program, and a Phase I clinical trial. Although the promised funds did not materialize, Francis Collins, M.D., Ph.D., NIH director, allocated $40 million from a discretionary fund to support these initiatives, at least in part. Applications for these initiatives are under review. Dr. Hodes also noted two papers published in 2013: a JAMA paper reporting a genotype strongly associated with increased risk for late-onset AD among African American adults and a New England Journal of Medicine paper reporting the annual monetary costs attributed to dementia (see below).
In response to questions from Ronald Petersen, M.D., Ph.D., Dr. Hodes noted that in light of continuing uncertainty regarding the $80 million AD investment, NIA will use its best judgment in determining how to fund out-years for the AD applications under review. Commitment to funding for all years might be considered for projects that appear to be at lowest risk for non-completion, whereas year-by-year funding might be applied for those at higher risk.
In 2012, the success rate was 17.6% for NIH overall and 15.5% for NIA. With respect to the distribution of success rates, NIA continues to fall in the middle, along with institutes it often partners with, such as the National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Heart, Lung, and Blood Institute; and the National Cancer Institute. Even with the sequester, paylines for 2013 will be what they were in 2012.
Dr. Hodes also reported on federal efforts to centralize coordination of science, technology, engineering, and mathematics (STEM) education programs to eliminate or minimize duplications and inefficiencies in kindergarten through 12th grade (K-12) programs. As a result, funding of new K-12 programs at NIH has been paused. Dr. Hodes and Robin Barr, D.Phil., noted that NIA is not directly affected by these changes. However, they pointed out that the NIH Office of Science Education has been affected, as have programs supported by the National Institute of General Medical Sciences. Dr. Hodes added that Council members’ institutions might be affected by these changes.
Dr. Hodes closed his report by noting a new NIA blog  (http://www.nia.nih.gov/research/blog ) for researchers and by announcing a Summit on Advances in Gerosciences, which will be held Oct. 30–31, 2013. He noted that the Geroscience Initiative, which now includes 20 ICs, has held several workshops and issued its first funding announcements.
Several new NIA staff were introduced:
Sept. 17–18, 2013 (Tuesday and Wednesday)
Feb. 25–26, 2014 (Tuesday and Wednesday)
May 20–21, 2014 (Tuesday and Wednesday)
Sept. 16–17, 2014 (Tuesday and Wednesday)
Dr. Robin Barr noted that because of the later meeting date in June, NIA will likely request an expedited review of applications.
The minutes of the January 2013 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.
Eliseo Perez-Stable, M.D., reported that the Task Force had heard a presentation by Roy Wilson, M.D., deputy director for strategic scientific planning and program coordination at the National Institute on Minority Health and Health Disparities (NIMHD), on the Building Infrastructure Leading to Diversity initiative (BUILD). Funded by the NIH Common Fund, this initiative aims to create a network of mentors and, ultimately, to increase the number of underrepresented minorities who pursue doctoral degrees in biomedical research. Applications submitted for planning grants will be reviewed in July 2013 and awards will be made in September. Larger grants will be funded in 2014. BUILD will include a separate evaluation process, which could include a 10- to 20-year plan to examine outcomes and impact.
The Task Force also heard a presentation by Keren Witkin, Ph.D., from the NIH Office of Science Policy Analysis on the Women of Color Research Network, a social network site that potentially could create an informal mentoring network and link to the BUILD initiative. Dr. Perez-Stable emphasized that one does not have to be a woman or of color to participate in this network.
Dr. Perez-Stable reminded the Council that the Task Force had reviewed the health disparities and minority aging research and training activities at NIA. This review examined 10 years of data provided by the NIA Office of Planning, Analysis, and Evaluation, and it identified 985 grants with at least 10% of effort dedicated to health disparities research or diversity training. Dr. Perez-Stable highlighted several recommendations:
The final report is available for distribution and review.
A motion to accept the report and make these recommendations to NIA was forwarded and seconded. During discussion, Dr. Perez-Stable clarified that the definition of “health disparities” cited in the report was taken from the Centers for Disease Control and Prevention and was cited only as an example. However, the Task Force intended that the definition used in its review and recommendations would be broader and more inclusive. Thus efforts to address these recommendations could align with the HHS action plan for reducing health disparities. Marie Bernard, M.D., NIA deputy director, added that a public law has mandated how health disparities should be defined as NIMHD leads the NIH-wide strategic plan to address health disparities. Both she and Dr. Perez-Stable suggested that representatives from NIMHD be invited to speak at a future Council meeting.
The motion passed unanimously.
Terrie Wetle, Ph.D., provided highlights from the May 14, 2013 Council of Councils (CoC) meeting, which included:
CoC also heard a presentation on the NIH Director’s Pioneer Awards program, one of the first initiatives of the NIH Roadmap. Intended to support high-risk, visionary research through a new application and review model, the Pioneer Awards program has been cited as an example of successful government innovation, as several awardees have done extraordinary work and created new fields of research. However, it has not been clear whether this program is better at identifying and supporting high-impact and innovative research, compared with traditional funding models or the Howard Hughes Medical Institute (HHMI) model. Thus a formal evaluation by a panel of experts was undertaken that compared Pioneer awardees with matched R01 investigators (i.e., at a similar career stage and at similar institutions in terms of available resources), funding-matched R01s (i.e., at the same funding level during the period of time examined), Pioneer Award finalists who were not selected for funding, and HHMI investigators. The analyses showed that the Pioneer Awards had a similar level of impact and innovation to that seen with HHMI awards. With respect to bibliometric impact, Pioneer awardees performed the same as or better than matched R01s, better than Pioneer Award finalists, and similarly to HHMI investigators in most areas. Thus, the evaluation concluded that the Pioneer Awards program is successful in identifying investigators who are likely to conduct innovative, high-impact work.
Discussion focused on the Pioneer Awards evaluation, which focused on the program’s ability to identify investigators who are likely to make an impact. Richard Morimoto, Ph.D., described his experiences on a review panel for these awards. He noted that these panels did not put undue emphasis on the reputation of the investigators but rather focused on the proposed project and whether it represented a new direction or needed a setting different from the traditional R01 mechanism. Thus, the Pioneer Awards primarily recognized the best ideas (which, of course, were closely connected to their respective investigators). Because of the mixed background of the panels with few subject-matter experts, the applicants often used catchy titles for their ideas. Jonathan Skinner, Ph.D., suggested that such titles might actually be useful in the evaluation process, because they facilitate follow-up searches (e.g., simple Google queries) to determine whether an idea has been adopted and built on by others. In response to a question raised by Jennie Hansen about whether societal impact was measured, Dr. Wetle noted that the evaluators looked at the publications arising from the Pioneer Awards and assessed several related factors to evaluate the impact of these awards on science. She further noted that many of the awards have funded basic science projects and that the societal impact might not be apparent for a while.
Dr. Morimoto reported that the Working Group had considered several concept clearances for RFAs or requests for proposals (RFPs).
Dr. Barr noted the statistical data package and pointed out that the high number of applications received by NIA for this round arose from the new RFAs that were issued. He also pointed out that the success of CSR-reviewed applications in this round and the previous two rounds was slightly below average.
Ana Maria Cuervo, M.D., summarized the Human Cell Reprogramming for Functional Genetics of AD concept, which proposes the use of set-aside funds and special review to support the use of induced pluripotent stem cells (iPS cells) as a bridge between mouse models of AD and human studies. Genomic analyses and genetic modification studies in these cells could provide insights into AD and potential therapeutic approaches. The working group motioned that this concept be approved and recommended that NIA ensure that all investigators benefit from these studies, for example through repositories and training. Council members added that workshops will be needed to help investigators understand how best to use iPS in their own work. The motion passed unanimously.
Arlan Richardson, Ph.D., described the Inflammation and Age-Related Diseases concept. Over the past decade, it has become more evident that inflammation is associated with several age-associated diseases, including neurodegenerative diseases, diabetes, and cancer. However, most of the evidence is associative. The proposed RFA seeks to support studies identifying the basis and source of inflammation, the types of cells involved, and the positive and negative effects of preventing chronic inflammation. Dr. Richardson noted that this concept arose from a Geroscience Initiative workshop involving eight ICs and thus could have a broad impact. The working group motioned that this concept be approved. The motion passed unanimously.
Kevin High, M.D., summarized a concept to renew and expand the Interventions Testing Program Cooperative Agreement. This program tests potential interventions in heterogeneous strains at three different centers under well-controlled conditions. So far, 25 compounds have been studied, including rapamycin. The concept proposes to use a cooperative agreement (U01) mechanism and limited competition. Whereas the previous iteration focused primarily on lifespan, the renewal will include extensive evaluation of mechanisms, histology and banking, and development and validation of health span outcomes. The Working Group motioned that this concept be approved. The motion passed unanimously.
Dr. Morimoto noted that a concept on the Development of Measures of Fatigability in Older Adults was discussed extensively by the Working Group. The Working Group motioned that this concept be deferred for future consideration by the Council. The motion passed unanimously.
Stephanie Studenski, M.D., summarized the Multifactorial Fall Injury Prevention Intervention in Older Persons concept. She noted that NIA has been a leader in the development of an evidence base for risk factors and treatments related to unsteadiness and falls, which is of great concern to older adults. However, the extent to which this knowledge can be implemented in practice and how it affects falls and injuries is not clear. The Patient-Centered Outcomes Research Institute (PCORI) has developed a set of high-priority focus areas, including a large, public health-oriented clinical trial of intervention for prevention of falls-related injuries, and it is collaborating with NIA, which will be responsible for the oversight, RFA, review, implementation, and monitoring of this trial. Dr. Studenski noted this concept as a landmark model of collaboration between PCORI and NIH. The Working Group motioned that this concept be approved. The motion passed unanimously.
Dr. Petersen presented the final report from the review of the DN program. He reminded the Council that the purpose of this review was to assess the current state of DN research, the quality of its portfolio, and the ability of DN to respond to rapid changes in the field, particularly with respect to the AD initiative. In particular, the review panel focused on transparency with respect to allocation of AD funds, succession planning, and portfolio overlap. Dr. Petersen highlighted some of the panel’s recommendations:
Overall, the review panel commended DN on the quality of research it supports and for the nimble nature in which it has responded to changes in the field, such as the American Recovery and Reinvestment Act, the National Alzheimer’s Project Act, and the new AD initiative. Portfolio overlap and succession planning will be addressed.
A motion to approve the final report was forwarded and seconded. As a member of the review panel, Dr. Morimoto thanked the DN staff for their efforts in providing materials to the panel. The motion passed unanimously.
Dr. Morimoto reminded the Council that this memorandum outlines areas of interaction between NACA and NIA and notes where NIA staff can take actions on the research portfolio, on behalf of the Council. This year, the memorandum has been changed from allowing expedited awards of applications from the 20th percentile to allowing expedited awards of applications from the percentile projected for the year’s funding. Other modifications include increasing the cost amount from $250,000 to $500,000 and removing “by fax” from the statement regarding secondary review. A motion to approve the amended memorandum was forwarded and seconded. The motion passed unanimously.
Linda Harootyan, chair of the Friends of the NIA (FNIA), provided a brief overview of the coalition, which was created in 2007 to provide a bridge between NIA and interested organizations and to advocate in ways that NIA cannot as a federal agency. FNIA is a broad coalition encompassing 50 organizations and individuals who represent aging research and patient advocacy. Harootyan focused her remarks on FNIA’s efforts to advocate for continued investment in NIA. This year, such efforts have included:
Harootyan also noted that FNIA is establishing an FNIA newsletter and that information about NIA’s new blog has been distributed among FNIA members. Efforts also are under way to expand FNIA membership. Harootyan also pointed out that the Geroscience Interest Group has resonated with many members of Congress and that several members are planning to attend the summit in October.
Following her remarks, Harootyan and Susan Peschin led a discussion on ways to engage more researchers in advocacy, particularly with respect to budget issues and their effects on research and the researcher pipeline. Although they acknowledged that researchers are often uncomfortable with advocacy, they pointed out that visits to Capitol Hill are far more effective when researchers share their personal stories about the impact of budget cuts on their work, their laboratories, and staff. Harootyan, Peschin, and Council members also noted that continuing uncertainty about funding, along with factors such as educational debt and the desire or need to support a family, can discourage talented individuals from continuing in science. Dr. Hodes added that even established scientists, such as Nobel Prize winner Carol Greider, are facing difficulties, for example in training new scientists.
Suggestions from Council members for FNIA included:
Dr. Hodes thanked FNIA for its efforts and noted its successes, particularly in representing a broad coalition to Dr. Collins and in inviting NIA staff to talk with the public. He added that although Council members are federal employees during meetings, they are allowed to share information about the science supported by NIA and their connections with their own communities help NIA to communicate. Harootyan and Peschin described their success in recruiting researchers to sign a letter to Dr. Collins and pointed out how impressed Dr. Collins was when he received a letter with more than 500 signatories. Thus increasing the number of researchers in advocacy makes an impression not only with Congress but also with the NIH.
Although AD develops over many years, clinicians and researchers agree that waiting until the full-blown dementia stage is waiting too late to intervene. Thus efforts are under way to determine whether individuals at risk can be identified before symptoms appear. The Biomarkers for Older Controls at Risk for Dementia study (BIOCARD) was established in 1995 to enroll up to 350 individuals, 75% of whom had a family history of dementia, and perform cognitive and clinical assessments to identify predictors for progression to mild cognitive impairment (MCI) or dementia. Assessments included magnetic resonance imaging (MRI) and collection of cerebrospinal fluid (CSF).
Marilyn Albert, Ph.D., of the Johns Hopkins University School of Medicine, described work in her laboratory to re-enroll the initial BIOCARD cohort, perform annual clinical and cognitive evaluations, and analyze prior data. She and her colleagues received funding in 2009 to reinitiate the study, and since then, approximately 90% of the study participants have re-enrolled. Participants have undergone an average of 9 years of follow-up, with a minimum of 7 years and a maximum of 17 years. All initial analyses have been completed. Annual assessments are comparable to those done in the AD Research Centers. Analyses of CSF samples are comparable to those performed in the Alzheimer’s Disease Neuroimaging Initiative.
On the basis of the CSF analyses, Dr. Albert and her colleagues have found that baseline Ab and phosphorylated tau protein (p-tau) are significantly associated with time to onset of dementia. These findings confirmed previous results from other laboratories. In addition, although baseline ratios of Ab to tau were not associated, increased rates of change for tau/Ab and p-tau/Ab ratios were significantly associated with time to onset. Changes in CSF values were apparent at least 6 years before clinical onset. These results are very encouraging because they indicate that the CSF samples did not degenerate during storage and that the remaining large collection of such samples will yield stable results.
Dr. Albert and her colleagues also have identified MRI-based predictors, with the volume of the entorhinal cortex and the right hippocampus significantly associated with time to onset. The rate of change in entorhinal volume and amygdala volume also are associated significantly. These changes were apparent at least 6 years before symptoms appeared. Lower baseline scores on nine cognitive tests also predicted time to onset, particularly in individuals carrying the ApoE4 allele. Dr. Albert and her colleagues are now interested in studying additional CSF markers and applying automated analyses to MRI scans. They intend to collect novel cognitive measures and amyloid images and to re-initiate collection of CSF samples and MRI scans.
Council members cited the BIOCARD cohort as a valuable resource and noted the importance of this work for early detection of AD. They also noted that this work could have broader implications, for example for age-based policies, because it could redefine “normal” cognitive aging. However, they noted that the cohort was fairly homogenous with respect to race and educational background. They emphasized the importance of showing the value added by CSF collection before such measures are incorporated into clinical practice. Dr. Albert and Council members also pointed out that even after considerable effort, variability in measures is still about 10% within laboratories and 30% across laboratories.
Dementia is strongly age-related. Although age-specific rates of dementia do not change, an increasing proportion of the U.S. population will have dementia as the baby boom generation ages. Costs associated with dementia are expected to rise, not only because of demographics but also because of increasing health care costs in general. Moreover, because of an increasing number of adults who have no children by the time they reach 40 to 44 years of age, more individuals will reach retirement with no children or blood relatives in the next generation to take care of them. Thus caregiving costs will shift toward the formal sector. Yet many individuals with dementia still receive informal care and estimates of costs associated with dementia have not accounted for this type of care.
Michael Hurd, Ph.D., of the RAND Corporation, described work using data from the Health and Retirement Study (HRS) to estimate the actual costs attributable to dementia in terms of actual spending and informal care. Specifically, he and his colleagues have focused on data from the Aging, Demographics, and Memory Study (ADAMS), a supplemental study of 856 HRS participants aged 70 or older who underwent an in-field assessment for dementia in 2001 through 2003. Dr. Hurd and his colleagues estimated relationships between HRS variables and outcomes in the ADAMS sample, used those relationships to impute dementia status to the larger HRS sample, and then used statistical methods to estimate attributable costs in the larger sample. Analyses were adjusted for comorbidities and functional limitations.
On the basis of these analyses, Dr. Hurd and his colleagues estimated that dementia accounted for an additional $6,194 in annual out-of-pocket costs, an additional $2,700 in Medicare costs, an annual formal home care cost of $5,678, and nursing home costs of $13,876 in 2010. Thus total spending attributable to dementia was $28,501. Dr. Hurd and his colleagues also estimated that 34.6 hours of informal care were attributable to dementia and that such care cost $27,789 in replacement costs and $13,188 in foregone wages. Thus total costs attributable to dementia were estimated at $41,689. On the basis of the prevalence rate of 14.7% seen in ADAMS, assuming an unchanging age-specific prevalence, and accounting for foregone wages associated with informal caregiving, Dr. Hurd and his colleagues estimated that $159 billion was spent on dementia in 2010. They further anticipated that costs will increase to $379 billion by 2040.
Council members noted that each published estimate of costs associated with dementia meets criticisms about overestimates. However, as each study uses better and more nationally representative data, and as analyses are done ever more carefully, the estimated costs increase. They also discussed potential cost-savings associated with disease-modifying interventions and speculated that, although such interventions might increase costs because more people are living longer, the benefit might outweigh the cost. Other discussion focused on the complexity of dementia-associated costs with respect to income and wealth.
In the renin-angiotensin system, which plays a role in blood pressure regulation, angiotensinogen is converted to angiotensin I, which in turn is converted by angiotensin-converting enzyme (ACE) to angiotensin II. Angiotensin II binds to angiotensin type 1 (AT1R) and type 2 (AT2R) with equal affinity, but these receptors differ significantly. Binding of angiotensin II to AT1R increases inflammation, cell proliferation, and de-differentiation and is seen as vasoconstrictive, whereas binding of angiotensin II to AT2R decreases inflammation and cell proliferation, promotes cell differentiation, and is possibly vasodilatory. Jeremy Walston, M.D., principal investigator of the Older Adults Independence Center (OAIC) at Johns Hopkins University, described studies focused on the role of the renin-angiotensin system in wound healing among older adults.
Researchers at the OAIC have identified a mitochondrial renin-angiotensin system and found that older age alters the balance of this system, for example through upregulation of AT1R. They also have found that angiotensin receptor blockers (ARBs) reset that balance and affect the healing and repair of connective tissue in older mice but not younger ones. In addition, treatment of sarcopenic mice with the ARB losartan improves muscle remodeling and in vivo function and it prevents muscle atrophy associated with disuse in older mice.
The renin-angiotensin system is also present in the skin, particularly in the dermal layer, and activation of this system influences all phases of wound-healing. Among older persons or persons with diabetes, angiotensin II signaling increases and the pro-inflammatory AT1R is upregulated. Although inflammation is necessary for wound-healing, increased and longer-term angiotensin II signaling results in thinning epidermis, collagen degeneration, fracture of the dermal layer, and atrophy of subcutaneous fat and thus to delayed wound-healing. Work at the OAIC suggests that wound-healing in older or diabetic individuals halts during the inflammatory phase and therefore does not reach the proliferative phase.
On the basis of observations in the mitochondrial renin-angiotensin system, Dr. Walston and his colleagues have explored the use of losartan to improve wound-healing. They have found that continuous losartan treatment improves healing of punch biopsies in mice and that losartan-treated skin is stronger and more elastic than that treated with placebo. However, the best healing occurs when losartan treatment begins 7 days after the injury, during the proliferative phase. Results were consistent with other ARBs such as valsartan. Thus treatment of wounds in older or diabetic adults is likely to be most effective when their wounds have passed into the chronic and non-healing phase. Likewise, targeting the renin-angiotensin in the skin could decrease the risk for systemic complications associated with ARBs. Larger studies are under way.
Discussion focused on topical versus systemic application of ARBs and on translation of these findings to human studies.
Aging is associated with many pathologies characterized by the loss of homeostasis and defects in injury repair. These dysfunctions affect many systems semi-synchronously and studies in model organisms suggest that aging phenotypes are non-autonomous; that is, changes in one cell type can influence changes in others. Amy Wagers, Ph.D., of the Harvard University Medical School, described work using the parabiotic mouse model to explore age-related changes in tissue regeneration. This work has shown that resident stem cell populations become dysfunctional with older age and that exposure to a younger circulatory system rejuvenates stem cell function and thus improves tissue repair. Thus, it is possible that a systemic regulatory axis controls the regenerative function of stem and progenitor cells.
Dr. Wagers and her colleagues have explored whether this axis also influences homeostatic changes seen with age. They have found that exposure to circulatory factors from younger animals remodel muscle fibers and reverse age-related fragmentation of neuromuscular junctions in older mice. In a collaboration with Richard Lee, M.D., Dr. Wagers and her colleagues also have explored age-related changes to the heart and found that exposure to a younger circulatory system reduces changes associated with diastolic dysfunction, such as cardiomyocyte hypertrophy and fibrosis. Thus the systemic regulatory axis identified by Dr. Wagers and her colleagues influences both regenerative potential and homestatic maintenance.
Following an extensive search, Dr. Wagers and her colleagues identified growth differentiation factor 11 (GDF11) as one factor in this axis. GDF11, also known as bone morphogenetic protein 11 (BMP11), is a member of the transforming growth factor beta superfamily. It has been understudied, particularly in the context of aging, but it appears to play a role in development of the nervous and endocrine systems, the kidney, and the pancreas. GDF11 expression disappears in older mice, but GDF11 supplementation to youthful levels reverses age-related cardiac hypertrophy and molecular remodeling. GDF11 supplementation also improves regenerative potential in skeletal muscle and increases the frequency and functional activity of muscle satellite cells. Similar results have been observed with other tissues and studies of mechanisms are under way.
Discussion focused on the source of GDF11, which may be mainly produced by the spleen, on technical aspects of Dr. Wagers’ work, and on connections with other signaling pathways, such as Notch signaling, implicated in wound-healing.
The open session of the 119th meeting of the NACA adjourned at 1 p.m. on June 5, 2013. The next meeting is scheduled for Sept. 17–18, 2013.
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.
Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
9000 Rockville Pike
Building 31, RM 5C35
Bethesda, MD 20892
Kimberly D. Acquaviva, Ph.D., MSW (2016)
Director of Faculty Affairs
The George Washington University
School of Nursing
Washington, DC 20037
Norman B. Anderson, Ph.D. (2014)
Chief Executive Officer and Executive Vice Chair
American Psychological Association
Washington, DC 20002
Robert M. Califf, M.D. (2013) (Term ends December 31)
Vice Chancellor and Professor
Department of Medicine
Duke University Medical Center
Durham, NC 27710
Laura L. Carstensen, Ph.D. (2015)
Department of Psychology
Stanford, CA 94305
Ana M. Cuervo, Ph.D., M.D. (2015)
Albert Einstein College of Medicine
Department of Development and Molecular Biology
Bronx, NY 10461
Hugh C. Hendrie, DSC, Ph.D. (2013) (WGoP Member) (Term ends December 31)
Professor of Psychiatry
Indiana University School of Medicine and Regenstrief Institute, Inc.
Indiana University Center on Aging Research
Indianapolis, IN 46202
Kevin P. High, M.D. (2016)
Associate Dean for Clinical Research
Department of Internal Medicine
Section of Infectious Diseases
Wake Forest University School of Medicine
Winston-Salem, NC 27157
Bradley T. Hyman, M.D., Ph.D. (2016)
Professor and Director
Department of Neurology/Alzheimer’s Research
Massachusetts General Hospital
Charleston, MA 02129
Richard I. Morimoto, Ph.D. (2014) (WGoP Member)
Bill and Gayle Cook Professor of Biology
Departments of Biochemistry, Molecular and Cell Biology
College of Arts and Sciences
Evanston, IL 60208
Eliseo J. Perez-Stable, M.D. (2014) (WGoP Member)
Department of Medicine
University of California, San Francisco
School of Medicine
San Francisco, CA 94143
Daniel P. Perry (2013) (Term ends December 31)
President and CEO
Alliance for Aging Research
Washington, DC 20006
Ronald C. Petersen, Ph.D., M.D. (2013) (Term ends December 31)
Professor of Neurology
Cora Kanow Professor of Alzheimer’s Disease Research
Director, Mayo Alzheimer’s Disease Research Center
Director, Mayo Clinic Study of Aging
Rochester, MN 55905
Arlan G. Richardson, Ph.D. (2013) (Term ends December 31)
Barshop Institute on Longevity and Aging Studies
University of Texas Health Science Center
San Antonio, TX 78245
Jonathan S. Skinner, Ph.D. (2015)
Professor of Community and Family Medicine
Department of Economics
Institute for Health Policy and Clinical Practice
Lebanon, NH 03755
Terrie F. Wetle, Ph.D. (2013) (WGoP Member) (Term ends December 31)
Associate Dean and Professor
Brown University Medical School
Providence, RI 02912
Department of Health and Human Services
Hubert H. Humphrey Building
Washington, DC 20202
Francis S. Collins, Ph.D., M.D.
National Institutes of Health
Public Health Service
Building 1, Room 126
Bethesda, MD 20892
Edwin L. Walker
Deputy Assistant Secretary
U.S. Department of Health and Human Services
Administration on Aging
Administration for Community Living
Washington, DC 20001
Kenneth G. Pugh, LCDR, MC
Department of Medicine
National Naval Medical Center
Bethesda, MD 20889
Robin A. Barr, D.Phil
Director, Office of Extramural Activities
National Institute on Aging
Bethesda, MD 20892