The 117th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, September 18, 2012, at 3 p.m. in Building 31, Conference Room 10, National Institutes of Health (NIH), Bethesda, Maryland. Dr. Richard J. Hodes, Director, National Institute on Aging (NIA), presided.
In accordance with the provisions of Public Law 92–463, the meeting was closed to the public on Tuesday, September 18, 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. 1 The meeting was open to the public on Wednesday, September 19, from 8:00 a.m. to 1:30 p.m.
Dr. Norman Anderson
Dr. Robert Califf
Dr. Laura Carstensen
Dr. Ana Maria Cuervo
Dr. Hugh C. Hendrie
Dr. Andrea LaCroix
Dr. Victor Molinari
Dr. Richard Morimoto
Dr. Lennart Mucke
Dr. Eliseo Pérez-Stable
Mr. Daniel P. Perry
Dr. Ronald C. Petersen
Dr. Arlan G. Richardson
Dr. Jonathan Skinner
Dr. Terrie F. Wetle
Dr. Dennis Choi
Ms. June Simmons
Dr. Stephanie Studenski
Dr. James F. Burris, Department of Veterans Affairs
Mr. Robert Hornyak, Administration on Aging
Dr. Kenneth G. Pugh, National Naval Medical Center
Mr. James Wren, Administration on Aging
The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as attachment A.
Dr. Samuel Edwards, Center for Scientific Review (CSR), NIH
Dr. Rene Etcheberrigaray, CSR, NIH
Dr. Yuan Luo, CSR, NIH
Dr. Joseph Mosca, CSR, NIH
Dr. Suzan Nadi, CSR, NIH
Dr. George Vogler, CSR, NIH
Dr. Kevin Walton, CSR, NIH
Dr. Laurent Taupenot, CSR, NIH
Dr. Biao Tian, CSR, NIH
Dr. Wei-Qin Zhao, CSR, NIH
Dr. Andrea Baruchin, Foundation for NIH
Dr. David A. Bennett, Rush University Medical Center
Ms. Erica Froyd, Lewis-Burke Associates
Ms. Mary Jo Hoeksema, Association of Population Centers
Dr. Sei Lee, University of California, San Francisco
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Ms. Nancy Moy, SRI International
Dr. Virginia Neale, Northwestern University
Dr. David Walker, University of California, Los Angeles
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 996 applications requesting $1,675,446,968 for all years underwent initial review. The Council recommended 564 awards for a total of $1,143,114,279 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 117th NACA meeting and called the meeting to order at 8:10 a.m. on Wednesday, September 19, 2012.
Dr. Hodes reported that the news is limited with respect to the FY2013 budget. The House has passed a 6-month continuing resolution, which is expected to pass the Senate and be signed by the President. Although the continuing resolution provides some stability, a large amount of uncertainty remains.
Events since the May Council meeting include the release of the National Plan to Address Alzheimer’s Disease (AD) as part of the National Alzheimer’s Project Act (NAPA). A major component of the plan is the International AD Research Portfolio (IADRP), which was developed by NIA in collaboration with the Alzheimer’s Association. The IADRP is intended to be a comprehensive database of ongoing research at the national and international levels and to facilitate future planning and coordination. Information about the research portfolios for most Federal agencies has been entered into IADRP, and users can search for specific research grants. National and international organizations are preparing to enter information about their portfolios into IADRP.
Dr. Hodes reminded the Council that the FY2012 budget included a White House initiative that allocated $50 million to AD research, above and beyond research that was already planned. Major categories of research include whole genome sequencing efforts, a prevention trial testing the ability of crenezumab to bind and clear abnormal amyloid in patients with early-onset familial AD, and a treatment trial of intranasal insulin versus placebo in individuals with mild cognitive impairment (MCI) or AD dementia. Other research includes the use of induced pluripotent stem (iPS) cells to explore the cellular processes underlying AD, support to the Atherosclerosis Risk in Communities study to explore enhanced neuroimaging markers to identify AD risk factors, and small business grants to encourage research in the private sector. The White House also proposes an additional $80 million for FY2013, which faces uncertainty, much like other initiatives planned for FY2013.
Dr. Hodes also reported that NIH Director Francis Collins, M.D., Ph.D., had asked representatives from the Institutes and Centers (ICs) to identify areas of highest opportunity and priority that could be supported with a 1-year allocation of funds. NIA took the lead in developing funding opportunity announcements (FOAs), which were reviewed by Council at this meeting.
Another event that has taken place is the expansion of the Geroscience Interest Group (GSIG), which was founded in 2011 to further collaboration among ICs on aging as it relates to their missions. GSIG has expanded from involving 5 ICs in 2011 to 20 today. GSIG has held several meetings, including a symposium on inflammation, and Dr. Collins has given a lecture at a recent meeting. Dr. Hodes noted that the efforts of GSIG reflect the importance of understanding the biology of aging and its relevance to research across NIH, as well as the importance of further collaboration at a time when budgets are increasingly limited. He credited the staff of the Division of Aging Biology (DAB) for their efforts in getting GSIG off the ground.
Dr. Hodes closed his presentation by noting the following:
The bulk of discussion focused on the budget and the looming fiscal cliff. In response to questions from the Council, Dr. Hodes and Dr. Robin Barr noted that NIA and NIH have been discussing how to move forward in the face of so much uncertainty. Dr. Hodes acknowledged that the Institute would have to proceed conservatively, for example by looking at what percentage of funding for non-competing awards will move forward. He also noted that for competing awards, NIA will use some FY2012 funds to support the very highest priority awards for FY2013 and, as a result, is unlikely to announce its payline for some time. Dr. Hodes added that even though there is some stability with the 6-month continuing resolution, it is difficult to say what will happen beyond that. However, NIA, like other ICs at NIH, are planning for several possibilities. Dr. Hodes also indicated that the Institute’s planning aims to evenly distribute the pain or hardship, should automatic spending cuts (sequestration) take place. More will be known by the January Council meeting.
Dr. Andrea LaCroix expressed the most concern for grantees with excellent but not exceptional A1 applications, which could be adversely affected by delays in funding decisions. She questioned whether opportunities will be missed if NIA proceeds too conservatively. Dr. Arlan Richardson also suggested that NIH re-consider its one-submission rule. Dr. Barr responded that NIH can keep applications active for more than three rounds if necessary. He also pointed out that NIH has considered the one-submission rule, but that models project that success rates will actually worsen, because of increased numbers of A2s.
Dr. Jonathan Skinner suggested that in some cases, particularly for junior faculty, simply having an award, even one funded at half the price, can be beneficial because it signals to their institutions that their research is valuable. Dr. Richard Morimoto agreed, adding that university administrations and deans, many of whom are not funded researchers, will not acknowledge sequestration or other difficulties at NIH. Dr. Hodes noted that the Institute can make these decisions on a case-by-case basis but that it will have to do so realistically, for example by requiring a modification of specific aims. Dr. Barr added that NIA is already making some of these types of decisions and implementing controls to reduce the costs of awards. However, NIA remains cognizant of the fact that the best way to increase public support for research is by ensuring that the best science moves forward. Dr. Hodes stated that while NIA does not want to give false hope, it also does not want to sacrifice careers, which in turn can harm the scientific enterprise.
Dr. Robert Califf also pointed out that sequestration can be even more catastrophic because of its effects on the payment side of a health care system. Every aspect of an academic medical center will implode at the same time, and the center therefore will have no reserves from which to draw to keep its scientists funded. It is difficult to model the full effects of sequestration on all activities of an academic medical center.
Dr. Ronald Petersen suggested that investigators be encouraged to leverage their funding, but he also acknowledged that NIH cannot do that from a policy perspective.
Other discussion points included an announcement by Dr. Terrie Wetle that the Gerontological Society of America (GSA) has awarded the 2012 Kent Award to Dr. Sidney Stahl of DBSR. She pointed out that GSA had awarded the 2011 Freeman Award to Dr. Luigi Ferrucci, NIA Scientific Director. Dr. Suzman also introduced Mr. Dennis Edgar, the new Extramural Program Office Manager in DBSR.
January 29–30, 2013 (Tuesday and Wednesday)
June 4–5, 2013 (Tuesday and Wednesday)
September 17–18, 2013 (Tuesday and Wednesday)
February 25–26, 2014 (Tuesday and Wednesday)
The minutes of the May 2012 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.
Dr. Pérez-Stable summarized the council subcommittee report on Health Disparities Research and Minority Researcher Training. This committee was formed in response to a request by Council at its January 2012 meeting. Working with Dr. Marie Bernard, NIA Deputy Director, Dr. Chyren Hunter, and Dr. Samir Sauma, the committee held several conference calls and reviewed a substantial amount of data. For this analysis and subsequent report diversity was defined as including underrepresented minorities (as defined by their home institutions), persons of disadvantaged socioeconomic status, and persons with a disability. Health disparities research was defined as research on disparities based on race, ethnicity, or socioeconomic status. A grant was deemed to involve diversity or health disparities research when at least 10% of its content base included diversity or health disparities in the abstract and was confirmed in a review of specific aims.
The committee reviewed a sample of approximately 985 grants, including research, training, and conference grants, totaling more than $2.3 billion over 10 years. Sixteen percent of these grants,(18% of R01s, 12% to 16% of grants supporting faculty or investigator development) were related to diversity or health disparities, and this proportion has remained fairly steady over the past 10 years. Among the relevant grants, 18% had been submitted in response to a request for applications (RFA) and 44% to program announcements (PAs); 38% were investigator initiated. Grants in DAB were primarily devoted to training, whereas grants in the other three Divisions were primarily research grants while 11% to 18% were training grants.
The NIA Health Disparities Strategic Plan was one area of emphasis for the committee’s review. The proportion of research aligned with this plan varied by research area, and although the committee was not sure whether these proportions were appropriate, these data can help NIA with future analyses or comparisons. The committee also noted that the Division of Geriatrics and Clinical Gerontology (DGCG) had more grants than other Divisions related to interventions to reduce health disparities, and it suggested that more be done by NIA as a whole to develop and assess such interventions. All areas of diversity and health disparities research, particularly dementia and behavioral and social science research supported by NIA have proven robust with respect to publications. More than 44,000 publications cited 911 NIA grants, and 40% percent of the findings in these publications were related to factors influencing health and well-being, whereas 23% documented health-related differences.
Dr. Pérez-Stable discussed the NIA Resource Centers for Minority Aging Research (RCMAR) program, which was implemented in 1997 and is beginning its fourth funding cycle. The RCMAR program, which currently includes seven centers and a coordinating center at the University of California, Los Angeles, is funded through a fairly stable P30 mechanism, with co-funding by other NIH groups, currently the Office of Behavioral and Social Science Research and prior support from the NIMHD. Dr. Pérez-Stable also noted the NIA AD Research Centers (ADRC) program, which includes a substantial portfolio of health disparities research and funds principal investigators of diverse backgrounds. With one exception, the RCMARs are located in the same institutions as ADRCs, and the committee suggested increasing synergy between the RCMARS and the AD centers.
Training was another area of emphasis in the committee’s review, with training, dissertation, and career development grants well-distributed across NIA Divisions. After excluding diversity supplement (S) and institutional training (T) awards, 84% of grants to minority trainees were dissertation-related (F31, R36), including summer research experience (R25); the remainder were career (K07, K12) awards, small grants (R03), and meeting grants (R13). In contrast, all but one trainee in health disparities research received a K-award (K08, K23, K25, and K99). The levels of success in terms of subsequent funding and publications were similar across grant mechanism.
Dr. Pérez-Stable called attention to the NIA Diversity Supplement Program, which has been underused and support up to 50% of applications submitted. The committee evaluated the intermediate outcomes, including grant application success, current placements, and publications, among individuals who received minority or diversity supplements as postdocs or junior faculty. The success rate among these individuals was 18% for funded research grant applications, although few appeared to have advanced to R01 awards. Dr. Pérez-Stable suggested that if investigators reach the level of postdoctoral fellowships, every effort should be made to nurture them toward success in securing their first independent grant award.
Dr. Pérez-Stable also highlighted the Summer Institute on Aging, which was initiated as a program to promote diversity in the workforce. The Summer Institute involves lectures, seminars, and several opportunities for participants to network and learn about the research funding process. About 27% of Summer Institute participants go on to assistant professorships, but the outcomes for 39% are unknown. Little is known about the race and ethnicity of participants. Dr. Pérez-Stable also noted the NIA Technical Assistance Workshop, which is usually held at the annual GSA meeting. Approximately 500 participants attended this workshop between 1999 and 2011.
In summary, the committee made several recommendations:
The committee also provided a list of topics in which health disparities should be studied. NIA currently supports research in many of these areas.
During discussion, Dr. Wetle suggested that NIA also support research on social and economic factors that predict health and well-being by race, in recognition that the intersection between social conditions and health outcomes is critical. Dr. LaCroix suggested that, as a result of this report, NIA routinely examines topics by race, ethnicity, and socioeconomic status to determine whether its research has made any impact in narrowing disparities. Dr. Norman Anderson emphasized that NIA has done well in prioritizing workforce diversity and health disparities research, and he recognized Dr. Hodes for his leadership and Dr. J. Taylor Harden, who served as the point person for these areas before she retired. Dr. Anderson encouraged NIA to identify someone who can continue to pay attention to these issues daily, as Dr. Harden did.
Dr. Anderson also clarified his comment regarding a conceptual model of what health disparities research means to the Institute. NIA should identify what areas are important to examine and how various dimensions or factors leading to health disparities interact. These questions are important, because the biological factors underlying health disparities are not independent of socioeconomic factors, and health disparities will not be understood simply by focusing on one level of analysis.
In response to questions, Dr. Pérez-Stable acknowledged that the committee did not address the use of telemedicine to address health disparities. He noted the value of human contact in the medical care setting, but he also acknowledged the attractiveness of telemedicine, from a systems perspective, in getting specialized care to areas with lower access. Dr. Pérez-Stable also pointed to opportunities with mobile health and smartphone applications.
In response to questions about increasing use of the Diversity Supplement Program, Dr. Hodes noted that it is possible to request alterations in line-item allocations, but that increases would likely come at the expense of other research grants.
Dr. Wetle reported on the September 5 Council of Councils (CoC) meeting, which included a scientific presentation on comparative medicine and a discussion of the new Office of Research Infrastructure Programs. In his remarks to the CoC, Dr. Francis Collins, NIH Director, highlighted the uncertainty and threats to research funding, but he also expressed excitement for ongoing initiatives and noted that the promise of biomedical science has never been greater.
The CoC meeting also included an update by the Working Group on the Use of Chimpanzees in Research, which was convened to respond to recent recommendations made by the Institute of Medicine (IOM). Specifically, the Working Group was charged with:
The Working Group has established several subgroups, organized its efforts, and set a goal for several deliverables, and it is still holding meetings and visiting chimpanzee colonies. A final report will be presented at the January 2013 CoC meeting and open to public comment thereafter.
Another major topic explored by CoC was tobacco control regulatory science and the new opportunities made possible by the Family Smoking Prevention and Tobacco Control Act. Dr. Cathy Backinger, of the Center for Tobacco Products at the U.S. Food and Drug Administration (FDA), presented an overview of the authorities given to FDA by the Act, including the authority to allocate user fees from tobacco company assessments to support regulatory research. NIH and the FDA are partnering on this research, which will be overseen by the NIH Office of Disease Prevention.
Dr. Richard Morimoto reported that the working group had considered several advisory workshops and nine RFA concept clearances, several of which are related to the President’s 2013 funding initiative for AD research. Working group members described their assigned items, and the Council voted on motions forwarded by the Working Group.
Dr. Richardson noted that “Age-related Changes in Osteoimmunology: An Integrative Physiological Approach,” which was presented by DAB, is the first initiative focused on the relationship between the skeletal and immune systems. Whereas previous studies have been limited to animals that are 3-months old or younger, the concept proposes to use existing models to study aging and its effects on bone-immune interactions. The Working Group motioned that the concept be approved. The motion passed unanimously.
Dr. Ana Maria Cuervo considered the concept, “Genetic Analysis,” which proposes to employ a global approach to identify risk factors for and protective factors against AD by building on ongoing efforts to fully sequence the genome in AD patients. The RFA will set aside money to provide the technology and infrastructure needed to facilitate analysis of the sequence data and thus fuel the pipeline for therapeutic development. The Working Group motioned that the concept be approved. The concept passed unanimously.
In discussing the concept “Target Identification and Validation,” Dr. Lennart Mucke noted the importance of fueling the therapeutic pipeline by identifying and validating additional targets at the preclinical level. The Working Group on Program motioned that the concept be approved, and the motion passed unanimously.
Dr. Califf addressed the concept “Phase I Clinical Trials for AD Therapeutics,” which would support proof-of-concept and extensive, detailed clinical testing of candidate molecules for AD in humans. The Working Group discussed the importance of the proposed mechanism and the need for balance between a pure academic “free-for-all” and the rote execution of protocols by contract research organizations. Group members also debated the potential upside for NIH should a candidate molecule prove successful. The Working Group motioned that the concept be approved, and the motion passed unanimously.
Dr. Mucke described “BluePrint Neurotherapeutics,” which was developed in response to recommendations by the AD Summit for diversification of the AD drug development portfolio. The concept would provide funding for 2 years to support development of small-molecule therapeutics for the prevention and treatment of AD. The Working Group encouraged NIA to expand the RFA to consider additional mechanisms that could promote therapeutic development. The group motioned that the concept be approved, and the motion passed unanimously.
In discussing “Prevention Trials,” Dr. Petersen noted the importance of clinical trials focused on the prevention or delayed onset of AD. The concept proposes to investigate pharmacological and nonpharmacological approaches in normal individuals and those with MCI. Although the Working Group agreed on the importance of this concept, members expressed concern that it was too broad, which could affect the size of the RFA and the budgets that would appear in applications. Dr. Skinner noted that the identification of molecules that could be applied broadly could have a large impact on the population, and Dr. Califf expressed concern that unless NIH can find creative ways to reduce the cost of clinical trials, the proposed studies would not be feasible in a time of constrained budgets. Drs. Molinari and LaCroix appreciated the inclusion of nonpharmacological approaches, and Dr. LaCroix referred to a cross-NIH interest group focused on exercise interventions. The Working Group motioned that the concept be approved, with NIA giving attention to these comments. The motion passed unanimously.
Dr. Molinari discussed “Drug Discovery Training for Academic Scientists,” a concept proposed by DN based on the increasing need for academic scientists to gain exposure to drug discovery in the context of the pharmaceutical or biotechnology industries. The concept will support mentoring of NIA-supported investigators for 3 months to 1 year. The concept was limited to investigators at an academic rank of assistant professor or higher, but the Working Group suggested that including senior graduate students and postdocs also would be valuable. Working Group members also suggested that NIH identify key contacts in these industries, because academic scientists are less likely to know who to contact. However, some Working Group members cautioned NIA to carefully integrate activities to avoid overlap with efforts that are already under way at medical centers. NIA staff will integrate these comments into the RFA. The Working Group motioned that the concept be approved. The motion passed with two abstentions.
Dr. Mucke discussed “Preclinical Animal Model Testing,” noting that existing animal models do not predict accurately how drugs will fare in clinical trials for AD. Although he acknowledged many reasons for this, one hypothesis is that these models do not fully simulate the complexity of AD. The concept proposes to support the establishment of better models of disease, including compound models that combine genetic manipulation and other strategies, and the testing of them in rigorous trials. Dr. Mucke noted that the RFA would provide the infrastructure and models needed to evaluate drugs at the preclinical stage. The Working Group motioned that the concept be approved, and the motion passed unanimously.
Dr. Morimoto discussed the “Preclinical Testing Data Repository” concept, which would create a repository housing all data, including negative data. This concept would support a contract for the creation of such a database, which would be available to the entire scientific community and managed by NIA staff with input from the community. The Working Group motioned that the concept be approved, and the motion passed unanimously.
Following discussion of these concepts, in response to questions about the uncertainty of funding for the AD initiatives, Dr. Hodes noted that these initiatives, like any other initiative put forward by NIA, are contingent upon the availability of funds.
Dr. Morimoto highlighted a report he and Dr. Mucke gave to the Working Group on the German Center for Neurodegenerative Diseases (DZNE), an entity established by the Helmholtz Association and supported by the German government. Headquartered in Bonn, with several sites throughout Germany, DZNE has expanded from two employees in 2009 to more than 500 scientists, and it engages in unique, site-specific partnerships with universities and the state. Dr. Morimoto pointed out that many DZNE initiatives have priorities identical to those of NIA and the AD Initiative and that DZNE therefore presents a good opportunity for interactions. Dr. Mucke echoed Dr. Morimoto’s comments and added that a relationship between NIA and DZNE would be mutually beneficial. Dr. Hodes agreed that such an interaction would align well with NAPA, which encourages international collaboration.
Dr. Barr referred Council members to the statistical package for this round. NIA received a total of 1,066 applications this round, indicating that the total number of applications is back to the level of 2010. Dr. Barr also pointed out that the percentage of NIA-assigned applications obtaining the top decile in review was close to 10%, which is considerably improved since the May Council meeting. It is not clear how many applications the NIA will be able to fund in 2013. Dr. Barr noted that the costs of the applications submitted this round are lower than those in previous rounds.
Dr. Hodes recognized Drs. LaCroix, Molinari, and Mucke, who are rotating off the Council. Ms. June Simmons, who was unable to attend this meeting, is also retiring from the Council.
Dr. LaCroix saw serving on the Council and interacting with NIA as a privilege. She shared several observations:
Dr. Molinari thanked NIA for the opportunity to serve on the Council. He noted that when he started, he did not have as much grant writing experience as other Council members. Gaining experience in that area was one example of ways in which his service on the Council gave him more than he has given. He thanked the NIA staff for making service on the Council a pleasant experience.
Dr. Mucke commended the NIA staff for its genuine dedication and brilliance. He expressed concern about the potentially stifling effects of constraints imposed by regulations in government processes, and he cautioned that enthusiasm and dedication can subside if one encounters these constraints for a long-enough period of time. Dr. Mucke also challenged new Council members to continue to “rock the boat” and find ways to tweak the system, particularly now, when many great things are on the horizon.
Dr. David Bennett, of the Rush University Medical Center, has incorporated neuropathology studies into two cohort studies and found that the AD phenotype is neurobiologically heterogeneous. The vast majority of individuals with probable AD phenotypes meet the pathological criteria for the disease, but more than half have comorbidities driving the disease phenotype, and many show no clinical signs of AD at all. In addition, many of the risk factors for clinical AD do not appear to be risk factors for AD pathology; some are risk factors for the comorbidities that drive the disease, and others work through unidentified mechanisms. Dr. Bennett and his colleagues also have seen a large amount of heterogeneity in cognitive aging, with less than half the cases of cognitive decline explained by the four most common pathologies (AD, cardiovascular disease, Lewy bodies, TDP-43).
The manifestation of clinical dementia thus appears to depend on an individual’s neural reserve, or an individual’s ability to tolerate accumulating pathology in the brain. The identification of therapeutic targets and the ability to prevent cognitive decline and aging therefore will depend on an understanding of what constitutes neural reserve and how important it is. To explore neural reserve further, and to begin to identify links between risk factors to cognitive decline and dementia, Dr. Bennett and his colleagues have collected several phenotypes and traits and are compiling a multilayer dataset, including genomic, epigenomic, transcriptomic, and proteomic data.
Dr. Bennett described three complementary studies to identify proteins associated with neural reserve. A study focused on complexin II, which interacts with the SNARE protein complex to promote vesical release, shows evidence that an individual’s neural reserve is directly related to the level of complexin II expression in the brain. In a less-targeted study, Dr. Bennett and his colleagues have studied an antibody microarray of more than 500 proteins from the synaptosomal fraction and found 15 that distinguish AD resilience from AD dementia. The third study is a genome-wide association study of neural reserve, controlling for all pathologies and demographics. Dr. Bennett and his colleagues have identified three hits of genome-wide significance. The proteins identified in these studies are likely to be therapeutic targets.
The bulk of discussion focused on technical aspects of and speculation arising from Dr. Bennett’s work, particularly as it relates to aging. In addition, Dr. Mucke noted that, as highlighted by this work, many pathologies proposed as relevant are in fact red herrings, and some areas of dysfunction are not readily explained by classical hallmarks of AD.
Investigators who study aging and lifespan in invertebrate models often do so at the level of the organism. Yet too often the measure of aging is simply whether the animal is alive or dead. Dr. David Walker, of the University of California, Los Angeles, looks at changes at several levels, including cellular and molecular changes and changes in organ or tissue homeostasis, that increase risks for disease and death.
Mitochondrial dysfunction has been implicated in several age-onset diseases, cancer, and neurological disorders. In addition, several published studies that have used microarrays to examine altered gene expression indicate that genes involved in electron transport are switched off with increasing age. These include members of the PGC1 family of transcription coactivators, which are major regulators of mitochondrial energy metabolism whose increased activity leads to the upregulation of other mitochondrial genes. Dr. Walker and his colleagues have used Drosophila genetics to explore the effects of increased expression of the Drosophila PGC1 homolog (DPGC1). As expected, they have found that overexpression of DPGC1 increases the abundance of respiratory enzyme complex, which in turn leads to increased respiratory chain activity.
They also have been surprised to find that increased DPGC1 activity, particularly in the gut, extends the lifespan. This was especially true when Dr. Walker and his colleagues targeted DPGC1 expression to stem and progenitor cells in the gut. Further work has shown that DPGC1 activity in the gut declines with age and that this decline can be reversed by transgenic DPGC1. In collaboration with Dr. Leanne Jones’ group at the Salk Institute, Dr. Walker and his colleagues have looked further at the behavior of stem and progenitor cells in the gut and found that with age, the numbers of these cells increase in the intestinal epithelium and several cellular markers are expressed inaccurately. These changes can be suppressed with DPGC1 overexpression. Thus targeted expression of DPGC1 in a cell population within the intestine has effects on mitochondrial metabolism, with increased mitochondrial activity and decreased production of reactive oxygen species. Using a noninvasive assay, Dr. Walker and his colleagues also have shown that DPGC1 overexpression suppresses the increased intestinal barrier dysfunction normally seen with age.
Discussion focused on technical aspects and possible implications of Dr. Walker’s work.
Preventive care often can expose patients to immediate risk for harm before symptoms appear, while benefits do not become apparent until years later. For older adults with limited life expectancy, preventive care provides an immediate risk when the chances for reaping the benefit are small. Thus preventive interventions are likely inappropriate for them. Many guidelines therefore endorse the targeting of preventive services to patients with extended life expectancy.
The overarching goal of Dr. Sei Lee’s laboratory at the University of California, San Francisco, is to identify the patients more likely to benefit and those more likely to be harmed by preventive interventions. Their work on mortality prediction has focused on comorbidity measures and led to the development and validation of a prognostic index for 4-year mortality. Building on that work, Dr. Lee and colleagues have reviewed 16 prognostic indices to evaluate their quality with respect to older adults. To help clinicians find and use these indices, Dr. Lee and colleagues also have developed a website, ePrognosis, which has operationalized these indices into calculators. This website can guide clinicians to the most appropriate index for their specific question. ePrognosis has received media attention from the New York Times, The Daily Beast, and USA Today.
Dr. Lee and colleagues also study the lagtime to benefit, or the time between an intervention’s harms and benefits. Because studies are powered to determine whether an intervention works, rather than when the benefits will become apparent, the lagtime to benefit is unclear for many interventions. Dr. Lee and his colleagues have conducted a meta-analysis of high-quality trials of screening interventions for breast and colorectal cancer and used methods from several fields to estimate lagtime to benefit. With respect to colorectal cancer screening, they have found little difference between control and screening groups, in terms of reductions in absolute risk, until 9 years later.
The use of mortality predictors and lagtime benefit can help in individualizing care. However, many quality indicators encourage the same care for all adults at a certain age. For example, all adults aged 50 to 75 years are encouraged to undergo screening for colorectal cancer. Dr. Lee and his colleagues have found that existing quality indicators are unbalanced, and although they encourage more appropriate care, they do not discourage inappropriate care. Therefore, these indicators encourage more care overall. In addition, because existing quality indicators do not consider mortality risk, they encourage prevention in sicker, younger patients while ignoring healthier, older adults who might benefit. Dr. Lee speculated that with the use of electronic health records, mortality prediction could be automated to individualize quality indicators.
Members of the Council saw the value of targeting preventive interventions and agreed that it should be discussed more openly. However, they also noted that with existing outreach and education efforts about the value of prevention, the idea that screening might not always be appropriate could cause an uproar. Discussion focused on ways to effectively communicate such information when it is based so heavily on probabilities. Dr. Wetle suggested framing the conversation in terms of circumstances in which preventive services are justified for older adults, rather than on circumstances where such services should be withheld. The Council also discussed the scarcity of evidence for proper care of older adults, because many clinical trials exclude individuals older than 75 years.
Across the United States, per capita Medicare spending varies widely by region, but the reasons for this variation and its effects on mortality are not clear. Many attempts to characterize existing data have shown large variations in both risk-adjusted spending and risk-adjusted outcomes. Dr. Skinner and his colleagues have focused on productivity as a way to couch questions about spending and outcomes. They have found, for example, that among patients who have undergone a myocardial infarction, there was no correlation between spending and outcomes, but there was an association between outcomes and the time it took for hospitals to adopt new approaches, such as the use of aspirin. In another example, Dr. Skinner and colleagues looked at racial disparities in hemoglobin A1C testing and saw an interaction between these disparities and hospital productivity.
The passage of health care reform legislation has led to the rise of accountable-care organizations (ACOs), an outgrowth of physician-hospital networks that aim to provide coordinated, high-quality care to their patients. However, although ACOs have improved quality of care, their effects on cost are unclear. The Physician Group Practice Demonstration (PGP), an early pilot study conducted by the Centers for Medicare and Medicaid Services, has focused on one-sided shared savings, in which physicians receive 80% of the savings above a threshold if quality targets are met; an increase in spending with a local comparison group rate; and a risk adjustment for hierarchical condition categories. In a study published in JAMA a week before the Council meeting, Colla and colleagues explored annual Medicare payments per beneficiary between control hospitals and those that participated in PGP. The costs were relatively modest, about $100 per beneficiary per year, but real savings depended on how hospitals had responded to PGP.
Dr. Skinner concluded that which technologies and approaches diffuse will determine productivity gains in health care, and the innovations that save lives (such as aspirin and beta blockers) are not necessarily the most costly. How to make low-productivity institutions behave like high-productivity institutions remains unclear.
Dr. Califf pointed out that the analytical framework regarding spending, productivity, and outcomes does not account for the randomness of some measures, which is related to practical implementation. He also noted that the tendency to game the system—for example, hospitals “optimizing” their coding by sending “problem” patients elsewhere—is dangerous. Dr. Skinner and other Council members also discussed difficulties in providing feedback to hospitals with respect to outcomes and costs.
The open session of the 117th meeting of the National Advisory Council on Aging adjourned at 1:25 p.m. on September 19, 2012. The next meeting is scheduled for January 29–30, 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.
(Terms end December 31)
(* WGoP Member)
(** TFMAR Member)
Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
9000 Rockville Pike
Building 31, RM 5C35
Bethesda, MD 20892
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)
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
Dennis W. Choi, Ph.D., M.D. (2015)
New York, NY 10010
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)
Professor of Psychiatry
Indiana University School of Medicine and Regenstrief Institute, Inc.
Indiana University Center on Aging Research
Indianapolis, IN 46202
**Andrea Z. LaCroix, Ph.D., MPH (2012)
Fred Hutchinson Cancer Research Center
Women’s Health Initiative Clinical Coordinating Center
Seattle, WA 98109
Victor A. Molinari, Ph.D. (2012)
University of South Florida
Department of Aging & Mental Health
Louis De la Parte Florida Mental Health Institute
Tampa, FL 33612
*Richard I. Morimoto, Ph.D. (2014)
Bill and Gayle Cook Professor of Biology
Departments of Biochemistry, Molecular, and Cell Biology
College of Arts and Sciences
Evanston, IL 60208
*Lennart Mucke, M.D. (2012)**
Department of Neurology
University of California, San Francisco
San Francisco, CA 94141
**Eliseo J. Perez-Stable, M.D. (2014)
Department of Medicine
University of California, San Francisco
School of Medicine
San Francisco, CA 94143
Daniel P. Perry (2013)
Alliance for Aging Research
Washington, DC 20006
Ronald C. Petersen, Ph.D., M.D. (2013)
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)
Barshop Institute on Longevity and Aging Studies
University of Texas Health Science Center
San Antonio, TX 78245
June Simmons (2012)
Chief Executive Officer
Partners in Care Foundation
San Fernando, CA 91340
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
Stephanie A. Studenski, MPH, M.D. (2014)
Department of Medicine
University of Pittsburgh
Pittsburgh, PA 15213
**Terrie F. Wetle, Ph.D. (2013)
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
James F. Burris
Office of Research and Development
Department of Veterans Affairs
Washington, DC 20420
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