The 108th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, September 22, 2009, 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 22, 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 Public Law 92-463.1 The meeting was open to the public on Wednesday, September 23, from 8 a.m. to 1 p.m.
Dr. Lisa Berkman (September 22)
Dr. Dale Bredesen (September 22)
Dr. Kenneth Brummel-Smith (September 22)
Dr. Lawrence M. Friedman
Dr. Mary Ganguli
Dr. S. Michal Jazwinski
Dr. Sundeep Khosla
Dr. Andrea LaCroix
Dr. Victor Molinari
Dr. John C. Morris
Dr. Lennart Mucke
Ms. Orien Reid
Dr. Gerald Schatten
Ms. June Simmons
Dr. James P. Smith
Dr. Susan L. Swain
Dr. Peggye Dilworth-Anderson
Dr. Carl Eisdorfer
Ex Officio Participants:
Dr. James Burris, Department of Veterans Affairs
Absent Ex Officio Participants:
Ms. Lori Gerhard, U.S. Administration on Aging
Dr. Kenneth G. Pugh, National Naval Medical Center
The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as attachment A.
In Addition to NIA Staff, Other Federal Employees Present:
Dr. René Etcheberrigaray, Center for Scientific Review, NIH
Dr. Vilen Movsesyan, Center for Scientific Review, NIH
Dr. Alexander Yakovlev, Center for Scientific Review, NIH
Dr. Laurent Taupenot, Center for Scientific Review, NIH
Members of the Public Present:
Mr. James Appleby, Gerontological Society of America
Dr. Brian Kennedy, University of Washington
Ms. Pat Kobor, American Psychological Association
Dr. David Laibson, Harvard University
Dr. Rose M. Li, Rose Li and Associates, Inc.
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Mr. Jason Michelitch, National Capitol Captioning, LLC
Dr. Mark J. Sarnak, Tufts University
Dr. Michèle Saunders, Gerontological Society of America
Dr. David Scalzitti, American Physical Therapy Association
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 2250 applications requesting $3,098,467,653 for all years underwent initial review. The Council recommended 876 awards for a total of $1,181,412,882 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 108th NACA meeting and called the meeting to order at 8:01 a.m. on Wednesday, September 23, 2009.
Prior to giving his report, Dr. Hodes circulated a compendium of science advances for the period January 2008 to January 2009 and acknowledged a number of attendees, including Dr. Mackiewicz, the new program director for the Integrative Neurobiology and Sleep/Biological Rhythms section in the Division of Neuroscience, NIA; Mr. Appleby, the executive director of the Gerontological Society of America (GSA); Dr. Saunders, the new president of the GSA; and Dr. Scalzitti, Associate Director of Research Services for the American Physical Therapy Association.
Dr. Hodes announced the confirmation of Dr. Francis Collins, former director of the National Human Genome Research Institute, as the new NIH Director and the appointment of Senator Tom Harkin, ranking member of the Senate Appropriations Subcommittee and a champion of NIA interests, as the new chair of the Senate Committee on Health, Education, Labor, and Pensions. Dr. Hodes also reported that no final word has been given yet on appropriations, and it is likely that there will be a continuing resolution for at least 1 month. Proposed funding levels are similar between the House ($1.12 billion) and Senate ($1.10 billion).
Congress has proposed several bills, many of them focused on comparative effectiveness research (CER). Legislative themes include the creation of centers, commissions, and other oversight bodies to oversee and evaluate CER activities; where such oversight bodies would be placed; funding of CER; expansion of CER areas of focus; and how CER results would be used. Dr. Hodes particularly noted concerns that CER results would be used to guide insurance or reimbursement decisions and drug device labeling.
The American Recovery and Reinvestment Act of 2009 (ARRA) has committed $1.1 billion to CER, of which $400 million has been allocated to the NIH. Dr. Hodes and Dr. Elizabeth Nabel, Director of the National Heart, Lung, and Blood Institute (NHLBI), are co-chairing the NIH committee responsible for guiding how NIH’s CER allocation is spent. Although Dr. Hodes was not at liberty to discuss details at this time, he noted that CER awards will be announced once they are approved; that opportunities for additional CER activities supported by ARRA are likely; and that the NIH, the Department of Health and Human Services, and the Federal Government will be committed to this area of research for the long term. A more detailed report will be provided at the January Council meeting.
In later remarks, Dr. Hodes discussed the challenges facing the NIA and the NIH related to ARRA. Although this act provided positive stimulus, it did so against a backdrop of a payline of 11 or 12 percent and the expectation of a substantially larger pool of applications in 2010 due to resubmissions of applications that were not funded by ARRA funds. In addition, applications that did receive ARRA funds will see their awards ending in 2011, generating perhaps another source of new applications in 2011 and early 2012.
Dr. Hodes also noted the potential generational conflict associated with increased efforts toward support for newer investigators. He discussed concerns among senior and established investigators that such efforts will ignore the wisdom of peer review and fund less meritorious research. Dr. Hodes expressed hope that these conflicts would not hinder collaboration.
Finally, Dr. Hodes noted that although NIH staff members are prohibited from engaging in advocacy, they still have a responsibility to communicate the importance of their work at NIH. He discussed appropriate ways for Council members to be involved and emphasized the importance of acknowledging the funding agencies in scientific and research successes so that the public understands that institutions achieve these successes with support from the NIH. In addition, emphasizing NIH’s involvement in these successes can allow legislators to take pride in supporting the NIH. He also welcomed opportunities for NIA staff to speak with their constituencies about scientific findings and research directions.
Council members from Pennsylvania noted Senator Arlen Specter’s strong support for the NIH and asked about the level of support from the Republican counterpart, who has not yet been announced. Dr. Hodes noted competing agendas and priorities but speculated that the ranking member would be selected from among the current committee members, all of whom are dedicated and see the NIH as a crown jewel. Ms. Reid supported the idea of inviting NIA staff to speak in regions where Council members are located, noting, for example, that NIA staff should be present when possible replacements for Senator Specter “tour” NIH-supported achievements in southeastern Pennsylvania and even southern New Jersey.
Dr. Mucke noted the importance of continuing to diversify the type of awards, with some rewarding higher levels of innovation and others supporting more conservative approaches. He added that the NIH should follow up on the actual success of these diverse funding mechanisms and how such success is defined. In response, Drs. Hodes and Barr reported on ongoing evaluation activities.
Dr. Schatten commended the ability of the NIH to adapt to the changing needs of the research workforce. He noted that during the time when NIH budgets doubled, the NIH did an excellent job of drawing brilliant investigators into the system. Now that the research workforce faces an enormous downsizing, Dr. Schatten suggested that the system might be more sustainable if potential investigators in the bottom quarter, third, or half in terms of fundability would embrace options away from the laboratory bench.
In response to questions from Dr. Khosla regarding the effects of fixed budgetary commitments (for example, CER and Roadmap) on the funding for general applications, Dr. Hodes noted that the NIA and the NIH have been sensitive to the need to balance stated priorities with investigator-initiated research. He did not see an increase in monies set aside for large initiatives. The Common Fund still comprises only 2 percent of the NIH budget, and set-asides at the NIA generally range from 8 to 10 percent of the total research grant budget.
Dr. Khosla also asked about changes associated with the new NIH leadership. Dr. Hodes noted that interactions with Dr. Collins indicated his appreciation and support of the NIA, that he appears to be interested in dimensions of aging research, and that he appreciates the importance of basic biology and behavioral science and the translation of studies to health care and health care reform. Dr. Hodes expressed enthusiasm that Dr. Collins’ leadership would bode well for NIA research.
B. Future Meeting Dates
January 26–27, 2010 (Tuesday and Wednesday)
May 25–26, 2010 (Tuesday and Wednesday)
September 21–22, 2010 (Tuesday and Wednesday)
January 25–26, 2011 (Tuesday and Wednesday)
May 24–25, 2011 (Tuesday and Wednesday)
September 20–21, 2011 (Tuesday and Wednesday)
C. Consideration of the Minutes of the Last Meeting
The minutes of the May 2009 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.
Dr. J. Taylor Harden provided the report on behalf of Dr. Peggye Dilworth-Anderson. Dr. Harden began by thanking retiring Council members who had been active on the task force.
The bulk of the task force’s agenda focused on a presentation by Dr. Eliseo Perez-Stable on the Center for Aging in Diverse Communities (CADC) at the University of California, San Francisco (UCSF), one of six Resource Centers for Minority Aging Research (RCMARs) funded since 1997. Like other RCMARs, the CADC is organized around an administrative core, which includes a governing council, advisory board, seminars, and communication; a measurement and methods core, which provides measurement science, mentors, and statistics; an investigator development core, which funds three to four pilot studies per year and provides supplements; and a community liaison core, which assists with study participant recruitment and science. The CADC works across the campus on disparities and aging research, with a particular emphasis on Latino, African American, Pacific Islander, and Asian American (primarily Chinese) populations, and has a high degree of synergy with the community around UCSF. The Center has trained 54 self-identified minorities: Two are now in tenure track positions at the University of California, Los Angeles; 23 are in faculty positions at UCSF; and others have moved on to other institutions, including the National Cancer Institute. CADC has made several faculty development awards and diversity supplements and has begun to see some return on its investment in the establishment of R01-level investigators.
Dr. Harden highlighted several additional CADC achievements:
Dr. Harden then reported that the NIA will host another Summer Institute on Aging Research in 2010. Applications will be available in November 2009, and the meeting will be held in July 2010. The NIA also has a program announcement to support dissertation awards to increase diversity as well as a program announcement promoting aging and health disparities research. In addition, a Director’s regional meeting will be held in Nebraska in April 2010.
Dr. Harden concluded by reminding the Council of the Health Disparities Resource Persons Network, which is available on the NIA Web site under Research and Information. This resource offers guidance for recruiting women, minorities, and other underserved populations and provides networking opportunities for those interested in minority health and health disparities.
Dr. Morris discussed reports on three advisory workshops. No action was required on these reports.
Dr. Nancy Nadon, Division of Aging Biology (DAB), reported on a workshop to develop consensus criteria for defining normal aging in rodent models. The primary goal of this workshop was to define normal aging phenotypes, and a secondary goal was to identify informational gaps that should be addressed. Although the workshop was intended to focus on all rodent models, discussion centered primarily on mouse models. Workshop participants agreed that too little was known to develop an overarching definition of “normal aging,” but they also noted that changes associated with normal aging should be distinguished from disease-related changes, that standard measures should be developed, that there should be a focus on function, and that responses to challenges such as stress should be evaluated. They also called for a broad interpretation of “phenotype” and attention to analyses across the lifespan. A full report is available from the DAB.
Dr. Dallas Anderson, Division of Neuroscience, reported on a meeting on the prevalence of Alzheimer’s disease (AD). The meeting, held in collaboration with the Alzheimer’s Association, was motivated by recently published widely disparate estimates of AD prevalence in the United States. Meeting participants explored issues underlying the different prevalence estimates and ongoing work by Dr. Denis Evans in the Chicago Health and Aging Project. A report is in preparation and will be presented at the January Council meeting.
In response to questions from Ms. Reid about a new report on global prevalence, Dr. Anderson commended Dr. Martin Prince (Professor of Psychiatry, King’s College, London) for his efforts on that report. He also noted that such an effort required some simplifying assumptions that might affect the level of the estimate. Dr. Molinari noted that AD is often confluent with other dementias and suggested focusing on dementia in general to show the full scope of this problem. Dr. Anderson acknowledged that the distinctions among dementia subtypes are indeed blurry and that meeting participants had noted the need to avoid confusing the public with conflicting terminology.
Dr. Suzana Petanceska, Division of Neuroscience, reported on the second Investigators Meeting for Translational Research in AD. This meeting is part of a program that sets aside funds for exploratory and/or developmental research grants (R21s) and cooperative agreements (U01s) to accelerate the field. Although feedback from the meeting supports the value of the program, participants noted several needs, including encouragement of faster turnaround of applications for drug discovery, added guidance for investigators, and animal models for preclinical studies.
Dr. Robin Barr directed attention to the two statistical packages describing applications that the NIA had received and that the Council reviewed during the closed session. Unlike previous rounds, this time there is a separate statistical package for applications received in response to ARRA initiatives.
Dr. Hodes acknowledged retiring members Drs. Eisdorfer and Brummel-Smith, both of whom were absent. He then thanked and gave certificates to Drs. Friedman, Ganguli, Morris, and Schatten.
Prior to his service on NACA, Dr. Friedman had been a long-term senior member of the NHLBI staff. His expertise has been valuable as the NIA invests increasingly in intervention research. Dr. Friedman commented that serving on NACA had given him an appreciation for the wisdom of Council advice, that he had learned much during his service, and that he appreciated the strengths of the NIA staff and the kind of research being done at the NIA.
Dr. Ganguli provided a broad perspective and served as an outstanding mentor to new Council members. She commented that her service on the Council had debunked myths she had held regarding the power of Council, educated her about the inner workings of Government, and helped her appreciate the care and fairness with which the NIA spends taxpayer dollars. She noted that she had learned from other Council members, program staff, and speakers, and she expressed gratitude for the opportunity to serve.
Dr. Morris has shown great leadership in AD research; chaired a large number of committees; and exhibited high standards in his character and in his interactions with colleagues, peers, and patients. Dr. Morris thanked the NIA for the opportunity to serve on Council and expressed that it is a privilege to understand the depth, breadth, and quality of science supported by the NIA. He also noted how much he enjoyed interacting with other Council members.
Dr. Schatten was acknowledged as an active and, when required, provocative Council member. He commented that working with Council had been a privilege and honor and that he has learned a great deal about fields he had not appreciated before joining Council. Dr. Schatten expressed concern about the future of research and how it would affect investigators, noting that the work his colleagues do is heroic but receives little reward. He pointed out that although the numbers of applications will continue to increase, the constraints will remain the same, and NACA will have to consider the emotional toll related to dwindling resources on grantees and investigators who have devoted their scholarship and life’s work to aging research. Dr. Schatten stated his appreciation for the collegial nature of the Institutes and Centers of the NIH but feels it is vital that the NIA’s budget grows at a faster rate than it has as too many good ideas are at risk of not receiving support, and he pledged to redouble his efforts to help.
Ms. Reid reported that the last in-person meeting of the Council of Councils (CoC) took place in November 2008. However, the CoC convened by teleconference in August to provide a secondary review of applications for the Transformative R01 program, which will support highly innovative and high-risk projects. More than 700 applications were submitted by the January 2009 deadline, of which 96 were to be funded in September.
Ms. Reid concluded by noting the upcoming CoC meeting, which will take place in November 2009.
Dr. Jazwinski, chair of the DAB review committee, provided a final report to the Council. The initial report was given at the May 2009 Council meeting.
The DAB review committee began its work in January 2009 in a conference call where it established subcommittees to review several aspects of the division, including for each branch (Genetics and Cell Biology, Aging Physiology, Biological Resources), and other activities (Nathan Shock Centers; training; interdisciplinary and translational). The committee reviewed the division’s response to the 2005 review, activities since that review, future plans, the division’s current portfolio, and arising questions. Subcommittees reviewed a large volume of data and produced draft reports before review committee meetings, and a review of these drafts yielded questions for subsequent interviews. The posting of all review materials facilitated sharing among the subcommittees and the review committee. Following a face-to-face meeting in Bethesda, the review committee drafted a final report, which was submitted for approval in August 2009.
The DAB review committee determined that the DAB has responded positively to recommendations from the 2005 review and made remarkable progress despite declining funds in real dollars. The committee also agreed with the previous review finding that success in some areas such as training was difficult to gauge because of a lack of easily accessible outcome measures. The review committee noted continuing challenges such as low and declining funding; the relatively small size of DAB grants and an inadequate centers budget; and limited funding of P01, translation supplements, and fellowship (F32) grants. Dr. Jazwinski reported that the committee was surprised at these continuing challenges in light of the many major breakthroughs in the fundamental biology of aging.
Dr. Jazwinski summarized the committee’s major recommendations:
The review committee also found the following:
Other recommendations focused on publicizing certain funding mechanisms, study sections best suited to reviewing certain applications, maintaining portfolio diversity, redefining health span in terms of function rather than disease, interactions among disciplines, feedback from the broader community, requirements for Nathan Shock Center applications, translational and interdisciplinary research, and the need for more animal models.
The review committee commended Dr. Felipe Sierra for directing DAB in a creative way in the short time he has been with the division and acknowledged the division’s imaginative and committed staff. The committee also applauded the interactive and dynamic nature of DAB and encouraged the division to find ways to reward staff efforts and promote staff development and retention. Dr. Jazwinski concluded by thanking all DAB staff for their assistance with the review.
A motion to approve the review committee’s report was forwarded and seconded. The motion passed unanimously.
By using a replicative aging assay in yeast strains lacking nonessential genes and by exploiting interfering RNA screens of worm strains, Dr. Brian Kennedy (University of Washington) and colleagues have identified gene ortholog pairs that modulate aging in both organisms, reasoning that conserved pathways between these divergent species were likely to be conserved in mammals. This work has led them to components of the TOR nutrient signaling pathway, which modulates growth and development in response to nutrient availability. Current studies are aimed at understanding the mechanisms that link reduced TOR function to extended lifespan.
Dr. Kennedy and colleagues are extending their studies to mice to determine which components of the TOR pathway are conserved and to examine whether these genes are involved in sensitivity or resistance to age-associated diseases. Recent studies by the NIA Interventions Testing Program have demonstrated that downregulation or disruption of TOR, S6K, and protein kinase A and exposure of middle-aged mice to the TOR inhibitor rapamycin all extend lifespan. In addition, disruption of protein kinase A has been associated with improved metabolic performance, weight maintenance, and cardiovascular protection in old age in mice. Rapamycin has been tested against many diseases such as cancer, cardiovascular disease, and type 2 diabetes, suggesting that this inhibitor might slow the aging process and offer broad-spectrum protection from age-related diseases. However, this compound also induces side effects in humans. More studies of the TOR pathway are underway.
In response to questions from Dr. Mucke, Dr. Kennedy noted that little is known in mice about the additive or synergistic effects of different pathways that influence aging. The cause of death in mice with extended lifespans also is not clear. Further discussion focused on the technical aspects of and speculations arising from Dr. Kennedy’s work.
B. Division of Neuroscience: Strategies To Prevent Neural Network Dysfunction in Alzheimer’s Disease
Much evidence suggests that the etiology of AD is multifactorial. The amyloid b (Ab) peptide is normally produced and turned over at an equal rate, but in AD this balance is altered, resulting in an accumulation of fibrils and plaques. The tau protein also has been implicated in AD because it undergoes redistribution and hyperphosphorylation and forms neurofibrillary tangles. Apolipoprotein E4 (apoE4) is a major risk factor for AD. Inflammatory responses by microglia and astrocytes also might play a role. In some cases, these responses protect against amyloid accumulation, but in other cases they might result in the release of toxins. Because of the complex etiology of AD, replicating the disease in animal models is difficult.
Dr. Mucke (Gladstone Institute of Neurological Research, University of California, and current Council member) described work using transgenic mice to determine whether different factors in AD act independently or share pathogenic convergence points. Introduction of human amyloid precursor protein into mouse brains results in navigational deficits similar to those seen in patients with mild cognitive impairment. Oligomeric Ab assemblies acutely increase neuronal excitation in brain slices and chronically elicit neural network instability in these mice, giving rise to epileptiform activity, compensatory inhibitory mechanisms, and deficits in learning and memory. These effects are prevented when the levels of endogenous wild-type tau are reduced—the tau protein in these mice is soluble and not phosphorylated, and it does not appear to aggregate abnormally. Thus, Ab-induced neuronal dysfunction most likely is not mediated by abnormal tau protein. Instead, it is likely that wild-type tau allows Ab and other excitotoxins to induce aberrant neuronal activity. Indeed, reduction of tau in nontransgenic mice results in resistance to chemically induced seizures. Thus, the toxic effects of Ab accumulation on cognition depend on tau. However, the specific function of tau remains unknown.
Dr. Mucke closed his presentation by discussing possible clinical implications of these studies. It is likely in the long term that AD will be treated like other multifactorial conditions such as hypertension through multiple approaches with varying modes of action. In the case of AD, approaches such as tau reduction that confer resistance to pathogenic Ab assemblies could be used in conjunction with therapies aimed at reducing Ab itself.
In response to questions from Dr. Schatten, Dr. Mucke noted that mice normally do not exhibit neurofibrillary tangles. However, if these mice express human tau or tau associated with dementia, tangles do form, indicating a high degree of conservation in other genes involved in AD. In response to questions from Dr. Hodes, Dr. Mucke noted that the data thus far are not consistent with a model in which loss of tau function contributes to neurodegeneration.
C. Division of Behavioral and Social Research: Behavioral Economics and the Science of Behavior Change
Behavioral economics has changed the way economics is understood. Traditional economic mechanisms, such as financial incentives, self-interest, and information, are weaker than previously thought, whereas psychological mechanisms, such as defaults, deadlines, and framing, are more powerful. For example, Dr. David Laibson (Harvard University) and colleagues conducted a study of 400 Harvard staff members, generally with master’s degrees, and asked them to read prospectuses and allocate $10,000 across four S&P 500 index funds. Traditional economics would predict that study participants would allocate all the money to the lowest-cost index fund. However, only 3 percent of participants made that decision; the rest allocated their money to name-brand funds with good historical data, with a cost of $516 in fees. Even when a second set of participants were given information about fees, the percentage of participants making the rational decision increased only modestly, to 9 percent.
In another example, Dr. Laibson and colleagues found that half of employees aged 59 years and older were not taking advantage of employer matches in retirement savings even though the match was instantaneous with a risk-free return. An educational intervention, which helped employees to understand how much they would lose by not taking advantage of employer matches, resulted in an almost negligible change. Psychological manipulation, however, achieved better results.
Dr. Laibson described a model of quasihyperbolic discounting, in which immediate costs and benefits receive disproportionate weight in decision making. He referred to a large body of literature that shows individuals to engage in self-defeating behavior because they are unwilling to accept the immediate costs for future gain. In addition, a growing body of work suggests a tension between self-control and a taste for immediate gratification.
Dr. Laibson highlighted several low-cost interventions that could have marked effects on saving for retirement. These included: (1) Switching the default option to automatic enrollment into retirement savings plans; (2) Introducing deadlines for active decisions on enrollment; (3) Simplifying the enrollment process.
These interventions can achieve large behavioral changes with little to no social cost, whereas the traditional method of financial incentives is expensive.
It is not clear whether similar approaches will work with health behaviors. Dr. Laibson cautioned that these interventions would work only in cases where there is a strong consensus of the “right” behavior. He and members of the Council noted many areas in health where there is still strong disagreement on the right course. With these caveats, Dr. Laibson presented a pilot study in which individuals with chronic conditions switched from picking up prescriptions to receiving them in the mail. Although this approach ultimately reduces costs by eliminating the retail step, almost no one signs up for mail-order on their own. In the pilot study, participants were asked to make an active decision, and almost half chose home delivery. More study is needed about long-term cost savings and effects on health.
In response to questions, Dr. Laibson acknowledged that businesses might hesitate to offer automatic enrollments because of the increased costs associated with matching funds. Dr. Ganguli also pointed out that “nudging” individuals to make “correct” decisions could be paternalistic and that individuals might have intelligent reasons for their choices. In response to her questions, Dr. Laibson noted that thus far, he and his colleagues were unable to distinguish between patients who actively refuse prescriptions from those who passively fail to fill them. He also agreed on the need to increase the number of active choices rather than force individuals to make what experts might deem to be the right choice.
Council members also discussed problems with relying on education to achieve change. It seems that such methods are ineffective both for changing economic behavior and for changing health behaviors.
D. Division of Geriatrics and Clinical Gerontology: Kidney Function and Outcomes in Older Adults—A Focus on Cystatin C
In the United States, approximately 26 million individuals have chronic kidney disease (CKD). Many of these patients are elderly. Dr. Mark Sarnak (Tufts University) reported that patients with kidney failure have cardiovascular mortality rates that are 10- to 30-fold higher than the general population, controlling for age, gender, and race/ethnicity. On the basis of data from the Atherosclerosis Risk in Communities Study, the risk for developing cardiovascular disease (CVD) increases as estimated glomerular filtration rate (eGFR) decreases. At rates below 60 mL/min/1.73 m2, the traditional threshold level for CKD, individuals are at a 40 percent higher risk for CVD; further, these rates appear to be associated with decreased cognitive function, more hospitalizations, frailty, and decreased quality of life.
International guidelines recommend using creatinine-based equations to estimate GFR. However, all creatinine-based estimating equations have limitations due to non-GFR determinants of serum creatinine, largely muscle mass. This is a particular problem among the elderly who are likely to have reduced muscle mass. Recently, cystatin C has emerged as an alternative marker of kidney function that is less influenced by muscle mass. Cystatin C has a stronger association with outcomes than serum creatinine or estimated GFR based on serum creatinine and can be used to define a state of “preclinical” kidney disease.
Although cystatin C itself does not appear in the urine, it is closely related to creatinine-EDTA clearance. Evidence from four cohort studies—the Cardiovascular Health Study, the Health ABC Study, the Multi-Ethnic Atherosclerosis Study, and the PREVENT Study—indicates that cystatin C levels increase with age, regardless of the presence or absence of clinical risk factors for CKD. Unlike creatinine, which shows a J-shaped relationship with mortality, cystatin C shows a linear relationship with mortality and heart failure. In addition, higher cystatin C levels have been associated with decreased expectations for successful aging. Thus, cystatin C might be a better measure of prognosis and risk for poor outcomes.
However, cystatin C is not perfect, and the importance of non-GFR contributions to cystatin C is not known. Whereas measurement of creatinine has been standardized, cystatin C measurement has not, and equations to estimate GFR based on cystatin C differ. Additional studies are therefore needed to define use of cystatin C in clinical practice.
In response to questions from Dr. LaCroix about genome-wide association studies of cystatin C changes, Dr. Sarnak noted that such studies are underway but that the genetics related to cystatin C are somewhat complicated. For example, lower cystatin C levels in the arterial blood vessel wall have been associated with poorer outcomes, and because cystatin C is theoretically an inhibitor of detrimental processes, mechanisms underlying this function might differ from those underlying cystatin C as a marker of kidney function.
The open session of the 108th meeting of the National Advisory Council on Aging adjourned at 12:52 p.m. on September 23, 2009. The next meeting is scheduled for January 26 and 27, 2010.
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.
NATIONAL ADVISORY COUNCIL ON AGING
NATIONAL INSTITUTE ON AGING
(Terms end December 31) (*WGoP Member)
Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
Lisa F. Berkman, Ph.D. (2012)
Director and Professor
Harvard School of Public Health
Dept of Society, Human Development, and Health, and Dept of Epidemiology
Dale E. Bredesen, M.D. (2011)
Professor, Director & CEO
Buck Institute for Age Research
Kenneth V. Brummel-Smith, M.D. (2009)
Professor and Chair
Department of Geriatrics
Florida State University College of Medicine
Peggye Dilworth-Anderson, Ph.D. (2010)
Professor, Health Policy & Management
Associate Director, Aging and Diversity/ Institute on Aging
University of North Carolina, Chapel Hill
Chapel Hill, NC
Carl Eisdorfer, Ph.D., M.D. (2009)
Knight Professor and Director
Center on Aging
University of Miami
Lawrence M. Friedman, M.D. (2009)
*Mary Ganguli, M.D., M.P.H. (2009)
Professor of Psychiatry, Neurology, and Epidemiology
Department of Psychiatry
University of Pittsburgh
*S. Michal Jazwinski, Ph.D., (2010)
Department of Medicine
Tulane University Health Sciences Center
New Orleans, LA
*Sundeep Khosla, M.D. (2010)
Professor, Endocrine Research Unit
Division of Endocrinology, Metabolism, & Nutrition
Mayo Clinic College of Medicine
Andrea Z. LaCroix, Ph.D., M.P.H. (2012)
Fred Hutchison Cancer Research Center
Women’s Health Initiative Clinical Coordinating Center
Victor Molinari, Ph.D. (2012)
University of South Florida
Department of Aging and Mental Health
*John C. Morris, M.D. (2009)
Washington University School of Medicine
St. Louis, MO
Lennart Mucke, M.D. (2012)
Director and Professor of Neuroscience
Gladstone Institute of Neurological Disease
University of California, San Francisco
San Francisco, CA
Orien Reid (2010)
Chairman, Alzheimer's Disease International
President, Consumer Connection
*Gerald P. Schatten, Ph.D. (2009)
Professor, Pittsburgh Development Center
Magee-Womens Research Institute
University of Pittsburgh
June Simmons (2012)
Chief Executive Officer
Partners in Care Foundation
San Fernando, CA
James P. Smith, Ph.D. (2012)
Department of Labor and Population
Santa Monica, CA
Susan L. Swain, Ph.D. (2011)
President and Director
Saranac Lake, NY
Department of Health and Human Services
Hubert H. Humphrey Building
Francis S. Collins, M.D., Ph.D.
National Institutes of Health
Public Health Service
James F. Burris, M.D.
Geriatrics & Extended Care Strategic Healthcare Group
Department of Veterans Affairs
Director, Office of Planning & Policy Development
U.S. Administration on Aging, DHHS
Kenneth G. Pugh, M.D.
Department of Medicine
National Naval Medical Center