The 111th meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, September 21, 2011, 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 21, 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 22, from 8 a.m. to 12:30 p.m.
Dr. Lisa F. Berkman
Dr. Dale E. Bredesen
Dr. Robert M. Califf
Dr. Peggye Dilworth-Anderson
Dr. Hugh C. Hendrie
Dr. S. Michal Jazwinski
Dr. Sundeep Khosla
Dr. Andrea Z. LaCroix
Dr. Victor Molinari
Dr. Lennart Mucke
Mr. Daniel P. Perry
Dr. Ronald C. Petersen
Dr. Arlan G. Richardson
Ms. June Simmons
Dr. James P. Smith
Dr. Susan L. Swain
Dr. Terrie F. Wetle
Ms. Orien Reid
Ex Officio Participants:
Dr. James F. Burris, Department of Veterans Affairs
Dr. Jane Tilly, Administration on Aging
Absent Ex Officio Participants:
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. Ronald Abeles, Office of Behavioral and Social Sciences Research, NIH
Dr. Antonio Scarpa, Center for Scientific Review, NIH
Members of the Public Present:
Dr. Rose Maria Li, Rose Li and Associates, Inc.
Dr. Frances McFarland Horne, Rose Li and Associates, Inc.
Dr. Ralph Nixon, New York University
Dr. Norman Sharpless, University of North Carolina, Chapel Hill
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 1,199 applications requesting $451,992,740 for all years underwent initial review. The Council recommended 739 awards for a total of $304,646,683 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 111th NACA meeting and called the meeting to order at 8:03 a.m. on Wednesday, September 22, 2010.
Dr. Hodes began his remarks by acknowledging three retiring members of the NIA staff:
Dr. Hodes then discussed the NIH budget, which has received small increases in current dollar appropriation since the budget doubling ended in 2003. These increases have been subinflationary, resulting in an actual erosion of buying power by 15 percent. The budget presented by the President, which calls for a slightly subinflationary increase of 3 percent, represents the most optimistic option for FY2011. Congress is unlikely to pass a budget before the midterm elections, so NIH and other Federal agencies are under a continuing resolution that maintains the budget at FY2010 levels. In addition, the Office of Management and Budget has requested that all Federal agencies plan for a 5 percent decrease in appropriations for FY2012. If this reduction is based on FY2010 levels, it could result in a reduction in purchasing power by a cumulative 25 percent.
These budgetary constraints have affected NIA grant application success rates, which until 2009 had paralleled those of NIH overall. NIA’s payline of 8 percent may be the lowest among all NIH Institutes and Centers (ICs). Research grants continue to represent two-thirds of the NIA budget. About 90 percent of these grants derive from investigator-initiated applications, whereas the remaining 10 percent are in response to directed initiatives or set-asides. Although NIA remains committed to investigator-initiated research, it will have to institute policy changes to maximize its ability to fund applications and preserve the workforce in aging research. For example, the average cost of grants has increased, and in response NIA is establishing more stringent criteria for large grant applications and will limit the total dollars awarded to these applications. The Institute will need to triage applications and, once scores are in, explore options such as differentially funding the more- versus less-expensive applications.
Dr. Hodes closed by noting that FY2012 funding will be difficult to predict and that NIA is planning to manage continued stress on the payline. NIA remains committed to supporting the best and most important research and to trying to keep a generation of researchers from moving to other ICs that have better paylines.
In response to questions from Council members, Dr. Hodes said that he could not state what the FY2011 payline will be, because all incoming applications have not yet been reviewed. He and Dr. Robin Barr noted that, based on projections from the October round, the payline could be worse than 2010. However, the average cost of these applications appears to be lower, which might offset this trend. Dr. Hodes expected to have more information and a clearer picture by the January 2011 Council meeting.
Council members agreed on the urgency of the situation. Dr. Susan Swain noted possible impacts on animal research, which includes the costs for housing aging animals, and Ms. June Simmons pointed out the importance of assuring the continued entry of new talent to aging research. Dr. Hodes agreed that NIA will have to balance the needs to support people in training and the early stages of their careers and to maintain important established research. He also acknowledged that the strength of NIA’s research program derives in part from its large projects, and he clarified that the Institute is weighing the costs and benefits of continuing these projects.
In response to questions about educating elected officials on the importance of aging research, Dr. Hodes highlighted the efforts on the part of NIA, NIH, and the public in communicating these messages. Both NIA and NIH will continue these efforts. Dr. Hodes considered the real issue to be overall funding—there are more good applications than funds to support them.
Dr. Barr recognized Dr. Ronald Abeles, a former NIA staff member, who will be retiring from the NIH Office of Behavioral and Social Science Research (OBSSR). Dr. Barr credited Dr. Abeles with raising the stature of the NIA Division of Behavioral and Social Research (DBSR) and for recruiting him, Dr. Barr, to NIA. Dr. Abeles will continue to be involved with OBSSR in a limited capacity.
Dr. Marcel Edward Salive has returned to NIA, after serving in leadership positions at the Centers for Medicare & Medicaid Services, the Food and Drug Administration, and the National Heart, Lung and Blood Institute. He was formerly in the NIA intramural program, and has joined the Division of Geriatrics and Clinical Gerontology (DGCG).
January 25–26, 2011 (Tuesday and Wednesday)
May 24–25, 2011 (Tuesday and Wednesday)
September 20–21, 2011 (Tuesday and Wednesday)
January 24–25, 2012 (Tuesday and Wednesday)
May 22–23, 2012 (Tuesday and Wednesday)
September 18–19 (Tuesday and Wednesday)
The minutes of the May 2010 meeting were considered. A motion was made, seconded, and passed unanimously to approve the minutes.
Dr. Peggye Dilworth-Anderson summarized two presentations that addressed informed consent with respect to minority populations and aging research. In the first, Dr. William Freeman, of the Northwest Indian College, discussed the Havasupai Tribe, which in 1989 reached out to an Arizona State University researcher and consented to a study to better understand diabetes. However, the tribe was not informed that their members’ samples were also used for a separate genetic study on schizophrenia in the Havasupai, and that their medical records were accessed, again without their knowledge or consent. The schizophrenia study had been approved by the Arizona State institutional review board, which did not know that consent had not been given for samples to be used outside the diabetes study. The Havasupai Tribe filed two lawsuits in 2004, which were settled in 2010. The University issued a formal apology and returned the blood samples to the tribe, and the tribe agreed to collaborate with the University to develop programs and education. Dr. Freeman noted to the task force that the tribe remains interested in research but does not want to be mistreated.
Dr. Freeman’s presentation illustrates how different perspectives can impact the treatment of informed consent. For example, some scientists view DNA as a waste product that is regularly shed. Although it can be used to identify individuals, no harm is done if it is anonymized. However, the specimens hold a spiritual value for the Havasupai. As one member said after the settlement, “Their spirits will no longer be locked in a cooler. We are going to take them back down to Supai Canyon so they can rest in peace.” Recognition of differences in values plays a critical role in truly informed consent. In addition the Code of Federal Regulations requires researchers to provide “understandable” information to potential subjects as part of the informed consent process.
As illustrated by this presentation, the Havasupai settlement highlights the importance of:
In the second presentation, Dr. Jennifer Manly of the Columbia University Medical Center discussed the challenges associated with obtaining informed consent from individuals belonging to groups that have experienced or perceive mistreatment of minorities in medical research, potential misuse of results and disclosure of study participation, stigmatization, discrimination, and harm or painful experiences from medical tests. Real and perceived benefits, including awareness of the study, experience with specialized care, and values and beliefs about prevention, cure, and “knowing,” also present a challenge.
Dr. Manly’s work highlights actual challenges in the consenting process, such as literacy, which includes experience as well as educational background, and the time needed (about an hour). Her work also demonstrates the importance of tailoring recruitment strategies to particular communities. For example, newspapers, word-of-mouth, and churches worked best in New York, whereas churches, primary care physicians, and community talks worked best in the community served by North Carolina Agricultural and Technical State University.
Both presentations emphasized the importance of empowering and engaging, allowing more time for the community to talk and ask questions of the investigators, establishing a medical center that is used and trusted by the community, and providing participants with the resources to spread the word.
In response to questions, Dr. Dilworth-Anderson reported that Dr. Manly emphasized feedback; whenever she gave a community presentation, she spoke for 5 minutes and left the bulk of the time for community members to ask questions. Dr. Dilworth-Anderson also noted that in her own experience conducting research in minority and poor communities in rural areas, a trustworthy institution such as a church or civic organization can help to validate the researchers’ presence in the community. She further noted that the type of institution that could serve as a gatekeeper would depend on the historical background and the discrimination experienced by the community in question.
Dr. S. Michal Jazwinski reported that the working group heard the final report of the DGCG review (see below) and a summary of statistical data on the extramural program. The group also had a lively discussion of questions for Dr. Antonio Scarpa, Director of the Center for Scientific Review (CSR, see below). Dr. Barr added that the current round of applications contains the last of the applications submitted for programs funded by the American Recovery and Reinvestment Act (ARRA).
Dr. Arlan Richardson introduced a motion, which was subsequently forwarded and seconded, to establish a committee of current and former Council members to review the NIA extramural program, evaluate the effects of the low payline on the field of aging research, and identify strategies to raise that payline. Such a committee, which also would include representation from the four NIA divisions, would further examine the balance between large and small grants and, in accordance with the advisory capacity of the Council, assist NIA leadership in its decision-making. The committee would present its findings to the Council in May 2011. Dr. Hodes noted that this timing is appropriate, because more information about the budget situation is expected by the time of the January meeting, and the Institute could thus provide the necessary data for the committee to evaluate.
Dr. Richardson emphasized the need for the Council to assist the NIA leadership in decision-making with respect to research support, as a low and fluctuating payline for an extended period of time could cause extensive damage in the research workforce in aging. In response to questions, he suggested that Dr. Hodes appoint the committee as he does other review committees, but he also emphasized that the committee should represent all four NIA divisions. Dr. Lennart Mucke added that, unlike other review committees, this one should circulate its recommendations among the entire Council before finalizing its report.
Dr. Andrea LaCroix applauded the NIA leadership for its openness and expressed the hope that such a committee would not seek to micromanage NIA staff decisions. She expected that program staff participation in this review will afford the Council an opportunity to learn more about funding, budget, and extramural issues. She wondered how the committee would quantify the impact of the low payline in terms of the impact of the science not being done. Dr. LaCroix also expressed concern that tensions about fewer resources might lead to dissension between different types of researchers regarding which research is more important. In response, Dr. Richardson emphasized that the purpose of such a review is not to pit large versus small, or discipline against discipline, but to determine how to make the best use of the NIA budget.
Dr. Robert Califf commented on the steady increase in research costs and highlighted the need to work across ICs to increase research efficiency. He added that too much time is spent on attempting to shift costs elsewhere, rather than on addressing the problem of growing inefficiency. Dr. Jazwinski added that, on the basis of the Division reviews in which he has participated, many opportunities exist for collaboration among NIA Divisions. Such collaboration could improve efficiency and funding decisions.
The motion passed, with one member opposed. The committee will be appointed before the January Council meeting.
Dr. Toni Scarpa discussed the CSR review of NIA applications, the drivers for change, and recent enhancements to NIH peer review. He acknowledged the extraordinary work done by CSR and program staff during the summer of 2009, when an additional 30,000 applications had to be reviewed within 2 months. Although applications responding to ARRA initiatives were less of a factor in 2010, the number of applications reviewed during FY2010 was somewhat higher than average. So far in 2010, CSR has received 88,000 applications and reviewed 64,000 through 1,700 study sections and with 17,000 reviewers. Of these, 2,950 were NIA applications (excluding ARRA), the majority of which were R01s. Compared with other ICs, NIA is about average with respect to the percentage of applications scoring better than the 20th percentile; however, this percentage is smaller than 2 years ago.
Dr. Scarpa pointed out that although the NIH budget is one driver for the change in success rates, the major determinant is the number of applications received. This number increased significantly immediately following the years in which the NIH budget doubled. The number then declined in subsequent years, mostly because of a decrease in small business applications. Even without ARRA, the number of NIH grant applications will still exceed 90,000, affecting workload and the payline. Other drivers for change include the reviewers’ workload, which at present is about eight applications per reviewer, and the CSR budget, which, although generous, has faced the same inflationary pressures as experienced by other ICs. Dr. Scarpa reported that CSR has decreased the amount of money spent per reviewer and, by implementing some changes unrelated to peer review, saved an additional $30 million per year.
Dr. Scarpa also reported on CSR efforts to enhance peer review in response to complaints that the review process was too slow; favored predictable, conservative research over significant, innovative, and transformative research; did not include enough senior-level reviewers; and placed a heavy burden on both applicants and reviewers. CSR has improved study section alignment with developments in science, shortened review times, advanced additional review platforms such as electronic review, and changed to an editorial board style of peer review especially for complex science, small business, transformative research projects, and several ARRA mechanisms. In addition, CSR has implemented a number of successful strategies for reviewer recruitment, including holding one meeting a year on the West Coast, developing a national registry of volunteer reviewers, abolishing submission deadlines for reviewers and Council members, and providing flexible frequency of service for reviewers.
NIH also has implemented broader steps to enhance peer review, for example changing the scoring criteria to focus foremost on the potential impact and significance of an application and then its feasibility, the investigator’s record, the approach, and the research environment. Dr. Scarpa noted that although reviewers are now challenged to discuss a proposed project’s impact, the shift in paradigm is still ongoing. NIH also has employed template-based critiques, which is also a work in process. Although reviewers and applicants appear to favor the bullet point approach, some reviewers appear disinclined to make specific criticisms.
Dr. Scarpa closed by addressing concerns about the peer review process expressed by Council members in a letter to him sent months ago. He stated that no compression appears to have occurred from instituting the nine-level scoring range and that CSR had piloted a way to allow investigators to rebut critiques. He cautioned, however, that allowing a rebuttal process lengthens the time needed to complete reviews.
Several Council members argued that compression of scores was occurring. Dr. Jazwinski pointed out that, as the payline gets lower, ICs are forced to make decisions on an increasingly smaller part of the scoring scale. He further noted that if funding decisions are compressed at the lower part of the scale, then that part would have to be expanded. Although members of a study section are asked to spread the scale, they do not. Dr. Swain added that compressing the decisions does not fairly represent the spectrum of evaluations that exist during review and thus interferes with the ability to distinguish between applications. Dr. Sundeep Khosla added that individual reviewers are prioritizing based on their individual piles of applications.
Dr. Lisa Berkman expressed concern that, in many cases, strengths and weaknesses from the reviewers’ critiques are not helpful, particularly among better scoring applications where weaknesses are not reflected in written comments. Thus applicants have little guidance to revise the application. Dr. Berkman also noted that certain scores do not reflect the discussion of the study section and that previously, summary statements were not written until after the meeting. She suggested that reviewers at least revisit their scores following the meeting so that applicants will receive information reflecting the discussion in study section.
In response to questions about impact scores versus individual criteria scores, Dr. Scarpa noted that criteria scores were designed by the scientific community to help to justify overall scores based on the application and not the scientist. Thus the overall impact scores are not simply an averaging of individual criteria scores. Dr. Jazwinski added that individual reviewers might weigh criteria differently, depending on the application.
Drs. Mucke and LaCroix summarized the Council’s concerns by calling for reviewers to be asked to provide more information to justify their scores. Dr. LaCroix added that quality control should be done on summary statements to ensure that the Council has enough information on which to act.
Dr. Hodes acknowledged four members retiring from the Council.
Dr. Peggye Dilworth-Anderson was recognized for her work with the Task Force on Minority Aging Research and for her service as faculty in the NIA Summer Research Institute on Aging. Dr. Dilworth-Anderson expressed her pleasure in serving on the Council and at the Summer Research Institute and emphasized her commitment to having an influence on the next generation of researchers. She noted that she had learned much about the serious nature of supporting science and had enjoyed the opportunity to serve with her colleagues.
Dr. S. Michal Jazwinski was recognized for his leadership in the Working Group on Program. Dr. Jazwinski noted that prior to his service on the Council, he had never given much thought to what happens to an application after it is reviewed by a study section, but now he understood that the bulk of review process takes place during the initial review. He reminded Council members that the purpose of NIH is to improve the health of the American people, and, although science can help with that, it is unpredictable and therefore requires an assessment of its quality by initial review. Dr. Jazwinski described NIA as a user-friendly Institute, with Council members doing what is best for the Institute, the research community, and the aging population.
Dr. Sundeep Khosla was recognized for his service in the DGCG program review and his contributions across basic and clinical biology. Dr. Hodes recalled that NIA had to wait to appoint Dr. Sundeep Khosla to the Council until his service to CSR had ended and that several NIH Councils competed for his service. Dr. Khosla thanked Drs. Hodes and Barr and the NIA staff for a rewarding and informative experience. He saw service on the Council as useful to him as a scientist, because he gained an understanding of how grants are reviewed and funded, how program staff work, how the Institute sets priorities, and how the Council contributes to those functions. He further appreciated the program highlights of cutting-edge science across the four Divisions, because this has helped to broaden his own thinking. He viewed his service on the Council as a privilege and honor and thanked NIA for the opportunity to serve.
Ms. Orien Reid, who was absent, was also recognized for her service.
Dr. Khosla summarized the final report of the DGCG review group; an initial report was presented at the May 2010 Council meeting. The review group’s findings were positive overall about the Division’s accomplishments, especially in a constrained funding environment. The group also found the Division’s seven goals to be appropriate for addressing the spectrum of geriatric and gerontologic issues under its scope. The group made the following recommendations related to the DCGC research portfolio:
Dr. Khosla then highlighted the group’s recommendations with respect to the Division’s goals, interfaces with clinical specialties, translational research, and career development.
A motion to approve the review group’s report was forwarded, seconded, and passed unanimously.
Dr. Norman Sharpless, of the University of North Carolina, Chapel Hill, discussed ongoing work from his laboratory and others examining the role of INK4/ARF tumor suppressor locus in human aging. The INK4/ARF locus encodes two tumor suppressor proteins, and activation of the locus is intimately associated with senescence, and irreversible growth arrest. Expression of p16INK4A, one of the proteins encoded by the INK4/ARF, markedly increases with aging in humans and mice, and expression is further associated with exposure to DNA damaging agents and other gerontogens. Mice deficient for p16INK4A are cancer-prone, but also exhibit a resistance to a decline in the replicative capacity of certain stem and progenitor cells with aging. Human genome-wide association studies and candidate analyses have linked single nucleotide polymorphisms (SNPs) near the INK4/ARF locus to susceptibility to several common human age-associated conditions including various cancers, frailty, longevity, type 2 diabetes mellitus, and atherosclerotic disease. Work from the Sharpless lab has shown that the genotype of some of these SNPs correlates with INK4/ARF expression in humans. Therefore, diverse human and murine genetic studies demonstrate the amazing involvement of the INK4/ARF tumor suppressor locus in the regulation of human aging.
Discussion focused primarily on technical aspects and potential hypotheses arising from this work. In response to questions from Dr. Jazwinski, Dr. Sharpless noted that assays measuring p16 expression are easier to do than those looking at telomere length. He further clarified that although p16 might serve as a good marker, it might not always be the best one.
Today’s workforce includes more women, older workers, and dual-income couples and thus more diversity. In the 1950s, when many work policies were first implemented, only 10 percent of women with children aged 6 to 17 years, and only 5 percent of women with very young children, were in the workforce. Now a much larger number of women in the workforce have young children. Yet between 1981 and 1990, the United States had no parental leave, and even now family medical leave is not the norm, is unpaid, and does not allow for caregiving for parents, spouses, or siblings. In addition, there is a widening gap in flexibility with respect to vacation and sick leave by socioeconomic status (SES). Among the lowest SES, the majority of individuals lack sick leave, and if they have vacation, then it is 2 weeks or less. Yet a study among gas and electricity workers in France has shown a large relationship between low SES, multiple levels of work and family demands, and absence due to illness.
Dr. Lisa Berkman, of Harvard University, presented a pilot study done in conjunction with the Work, Family, and Health Network jointly funded by NIA, NICHD, and the National Institute for Occupational Safety and Health (NIOSH). This study used questionnaires, actigraphy, clinical measures, and biomarkers to explore managers’ practices, work, health, and sleep among more than 500 low-wage employees from four nursing homes in the Boston area. The study also included qualitative interviews with midlevel managers about practices and styles and coded managers’ responses based on creativity and openness. The study found that the odds of employees having two or more risk factors increased two-fold, and the amount of sleep declined, with managers who had medium or low scores. Inflexible managers’ practices were also associated with increased risk for diabetes and hypertension among employees. The association with cardiovascular risk factors was more apparent among health care workers than among non-health care workers. A workplace intervention has been designed and will be tested for health care workers.
Dr. Berkman closed her presentation by noting that although the pilot study involved a multi-level analysis with independent observations, there is some concern with its cross-sectional design and the selection of employees into work groups. She also noted concerns that the manager scores might not be specific to work-family practices but represent a more general phenomenon. A randomized field study is planned.
Discussion focused on the intervention that Dr. Berkman’s group will be testing. The idea is to give employees increased control over work hours and decision-making, permitting, for example, greater flexibility in rescheduling and shared shifts. Another component is to provide better supervisor support, to coach supervisors to be able to increase flexibility and to focus on results rather than hours at work.
Pioneering studies by Friedenstein (Transplantation 6:230, 1968) established that the bone marrow stroma contains plastic adherent stem cells capable of differentiation into a broad spectrum of mesenchymal tissues. These studies have, over the years, led to considerable work on the characterization of marrow stromal cells in rodent and in human systems with osteoblastic potential. More recent studies have also observed a quiescent population of circulating osteogenic cells in the peripheral blood. Although these cells are somewhat different and smaller than their counterparts in the bone marrow, they also share important similarities. The number of cells positive for osteocalcin and alkaline phosphatase have been found to increase during the pubertal growth stage and following bone fracture, and cells positive for the osteoblastic markers CD45 and type I collagen are more abundant in patients with heterotopic ossification. Thus the quiescent population of circulating osteogenic cells might serve a protective role during adolescence or bone repair, but be detrimental in later life. Indeed, several studies have found overlaps between high bone turnover and cardiovascular disease.
Because there is growing evidence of a link between bone metabolism and vascular calcification, Dr. Khosla, of Mayo Clinic College of Medicine, and his colleagues also have sought to test whether patients with coronary atherosclerosis have increases in circulating endothelial progenitor cells (EPCs) expressing an osteogenic phenotype. The percentage of osteogenic EPCs might be better (although more cumbersome) than C-reactive protein for identifying patients with atherosclerosis, and the percentage of osteogenic EPCs might be a useful biomarker even for early endothelial dysfunction. Dr. Khosla and colleagues have further found that these cells can mineralize on plastic and adopt a mesenchymal phenotype, particularly if they express high levels of osteocalcin. Patients with endothelial dysfunction retain osteocalcin-positive cells in the coronary vasculature, and transient exposure to extracellular calcium induces peripheral blood cells to become adherent, mineralize, and express mesenchymal characteristics. Thus the expression of osteogenic genes by circulating EPCs might promote vascular calcification rather than normal vascular repair. In addition, both increased bone turnover and vascular disease are associated with increased production of inflammatory cytokines.
Discussion focused on how these findings inform the current controversy regarding the appropriateness of calcium supplementation in women with osteoporosis. Dr. Khosla advised a moderate total calcium intake of about 1,000 to 1,200 milligrams a day because there is some evidence that at least that level of calcium intake with appropriate vitamin D intake is probably optimal for preserving bone mass in a range that is unlikely to have any adverse cardiovascular implications.
Dr. Ralph Nixon, of New York University, discussed the role of the lysosome in Alzheimer’s disease (AD). Autophagy, a critical pathway necessary for turning over organelles and long-lived proteins, involves sequestration of obsolete and damaged proteins in a double-membrane structure that fuses with the lysosome, where these proteins are digested by proteases. The process is essential for survival and has been implicated in mechanisms of cellular aging and in age-related disorders.
AD is characterized by plaques and tangles, and within each plaque are hundreds of degenerating neurites. Yet this disease is also characterized by blocks in lysosomal proteolysis, as demonstrated by the accumulation of proteins such as Ab. Early AD has been associated with mutations in presenilin 1 (PS1), which is synthesized in the endoplasmic reticulum, then cleaved and assembled into a component of gamma secretase. The involvement of PS1 in gamma secretase has always been assumed to be its main role, and the increase in Ab has been interpreted as a result of increased or mutant stimulation of gamma secretase activity. However, AD-associated PS1 mutations occur throughout the molecule, and Ab production occurs regardless of the mutation’s location in PS1.
Studies by Dr. Nixon and colleagues have shown that cells deficient in PS1 display an accumulation of engorged lysosomes and autolysosomes, indicating a block in autophagy similar to that seen in patients with AD. This block can be cleared not only by wild-type presinilin, but also by catalytically inactive forms of presinilin, further illustrating that gamma secretase is not necessary for PS1 involvement in autophagy. Dr. Nixon and colleagues have found that the block in autophagy occurs at the protein degradation step; although proteases are present in the lysosome in PS1-knockout cells, they are not acidified and therefore not activated. The failure to activate these proteases arises because the proton pump necessary for their acidification does not move from the endoplasmic reticulum to the lysosome. Instead, it is stuck in the endoplasmic reticulum in an unglycosylated form. On the basis of these observations, Dr. Nixon and colleagues have speculated that PS1 interacts with OST, a protein involved in glycosylation. This interaction facilitates the folding and translocation of the proton pump to the lysosome to acidify and activate proteases so that protein clearance can occur.
These observations and Dr. Nixon’s model are consistent with AD being an autophagy storage disorder similar to other primary lysosome disorders seen in children. Other work in his laboratory has also yielded evidence that early AD also is associated with pathologies affecting the endocytic pathway, as suggested by accelerated endocytosis and altered neurotrophin signaling. Both the autophagic and endocytic pathologies might explain the increase in amyloid seen in AD patients.
Discussion focused on possible links with PS2, apoE 3 and apoE4, and possible amyloid accumulation in childhood lysosomal diseases.
The open session of the 111th meeting of the National Advisory Council on Aging adjourned at 12:44 p.m. on September 22, 2010. The next meeting is scheduled for January 25 and 26, 2011.
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)(**Provisional member whose appointment is not yet official)
Richard J. Hodes, M.D.
Director, National Institute on Aging
National Institutes of Health
*Lisa F. Berkman, Ph.D. (2011)
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
Robert M. Califf, M.D. (2013)
Vice Chancellor for Clinical Research, Duke University
Director, Duke Translational Medicine Institute
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
Hendrie, Hugh C., MB, ChB, DSC (2013)
Professor, Department of Psychiatry, Indiana University School of Medicine
Research Scientist, Regenstrief Institute, Inc.
Center Scientist, Indiana University Center for Aging Research
*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
*Lennart Mucke, M.D. (2012)
Director and Professor of Neuroscience
Gladstone Institute of Neurological Disease
University of California, San Francisco
San Francisco, CA
Perry, Daniel P. (2013)
President and CEO
Alliance for Aging Research
Washington, DC 20006
Petersen, Ronald C., M.D., Ph.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
Orien Reid (2010)
Chairman, Alzheimer's Disease International
President, Consumer Connection
Richardson, Arlan G., Ph.D. (2013)
Barshop Institute for Longevity and Aging Studies
University of Texas Health Science Center
San Antonio, TX
June Simmons (2012)
Chief Executive Officer
Partners in Care Foundation
San Fernando, CA
James P. Smith, Ph.D. (2011)
Department of Labor and Population
Santa Monica, CA
*Susan L. Swain, Ph.D. (2011)
Department of Pathology S2-137
University of Massachusetts Medical School
Worcester, MA 01655
Wetle, Terrie F., Ph.D. (2013)
Associate Dean and Professor
Program in Public Health
Division of Biology and Medicine
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
Deputy Assistant Secretary for Policy and Management
U.S. Department of Health and Human Services
Administration on Aging
Kenneth G. Pugh, M.D.
Commander, MC, U.S. Navy
U. S. Naval Hospital Rota
PSC 819 Box 18-74