February 3-4, 2004
Attachment A - Roster of the National Advisory Council on Aging Attachment B - Director's Status Report
The 91st meeting of the National Advisory Council on Aging (NACA) was convened on Tuesday, February 3, 2004, at 3:00 p.m., in Building 31, Conference Room 6, 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, February 3, from 3:00 to 5:00 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, February 4, from 8:00 a.m. to 2:30 p.m.
Dr. Marie A. Bernard Dr. Melissa M. Brown Dr. John Cacioppo Dr. David Espino Dr. Linda P. Fried Dr. Alan M. Garber Dr. F. Michael Gloth, III Dr. Eugene M. Johnson, Jr. Dr. Lewis H. Kuller Dr. Ronald D. Lee Dr. Virginia M.Y. Lee Dr. Spero M. Manson Dr. Stanley Prusiner Ms. Judith Riggs Dr. Leon J. Thal
Mr. Donald Grantt for Mr. John Wren (AOA)
Dr. Elizabeth H. Blackburn
The Council Roster, which gives titles, affiliations, and terms of appointment, is appended to these minutes as Attachment A.
Dr. Nir Barzilai, Albert Einstein College of Medicine Dr. Frank Booth, University of Missouri - Columbia Dr. Stacey Fitzsimmons, Aspen Systems - Health Research Ms. Linda Harootyan, Gerontological Society of America Ms. Mary Jo Hoeksema, Population Association of America & Association of Population Centers Dr. Darlene Howard, Georgetown University Mr. Todd Kluss, Gerontological Society of America Ms. Pat Kobor, American Psychological Association Dr. Rose Maria Li, Rose Li and Associates, Inc. Dr. Sherry Marts, Society for Women's Health Research Ms. Martha Nolan, Society for Women's Health Research Mr. Tim Perrin, American Association for Geriatric Psychiatry
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 552b(c)(4) and 552b(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 831 applications requesting $863,830,606 for all years underwent initial review. Council recommended 591 for a total of $675,756,680 for all years. The actual funding of the awards recommended is determined by the availability of funds, percentile ranks, priority scores, and program relevance.
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 552b(c)(4) and 552b(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 831 applications requesting $863,830,606 for all years underwent initial review. Council recommended 591 for a total of $675,756,680 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 called the meeting to order at 8:10 a.m. on Wednesday, February 4, 2004, and welcomed members. Director's Status Report Dr. Hodes began by presenting the NIA and NIH budget picture and the implications for research support and planning over the next few years. Comparing NIA's actual budget for FY2003 ($993 million), the recently approved FY2004 appropriation ($1.05 billion), and the President's proposed FY2005 budget ($1.056 billion), Dr. Hodes noted a modest deceleration in growth from 3.2 percent to 3.0 percent. The 3 percent increases in recent years are in stark contrast to the 11-15 percent increases in the 5 years prior, and are lower than NIA has experienced in the last decade. He reminded Council that the President's budget is only the beginning of the appropriation process; a series of Congressional actions occurs before a final budget is enacted. Despite the doubling of the budget in the recent past, the success rate for grant applications has been relatively stable, in the high 20 percent range. It is expected that success rates will be significantly lower in FY2004 and FY2005; funding strategies and compensating funding strategies will need to be developed. The distribution of dollars over funding mechanisms is similar to past years, with about 65 percent of funds allocated to the NIA research project grant (RPG) line. The NIA RPG allocation is higher than the NIH average which tends to be in the mid to high 50 percent range. Centers comprise about 8.4 percent, contracts 5.5 percent, and administrative costs about 3.3 percent of the total NIA budget. The NIA intramural line, at 9.8 percent, has been relatively stable and below the NIH average. Focusing on the specific budget proposal, Dr. Hodes noted that the competing grants line, which indicates dollars available to fund new research grants, rose slightly from FY2003 ($150 million) to FY2004 ($166 million), but is projected in the President's FY2005 budget request to decline to $165 million. The narrative associated with the overall NIH FY2005 Appropriation states that the FY2005 request would support an estimated 10,393 competing RPGs, for $3,609 million, an increase of 258 competing RPGs over the FY2004 enacted level estimate of 10,135 competing RPGs. To realize this modest increase in RPGs, the FY2005 President's Budget provides an aggregate 1.3 percent increase in average cost for RPGs, consistent with the GDP deflator but substantially below the Biomedical Research and Development Price Index (BRDPI), the inflationary index for research. Within this 1.3 percent aggregate increase, and to achieve the President's FY2005 proposed budget numbers, NIH is expecting to adhere to an average cost increase of 1.9 percent for direct recurring costs in noncompeting continuation awards, and an average cost increase of 1.0 percent for competing RPGs. The NIA and NIH costs have been increasing at a much greater rate than what is now being prescribed, due to inflation and also to higher average costs associated with an increased focus on costly translational and multidisciplinary research. Should the President's budget become law, each Institute/Center (IC) would have to hold to the 1 percent average cost increase for competing RPGs. This might require substantial negotiations for cost reductions and would add a new dimension to NIA planning. There was discussion about transfers between the RPG and contract budget lines, this would require Congressional approval and is handled for NIH in the aggregate and not at an Institute level. The pay line for FY2004 will be determined by the total dollars available, the number of applications that are submitted (the denominator), and average costs. The President's proposed budget is based on actual FY2003 data and assumptions about FY2004. If average requested costs increase in FY2004 and FY2005 beyond these projections, NIA will consider reductions in costs in order to pay the allotted number of grants. Concern was expressed by Council members that the field is currently at the point of major scientific breakthroughs, and the current budget situation could compromise momentum for supporting the broader research agenda in aging. If the President's FY2005 budget is enacted, NIA will need to balance expensive awards with less expensive ones, and consider reductions without compromising research to meet average cost and grant number targets. Given that discretionary spending is such a small part of the federal budget, it will be difficult to find additional funds. The historical trend for most of the past decade has been for the President to propose a budget with a relatively low increase and for Congress in a bipartisan way to substantially increase the request. There is no reason to expect this to continue when Congress is feeling great pressure to constrain budgets and deficits. Future Meeting Dates
Dr. Hodes called the meeting to order at 8:10 a.m. on Wednesday, February 4, 2004, and welcomed members.
Dr. Hodes began by presenting the NIA and NIH budget picture and the implications for research support and planning over the next few years. Comparing NIA's actual budget for FY2003 ($993 million), the recently approved FY2004 appropriation ($1.05 billion), and the President's proposed FY2005 budget ($1.056 billion), Dr. Hodes noted a modest deceleration in growth from 3.2 percent to 3.0 percent. The 3 percent increases in recent years are in stark contrast to the 11-15 percent increases in the 5 years prior, and are lower than NIA has experienced in the last decade. He reminded Council that the President's budget is only the beginning of the appropriation process; a series of Congressional actions occurs before a final budget is enacted.
Despite the doubling of the budget in the recent past, the success rate for grant applications has been relatively stable, in the high 20 percent range. It is expected that success rates will be significantly lower in FY2004 and FY2005; funding strategies and compensating funding strategies will need to be developed.
The distribution of dollars over funding mechanisms is similar to past years, with about 65 percent of funds allocated to the NIA research project grant (RPG) line. The NIA RPG allocation is higher than the NIH average which tends to be in the mid to high 50 percent range. Centers comprise about 8.4 percent, contracts 5.5 percent, and administrative costs about 3.3 percent of the total NIA budget. The NIA intramural line, at 9.8 percent, has been relatively stable and below the NIH average.
Focusing on the specific budget proposal, Dr. Hodes noted that the competing grants line, which indicates dollars available to fund new research grants, rose slightly from FY2003 ($150 million) to FY2004 ($166 million), but is projected in the President's FY2005 budget request to decline to $165 million. The narrative associated with the overall NIH FY2005 Appropriation states that the FY2005 request would support an estimated 10,393 competing RPGs, for $3,609 million, an increase of 258 competing RPGs over the FY2004 enacted level estimate of 10,135 competing RPGs. To realize this modest increase in RPGs, the FY2005 President's Budget provides an aggregate 1.3 percent increase in average cost for RPGs, consistent with the GDP deflator but substantially below the Biomedical Research and Development Price Index (BRDPI), the inflationary index for research. Within this 1.3 percent aggregate increase, and to achieve the President's FY2005 proposed budget numbers, NIH is expecting to adhere to an average cost increase of 1.9 percent for direct recurring costs in noncompeting continuation awards, and an average cost increase of 1.0 percent for competing RPGs. The NIA and NIH costs have been increasing at a much greater rate than what is now being prescribed, due to inflation and also to higher average costs associated with an increased focus on costly translational and multidisciplinary research. Should the President's budget become law, each Institute/Center (IC) would have to hold to the 1 percent average cost increase for competing RPGs. This might require substantial negotiations for cost reductions and would add a new dimension to NIA planning.
There was discussion about transfers between the RPG and contract budget lines, this would require Congressional approval and is handled for NIH in the aggregate and not at an Institute level. The pay line for FY2004 will be determined by the total dollars available, the number of applications that are submitted (the denominator), and average costs.
The President's proposed budget is based on actual FY2003 data and assumptions about FY2004. If average requested costs increase in FY2004 and FY2005 beyond these projections, NIA will consider reductions in costs in order to pay the allotted number of grants.
Concern was expressed by Council members that the field is currently at the point of major scientific breakthroughs, and the current budget situation could compromise momentum for supporting the broader research agenda in aging. If the President's FY2005 budget is enacted, NIA will need to balance expensive awards with less expensive ones, and consider reductions without compromising research to meet average cost and grant number targets. Given that discretionary spending is such a small part of the federal budget, it will be difficult to find additional funds. The historical trend for most of the past decade has been for the President to propose a budget with a relatively low increase and for Congress in a bipartisan way to substantially increase the request. There is no reason to expect this to continue when Congress is feeling great pressure to constrain budgets and deficits.
Consideration of Minutes of Last Meeting The minutes of the September 2003 meeting were considered. A motion was made, seconded, and passed to approve the minutes.
The minutes of the September 2003 meeting were considered. A motion was made, seconded, and passed to approve the minutes.
Ms. Jane Shure, Director of NIA's Office of Communication and Public Liaison (OCPL), presented on NIA's public information activities to communicate research findings to the public. She framed her discussion by first noting that in 1913, Congress enacted the Gillette Amendment which states that “appropriated funds may not be used to pay a publicity expert unless specifically appropriated for that purpose.” However, as part of the mission of NIA, Congress mandated in authorizing legislation that OCPL “carry out public information and education programs to disseminate the findings of the Institute and all other relevant information which may assist all Americans, and especially the elderly, in dealing with the problems [of] and understanding the processes associated with aging.” As part of its health education efforts, OCPL has three goals: (1) Improve the health and quality of life of older people through the use of communications; (2) Bridge the gulf between basic laboratory science and practice; and (3) Increase demand for, use of, and access to NIA's information. OCPL's main duties include supporting the NIA's priorities by producing and distributing evidence-based health information, highlighting new research findings, responding to and monitoring public inquiries, and reviewing feedback. In 2003, NIA received a total of 92,444 requests for information on all topics except Alzheimer's Disease (AD) which are handled separately. Nearly two-thirds of the requests received by NIA were by telephone, about a fifth were by mail or fax, and another fifth received online (either by E-mail or Internet ordering). Most of the calls are from women. A total of about 1.5 million publications were requested in 2003. Exercise: A Guide from the National Institute on Aging is the most frequently requested material, followed by Exercise: A Video from the National Institute on Aging . There are a variety of promotional materials that keep the exercise materials in circulation, and NIA is committed to keeping the book free to requestors. Over 600,000 copies of the Exercise Guide have been distributed in the last 4 years. It has been translated into Japanese and there is a culturally adapted version in Spanish. Together with the Age Page on exercise, the exercise materials comprise nearly 50 percent of all publications requested in 2003. The other seven materials that round out the top 10 list address topics on talking with doctors, preventing falls, diabetes, osteoporosis, arthritis, and nutrition. The NIA Online ordering system counted a total of 139,569 unique user sessions since it was established in August 2003. The top 10 states from where requests in 2003 originated seem stable, with California, New York, and Florida leading the list. The NIA-supported Alzheimer's Disease Education & Referral Center (ADEAR) offers a more tailored and personalized operation to meet the demand for information on AD by health care providers and families. ADEAR is a full service information and referral center that is staffed with information specialists who answer specific questions, collect materials from the NIA-funded AD Centers, and refer questioners seeking more detailed information to academic centers. Any question that has an element of support and care are generally referred to the Alzheimer's Association (AA). Ms. Shure noted that NIA and AA have many shared interests, including recruitment of participants into research studies. For example, NIA is supporting a study on genetics of late-onset AD that seeks to establish a national cell repository of 3,000 families with AD siblings. It was clear that this was not going to be an easy recruitment. Given the importance of family access, NIA immediately sought out the assistance of the AA, and AA chapters have helped with the AD genetic study recruitment. NIA is working closely with AA to address the sensitivity of genetics research, and on promotional activities to highlight the genetics initiative. ADEAR handled 22,271 requests in 2003. About 43 percent of requests came by telephone; about 50 percent were received online; and less than 6 percent came by mail or fax. ADEAR distributed a total of 675,128 print publications in 2003, the top one being Unraveling the Mystery at 94,441 copies. The top 10 state requests were again led by California, New York, and Florida. There were also 49,710 unique visitors in 2003 to the AD Clinical Trials Database website. Recognizing that people over 60 are the fastest growing group of Internet users, the NIA established NIHSeniorHealth.gov, a senior-friendly website, in collaboration with the National Library of Medicine to maximize access to evidence-based information on health and wellness by seniors. The site offers quizzes, short videos, easy searching features, and a talking function for low vision users. On any given month, the site usually has over 1 million page hits. OCPL has also strived to address health disparities by making materials available in Spanish. Dr. David Espino was acknowledged for his substantial assistance in fielding interview requests in Spanish and assisting with message delivery. The Bilingual Information Center, a component of ADEAR, has distributed over 138,000 Spanish materials on behalf of the NIA, and over 65,000 ADEAR Spanish materials, and has fielded about 6,700 calls on the dedicated Spanish toll-free line. It has been challenging and very labor intensive to reach minority communities. OCPL is in the process of promoting exercise among older American Indians and Alaska Natives (AI/AN) where there is no word for “exercise” in their vernacular. The process began with initial research comprised of listening circles and phone interviews, and working with the AI/AN communities to develop materials and messages. OCPL is trying to reach out similarly to the African American community to develop culturally appropriate materials that are sensitive to literacy levels and life issues. Initial findings from literature reviews and phone interviews highlight the challenges of reaching the African American community, including competing physical ailments and other medical problems, the lack of awareness about appropriate exercises, and the low priority accorded exercise. One Council member suggested that partnering with the YMCA, particularly in predominantly African-American areas, could help to reach minority populations and should be explored. Ms. Shure also highlighted Vital Visionaries, a partnership between the NIA and the American Visionary Arts Museum that seeks to bring medical students together with vital older people to assess whether the positive interaction between the two groups results in a healthier outlook toward older people. The collaboration is spearheaded by Dr. Judy Salerno with assistance from Dr. Linda Fried.
Ms. Jane Shure, Director of NIA's Office of Communication and Public Liaison (OCPL), presented on NIA's public information activities to communicate research findings to the public. She framed her discussion by first noting that in 1913, Congress enacted the Gillette Amendment which states that “appropriated funds may not be used to pay a publicity expert unless specifically appropriated for that purpose.” However, as part of the mission of NIA, Congress mandated in authorizing legislation that OCPL “carry out public information and education programs to disseminate the findings of the Institute and all other relevant information which may assist all Americans, and especially the elderly, in dealing with the problems [of] and understanding the processes associated with aging.” As part of its health education efforts, OCPL has three goals: (1) Improve the health and quality of life of older people through the use of communications; (2) Bridge the gulf between basic laboratory science and practice; and (3) Increase demand for, use of, and access to NIA's information.
OCPL's main duties include supporting the NIA's priorities by producing and distributing evidence-based health information, highlighting new research findings, responding to and monitoring public inquiries, and reviewing feedback. In 2003, NIA received a total of 92,444 requests for information on all topics except Alzheimer's Disease (AD) which are handled separately. Nearly two-thirds of the requests received by NIA were by telephone, about a fifth were by mail or fax, and another fifth received online (either by E-mail or Internet ordering). Most of the calls are from women.
A total of about 1.5 million publications were requested in 2003. Exercise: A Guide from the National Institute on Aging is the most frequently requested material, followed by Exercise: A Video from the National Institute on Aging . There are a variety of promotional materials that keep the exercise materials in circulation, and NIA is committed to keeping the book free to requestors. Over 600,000 copies of the Exercise Guide have been distributed in the last 4 years. It has been translated into Japanese and there is a culturally adapted version in Spanish. Together with the Age Page on exercise, the exercise materials comprise nearly 50 percent of all publications requested in 2003. The other seven materials that round out the top 10 list address topics on talking with doctors, preventing falls, diabetes, osteoporosis, arthritis, and nutrition.
The NIA Online ordering system counted a total of 139,569 unique user sessions since it was established in August 2003. The top 10 states from where requests in 2003 originated seem stable, with California, New York, and Florida leading the list.
The NIA-supported Alzheimer's Disease Education & Referral Center (ADEAR) offers a more tailored and personalized operation to meet the demand for information on AD by health care providers and families. ADEAR is a full service information and referral center that is staffed with information specialists who answer specific questions, collect materials from the NIA-funded AD Centers, and refer questioners seeking more detailed information to academic centers. Any question that has an element of support and care are generally referred to the Alzheimer's Association (AA). Ms. Shure noted that NIA and AA have many shared interests, including recruitment of participants into research studies. For example, NIA is supporting a study on genetics of late-onset AD that seeks to establish a national cell repository of 3,000 families with AD siblings. It was clear that this was not going to be an easy recruitment. Given the importance of family access, NIA immediately sought out the assistance of the AA, and AA chapters have helped with the AD genetic study recruitment. NIA is working closely with AA to address the sensitivity of genetics research, and on promotional activities to highlight the genetics initiative.
ADEAR handled 22,271 requests in 2003. About 43 percent of requests came by telephone; about 50 percent were received online; and less than 6 percent came by mail or fax. ADEAR distributed a total of 675,128 print publications in 2003, the top one being Unraveling the Mystery at 94,441 copies. The top 10 state requests were again led by California, New York, and Florida. There were also 49,710 unique visitors in 2003 to the AD Clinical Trials Database website.
Recognizing that people over 60 are the fastest growing group of Internet users, the NIA established NIHSeniorHealth.gov, a senior-friendly website, in collaboration with the National Library of Medicine to maximize access to evidence-based information on health and wellness by seniors. The site offers quizzes, short videos, easy searching features, and a talking function for low vision users. On any given month, the site usually has over 1 million page hits.
OCPL has also strived to address health disparities by making materials available in Spanish. Dr. David Espino was acknowledged for his substantial assistance in fielding interview requests in Spanish and assisting with message delivery. The Bilingual Information Center, a component of ADEAR, has distributed over 138,000 Spanish materials on behalf of the NIA, and over 65,000 ADEAR Spanish materials, and has fielded about 6,700 calls on the dedicated Spanish toll-free line. It has been challenging and very labor intensive to reach minority communities. OCPL is in the process of promoting exercise among older American Indians and Alaska Natives (AI/AN) where there is no word for “exercise” in their vernacular. The process began with initial research comprised of listening circles and phone interviews, and working with the AI/AN communities to develop materials and messages. OCPL is trying to reach out similarly to the African American community to develop culturally appropriate materials that are sensitive to literacy levels and life issues. Initial findings from literature reviews and phone interviews highlight the challenges of reaching the African American community, including competing physical ailments and other medical problems, the lack of awareness about appropriate exercises, and the low priority accorded exercise. One Council member suggested that partnering with the YMCA, particularly in predominantly African-American areas, could help to reach minority populations and should be explored.
Ms. Shure also highlighted Vital Visionaries, a partnership between the NIA and the American Visionary Arts Museum that seeks to bring medical students together with vital older people to assess whether the positive interaction between the two groups results in a healthier outlook toward older people. The collaboration is spearheaded by Dr. Judy Salerno with assistance from Dr. Linda Fried.
Dr. David Espino reported on three main issues covered by the Task Force on Minority Aging Research at their meeting on February 3: (1) appropriate gender and minority representation in research projects; (2) minority supplements; and (3) K01 (development of a Career Development initiative) progress. The policy is that the Task Force must review at least annually the appropriate inclusion of subjects by gender and race and ethnicity in current research projects, certify that the NIA is in compliance, and make the information available to the public. The FY2002 and FY2003 Aggregate Enrollment Data for All Extramural Research Protocols was provided using both the 1977 OMB Standards and the 1997 OMB Standards which allows for multiple race reporting, separates out Hispanic ethnicity, and adds a Hawaiian/Pacific Islander category. Using the 1997 OMB standards, approximately 75 percent of total subjects were White in FY2003, compared to 81 percent in FY2002. During this same period, the proportion Black or African American subjects increased from 9 percent to 11 percent of the total, the proportion with race unknown or not reported increased from 3.3 percent to 8.4 percent, and the proportion identified as Hispanic or Latino increased from 3.5 percent to 8.7 percent. More males (151,103 or 51 percent of the total) than females (142,227 or 48 percent) were enrolled in FY2003, representing greater parity than in FY2002 when 110,904 males and 83,819 females were enrolled. Although the success rate for minority supplements remains relatively high, there has been a decline in success rates over the past three years (65 percent in FY2001; 51 percent in FY2002; and 49 percent in FY2003) largely as a result of an increase in applications. Dr. Espino praised NIA efforts to find additional funds for minority supplements in FY2003. Echoing Dr. Espino's positive assessment of the NIA minority supplement process, Dr. Spero Manson applauded NIA for the quality and systematic nature of the feedback and ongoing attention to minority supplement reviews, which he rated as significantly better than other ICs in his experience. In updating Council on a new mentored Career Research Development (KO1) initiative, which was designed to support career development of underrepresented minorities and to provide support for mentors, Dr. Espino stated that the K01 solicitation has been put on hold while NIH revises its criteria on various specific population initiatives to make eligibility consistent with the standard set by the U.S. Supreme Court in two cases involving the University of Michigan. The Task Force also heard NIA staff present on program highlights with respect to research initiatives related to underrepresented minorities, innovative research, and ongoing support for minority investigators. Finally, Dr. Espino announced the availability of The Science of Inclusion: Recruiting and Retaining Racial and Ethnic Elders in Health Research (Curry L and Jackson J, eds, 2003), a publication of the Gerontological Society of America that was a collaborative effort with the Resource Centers on Minority Aging Research (RCMARs).
Dr. David Espino reported on three main issues covered by the Task Force on Minority Aging Research at their meeting on February 3: (1) appropriate gender and minority representation in research projects; (2) minority supplements; and (3) K01 (development of a Career Development initiative) progress.
The policy is that the Task Force must review at least annually the appropriate inclusion of subjects by gender and race and ethnicity in current research projects, certify that the NIA is in compliance, and make the information available to the public. The FY2002 and FY2003 Aggregate Enrollment Data for All Extramural Research Protocols was provided using both the 1977 OMB Standards and the 1997 OMB Standards which allows for multiple race reporting, separates out Hispanic ethnicity, and adds a Hawaiian/Pacific Islander category. Using the 1997 OMB standards, approximately 75 percent of total subjects were White in FY2003, compared to 81 percent in FY2002. During this same period, the proportion Black or African American subjects increased from 9 percent to 11 percent of the total, the proportion with race unknown or not reported increased from 3.3 percent to 8.4 percent, and the proportion identified as Hispanic or Latino increased from 3.5 percent to 8.7 percent. More males (151,103 or 51 percent of the total) than females (142,227 or 48 percent) were enrolled in FY2003, representing greater parity than in FY2002 when 110,904 males and 83,819 females were enrolled.
Although the success rate for minority supplements remains relatively high, there has been a decline in success rates over the past three years (65 percent in FY2001; 51 percent in FY2002; and 49 percent in FY2003) largely as a result of an increase in applications. Dr. Espino praised NIA efforts to find additional funds for minority supplements in FY2003. Echoing Dr. Espino's positive assessment of the NIA minority supplement process, Dr. Spero Manson applauded NIA for the quality and systematic nature of the feedback and ongoing attention to minority supplement reviews, which he rated as significantly better than other ICs in his experience.
In updating Council on a new mentored Career Research Development (KO1) initiative, which was designed to support career development of underrepresented minorities and to provide support for mentors, Dr. Espino stated that the K01 solicitation has been put on hold while NIH revises its criteria on various specific population initiatives to make eligibility consistent with the standard set by the U.S. Supreme Court in two cases involving the University of Michigan.
The Task Force also heard NIA staff present on program highlights with respect to research initiatives related to underrepresented minorities, innovative research, and ongoing support for minority investigators.
Finally, Dr. Espino announced the availability of The Science of Inclusion: Recruiting and Retaining Racial and Ethnic Elders in Health Research (Curry L and Jackson J, eds, 2003), a publication of the Gerontological Society of America that was a collaborative effort with the Resource Centers on Minority Aging Research (RCMARs).
Dr. Lewis Kuller reported on the deliberations of the Working Group on Program (WGOP), which met on February 3. The WGOP discussed how NIA activities can be better linked with that of the Food and Drug Administration (FDA), a topic that was addressed in more detail during Dr. Mark McClellan's presentation with Council later in the day. A. Plan for Behavioral and Social Research Program Review The Behavioral and Social Research (BSR) Program review is scheduled for May 23-24, 2004. Dr. Richard Suzman provided background information to the WGOP on BSR's previous reviews and the evolution of the program. A subgroup met to plan the review, which is expected to include consideration of the types of data collection, training, and the appropriate mix of research project grants to achieve programmatic objectives of BSR. B. Update on Clinical Investigators Working Group The WGOP discussed the continuing challenges to stimulating approaches to increase the number of clinical investigators. Dr. Robin Barr presented data on physician investigators, a group targeted for development by NIH and NIA. NIA has collaborated with a number of private foundations to continue the Paul B. Beeson Career Development Awards in Aging initiative. The joint initiative attracted 35 applications from physician-investigators and a full report on the initiative will be provided at May Council. Questions were raised about additional ways to collaborate with foundations to further support initiatives that develop physician-investigators. There was also discussion about how to change the environment in medical schools to stimulate short term training in aging research, especially clinical investigation and linkages to systems biology of aging research. Another initiative, the loan repayment program, has had a positive effect in stimulating successful applications from clinical investigators. This program is attracting more applicants than available funds; most recently, about 80 percent of requests for payment were approved. This percentage is expected to decline as increasingly more investigators recognize this resource to lessen medical school debt. Council members contended that one of the best approaches for increasing the number of clinical investigators is to develop outstanding mentors and mentor-trainee relationships. It was suggested that NIA might encourage trainee connections to programs rather than to individuals. C. NIA-Sponsored IOM and NAS Reports Dr. Kuller reported that the WGOP had a lively discussion about the Institute of Medicine report on testosterone trials that was commissioned by the NIA and the National Cancer Institute (NCI) (Institute of Medicine, Testosterone and Aging: Clinical Research Directions . CT Liberman and DG Blazer, Eds. Washington, D.C.: The National Academies Press). Testosterone levels in men decline with age. There were 800,000 men reportedly undergoing testosterone therapy in 2002, double the number in 1999, a majority of whom are middle-aged and taking the hormone as a prophylactic because they think they are testosterone deficient. These numbers are much smaller than the approximately 6 million women on estrogen therapy, but with the new therapies in gel form available and the evolution of modified (androgen) SERMS, much like estrogen SERMS, utilization of testosterone therapies is expected to grow dramatically. The IOM Report concluded that there is insufficient evidence that testosterone treatment benefits elderly men in terms of bone density, muscle strength, reduction of frailty and sarcopenia, well-being, cognition, sexual function, and cardiovascular function. Information from research using sex steroid hormone therapy for post-menopausal women provides some indication of the types of issues involved. There are risks to testosterone therapy such as prostate cancer, benign prostatic hypertrophy, sleep apnea, and polycythaemia (an increase in red blood cells that can lead to blood circulation problems). Dr. Kuller referred interested parties to a NEJM review article (Rhoden EL and Morgentaler A. Testosterone therapy medical progress: risks of testosterone-replacement therapy and recommendations for monitoring. NEJM 350: 482-492, January 29, 2004) and accompanying editorial (Snyder PJ. Hypogonadism in elderly men—What to do until the evidence comes. NEJM 350: 440-442, January 29, 2004) for further elaboration. The WGOP discussion focused on possible clinical trials of testosterone. The IOM has recommended a focus on therapeutic rather than prevention trials, to begin with men who have sarcopenia, frailty, and/or disability, and undertake a therapeutic trial with clinically measurable outcomes, to examine benefits and safety profiles, to ensure that no harm is done based on objective outcomes, and to build on further research. There was discussion about whether such a design is sound and feasible, whether it should be a mixture of primary and secondary prevention, and about power calculations. An underlying issue is the cost and complexity of the trials; even small trials are not inconsequential. There is also a question of a window of opportunity since it will be difficult to convince men to remain off testosterone if treatment offers clear short-term benefits. The emphasis of the IOM report was to look at frailty and disability, sexual dysfunction, cognitive function, vitality and quality of life as endpoints for individuals with some degree of disability. NIA staff will proceed to determine the type of clinical trial to pursue. Two Council members have already expressed interest in participating in such planning; others are welcome to join the effort. Three NIA-supported National Academy of Sciences (NAS) reports were also highlighted: (1) Health and Safety Needs of Older Workers ; (2) Technology for Adaptive Aging , that focused on how to apply research on innovative technology for the benefit of older people, with collaboration from the National Academy of Engineering. The WGOP had some discussion about how to better involve engineers in research on measurable outcomes. The utility and quality of Small Business Innovation Research (SBIR) grants funded from 1993 to 2002 were examined, including whether more emphasis on cross-disciplinary approaches involving engineering should be encouraged, as well as a discussion of existing datasets that might inform this topic; (3) Whitehall in Washington , a report still under development, was inspired by the Whitehall Study of British civil servants which showed remarkable differences in mortality and health by occupational grade. The WGOP had a lively discussion about whether it makes sense to replicate in some form the Whitehall Study in Washington, D.C. Dr. Kuller added that his own prior research (cf. Federal Women's Study) also found remarkable differences in mortality outcomes according to grade, overwhelming the effects of ethnic and racial differences. D. Advisory Meetings, Conferences, and Workshops Finally, Dr. Kuller briefly summarized five presentations about past meetings and upcoming initiatives. Joint Workshop on Hutchinson-Gilford Progeria Syndrome The second workshop on Hutchinson-Gilford Progeria, co-sponsored by the Progeria Research Foundation, the NIA, the National Human Genome Research Institute, and the NIH Office for Rare Diseases, was held in July 2003. Although the number of people with Hutchinson-Gilford Progeria Syndrome is extremely small, the study of this genetic abnormality has led to an understanding of a variety of related genes, and has stimulated a great deal of molecular biology research which may have broad implications for the field of aging. Dr. Kuller described this as a model for how rare diseases may be interesting for understanding common diseases. Meeting of the NIA Task Force on Comorbidity The multidisciplinary NIA Task Force on Comorbidity met in October 2003 to evaluate the current state of knowledge and to identify directions for future research in this area. Some comorbidities are related to common etiology; some are related to adverse treatment effects. It is important to understand how comorbidities are linked and how they affect therapeutic and preventive strategies for older individuals. A proposal for an RFA on Multiple Morbidity in Geriatric Practice was presented to move this initiative forward. Within the discussion of the comorbidity RFA, Dr. Kuller noted that a recurrent issue that needs to be resolved is whether large clinical trials should be funded as grants or contracts. Meeting on Neuroimaging of Alzheimer's Disease NIA is sponsoring a meeting with the Centers for Medicare and Medicaid Services (CMS) in April 2004 to examine issues related to neuroimaging in Alzheimer's Disease (AD). This is a continuation of a series of meetings on whether CMS should be paying for PET scans and other imaging techniques for AD diagnoses. A project underway at NIA on neuroimaging might be a potential source for testing the value of PET scans and other modalities. The Biology of Premenopausal Protection Workshop This advisory workshop will be held in Bethesda, Maryland on May 26-27, 2004 to explore gaps in knowledge of the role of the steroid and peptide reproductive hormone levels across the menstrual cycle within the premenopausal hypothalamic-pituitary-ovarian (H-P-O) axis that may serve to protect premenopausal women from health problems associated with menopause. This meeting is focused on biology as opposed to therapies. Sex Steroid Studies: Bench to Bedside – What is Right? What Is Wrong? This two-day advisory workshop, proposed for Fall 2004, will focus on the basic science, epidemiologic, and available clinical trial data to identify what data are still needed for designing appropriate clinical trials on the use of sex steroids for prevention of cognitive decline in aging women. Of interest are drug and hormone therapies that may be available, differences in how they work, and route of administration. Many women may need short-term hormone therapies, and issues remain about effects of hormone therapy on cognition and overall well being of women. Dr. Miriam Kelty asked Council members for their concurrence to proceed on these planned advisory meetings and the proposed RFA, as they are likely to lead to initiatives involving NIA resources. All proposed initiatives that were brought to the meeting from the WGOP passed by voice vote. E. Approval of the Statement of Understanding The Statement of Understanding between the Council and Institute staff is acted on once a year to allow the business of the Institute to continue between Council meetings. In response to Council member questions, it was clarified that fewer than 100 requests for administrative supplements are received in any given year, and only a proportion of such requests are granted. As part of the approval process, NIA staff examines the awarded budget, unexpended funds, and negotiates an amount. A motion was made, seconded, and passed to approve the Statement of Understanding with no changes. F. Discussion Prompted by a question posed by a Council member, discussion ensued about health care costs for the elderly, and costs incurred in the last few years of life. NIA has funded research on the cost implications of extended life expectancy with varying assumptions about levels of disability. Dr. Ronald Lee shared conclusions from his research using Medicare data on costs during the 15 years leading up to death. Although there are more elderly people to whom health care must be provided, the costs for an elderly person are less on average because the proportion near death at any age declines as mortality declines. In practice, these two effects largely cancel each other out in the U.S. over a time span of approximately 75 years. It therefore makes little difference whether mortality declines rapidly or slowly in terms of projected Medicare costs. Dr. Suzman noted several strands of NIA-supported research that bear upon the issue. Researchers at the University of Chicago and elsewhere have found economic returns on the order of trillions of dollars, from the extension of life expectancy. There are also data showing that costs decline with age, and less intensive medical services are used after about age 80 or 85. Dr. Robert Fogel has predicted that over the next 100 years the percentage of GDP spent on health care is likely to rise from 15 percent today (which is the highest of any developed country in the world) to 20-25 percent since he sees health care as one of the last consumption frontiers, raising questions about the impact on the economy. Another strand of related research is by Dr. David Cutler and others showing positive returns from increased spending on health care, although on the margin, much money is ill-spent and wasted. Dr. Kuller observed that paying for care of preventable diseases means there is less money to pay for nonpreventable conditions. He suggested that the NIA message should be that by improving quality of life and preventing disease, NIA research ultimately helps the government pay for the nonpreventable costs of treating elderly patients at the end of life. Dr. Hodes suggested this topic as a good one to present as a Program Highlight at the next Council meeting. This suggestion was well received, with one member adding that there is still some controversy about issues related to life extension. Emphasizing better care for the elderly could reverse the trend of decreasing costs and actually raise costs in the future. G. Statistical Data on Extramural Program Dr. Kelty noted the availability of statistical data on applications assigned to the January 2004 Council round. There were no questions raised about these data.
Dr. Lewis Kuller reported on the deliberations of the Working Group on Program (WGOP), which met on February 3. The WGOP discussed how NIA activities can be better linked with that of the Food and Drug Administration (FDA), a topic that was addressed in more detail during Dr. Mark McClellan's presentation with Council later in the day.
A. Plan for Behavioral and Social Research Program Review The Behavioral and Social Research (BSR) Program review is scheduled for May 23-24, 2004. Dr. Richard Suzman provided background information to the WGOP on BSR's previous reviews and the evolution of the program. A subgroup met to plan the review, which is expected to include consideration of the types of data collection, training, and the appropriate mix of research project grants to achieve programmatic objectives of BSR. B. Update on Clinical Investigators Working Group
A. Plan for Behavioral and Social Research Program Review
The Behavioral and Social Research (BSR) Program review is scheduled for May 23-24, 2004. Dr. Richard Suzman provided background information to the WGOP on BSR's previous reviews and the evolution of the program. A subgroup met to plan the review, which is expected to include consideration of the types of data collection, training, and the appropriate mix of research project grants to achieve programmatic objectives of BSR.
B. Update on Clinical Investigators Working Group
The WGOP discussed the continuing challenges to stimulating approaches to increase the number of clinical investigators. Dr. Robin Barr presented data on physician investigators, a group targeted for development by NIH and NIA. NIA has collaborated with a number of private foundations to continue the Paul B. Beeson Career Development Awards in Aging initiative. The joint initiative attracted 35 applications from physician-investigators and a full report on the initiative will be provided at May Council. Questions were raised about additional ways to collaborate with foundations to further support initiatives that develop physician-investigators. There was also discussion about how to change the environment in medical schools to stimulate short term training in aging research, especially clinical investigation and linkages to systems biology of aging research. Another initiative, the loan repayment program, has had a positive effect in stimulating successful applications from clinical investigators. This program is attracting more applicants than available funds; most recently, about 80 percent of requests for payment were approved. This percentage is expected to decline as increasingly more investigators recognize this resource to lessen medical school debt. Council members contended that one of the best approaches for increasing the number of clinical investigators is to develop outstanding mentors and mentor-trainee relationships. It was suggested that NIA might encourage trainee connections to programs rather than to individuals. C. NIA-Sponsored IOM and NAS Reports
The WGOP discussed the continuing challenges to stimulating approaches to increase the number of clinical investigators. Dr. Robin Barr presented data on physician investigators, a group targeted for development by NIH and NIA. NIA has collaborated with a number of private foundations to continue the Paul B. Beeson Career Development Awards in Aging initiative. The joint initiative attracted 35 applications from physician-investigators and a full report on the initiative will be provided at May Council. Questions were raised about additional ways to collaborate with foundations to further support initiatives that develop physician-investigators. There was also discussion about how to change the environment in medical schools to stimulate short term training in aging research, especially clinical investigation and linkages to systems biology of aging research. Another initiative, the loan repayment program, has had a positive effect in stimulating successful applications from clinical investigators. This program is attracting more applicants than available funds; most recently, about 80 percent of requests for payment were approved. This percentage is expected to decline as increasingly more investigators recognize this resource to lessen medical school debt. Council members contended that one of the best approaches for increasing the number of clinical investigators is to develop outstanding mentors and mentor-trainee relationships. It was suggested that NIA might encourage trainee connections to programs rather than to individuals.
C. NIA-Sponsored IOM and NAS Reports
Dr. Kuller reported that the WGOP had a lively discussion about the Institute of Medicine report on testosterone trials that was commissioned by the NIA and the National Cancer Institute (NCI) (Institute of Medicine, Testosterone and Aging: Clinical Research Directions . CT Liberman and DG Blazer, Eds. Washington, D.C.: The National Academies Press). Testosterone levels in men decline with age. There were 800,000 men reportedly undergoing testosterone therapy in 2002, double the number in 1999, a majority of whom are middle-aged and taking the hormone as a prophylactic because they think they are testosterone deficient. These numbers are much smaller than the approximately 6 million women on estrogen therapy, but with the new therapies in gel form available and the evolution of modified (androgen) SERMS, much like estrogen SERMS, utilization of testosterone therapies is expected to grow dramatically. The IOM Report concluded that there is insufficient evidence that testosterone treatment benefits elderly men in terms of bone density, muscle strength, reduction of frailty and sarcopenia, well-being, cognition, sexual function, and cardiovascular function. Information from research using sex steroid hormone therapy for post-menopausal women provides some indication of the types of issues involved. There are risks to testosterone therapy such as prostate cancer, benign prostatic hypertrophy, sleep apnea, and polycythaemia (an increase in red blood cells that can lead to blood circulation problems). Dr. Kuller referred interested parties to a NEJM review article (Rhoden EL and Morgentaler A. Testosterone therapy medical progress: risks of testosterone-replacement therapy and recommendations for monitoring. NEJM 350: 482-492, January 29, 2004) and accompanying editorial (Snyder PJ. Hypogonadism in elderly men—What to do until the evidence comes. NEJM 350: 440-442, January 29, 2004) for further elaboration. The WGOP discussion focused on possible clinical trials of testosterone. The IOM has recommended a focus on therapeutic rather than prevention trials, to begin with men who have sarcopenia, frailty, and/or disability, and undertake a therapeutic trial with clinically measurable outcomes, to examine benefits and safety profiles, to ensure that no harm is done based on objective outcomes, and to build on further research. There was discussion about whether such a design is sound and feasible, whether it should be a mixture of primary and secondary prevention, and about power calculations. An underlying issue is the cost and complexity of the trials; even small trials are not inconsequential. There is also a question of a window of opportunity since it will be difficult to convince men to remain off testosterone if treatment offers clear short-term benefits. The emphasis of the IOM report was to look at frailty and disability, sexual dysfunction, cognitive function, vitality and quality of life as endpoints for individuals with some degree of disability. NIA staff will proceed to determine the type of clinical trial to pursue. Two Council members have already expressed interest in participating in such planning; others are welcome to join the effort. Three NIA-supported National Academy of Sciences (NAS) reports were also highlighted: (1) Health and Safety Needs of Older Workers ; (2) Technology for Adaptive Aging , that focused on how to apply research on innovative technology for the benefit of older people, with collaboration from the National Academy of Engineering. The WGOP had some discussion about how to better involve engineers in research on measurable outcomes. The utility and quality of Small Business Innovation Research (SBIR) grants funded from 1993 to 2002 were examined, including whether more emphasis on cross-disciplinary approaches involving engineering should be encouraged, as well as a discussion of existing datasets that might inform this topic; (3) Whitehall in Washington , a report still under development, was inspired by the Whitehall Study of British civil servants which showed remarkable differences in mortality and health by occupational grade. The WGOP had a lively discussion about whether it makes sense to replicate in some form the Whitehall Study in Washington, D.C. Dr. Kuller added that his own prior research (cf. Federal Women's Study) also found remarkable differences in mortality outcomes according to grade, overwhelming the effects of ethnic and racial differences. D. Advisory Meetings, Conferences, and Workshops
Dr. Kuller reported that the WGOP had a lively discussion about the Institute of Medicine report on testosterone trials that was commissioned by the NIA and the National Cancer Institute (NCI) (Institute of Medicine, Testosterone and Aging: Clinical Research Directions . CT Liberman and DG Blazer, Eds. Washington, D.C.: The National Academies Press). Testosterone levels in men decline with age. There were 800,000 men reportedly undergoing testosterone therapy in 2002, double the number in 1999, a majority of whom are middle-aged and taking the hormone as a prophylactic because they think they are testosterone deficient. These numbers are much smaller than the approximately 6 million women on estrogen therapy, but with the new therapies in gel form available and the evolution of modified (androgen) SERMS, much like estrogen SERMS, utilization of testosterone therapies is expected to grow dramatically. The IOM Report concluded that there is insufficient evidence that testosterone treatment benefits elderly men in terms of bone density, muscle strength, reduction of frailty and sarcopenia, well-being, cognition, sexual function, and cardiovascular function. Information from research using sex steroid hormone therapy for post-menopausal women provides some indication of the types of issues involved. There are risks to testosterone therapy such as prostate cancer, benign prostatic hypertrophy, sleep apnea, and polycythaemia (an increase in red blood cells that can lead to blood circulation problems). Dr. Kuller referred interested parties to a NEJM review article (Rhoden EL and Morgentaler A. Testosterone therapy medical progress: risks of testosterone-replacement therapy and recommendations for monitoring. NEJM 350: 482-492, January 29, 2004) and accompanying editorial (Snyder PJ. Hypogonadism in elderly men—What to do until the evidence comes. NEJM 350: 440-442, January 29, 2004) for further elaboration.
The WGOP discussion focused on possible clinical trials of testosterone. The IOM has recommended a focus on therapeutic rather than prevention trials, to begin with men who have sarcopenia, frailty, and/or disability, and undertake a therapeutic trial with clinically measurable outcomes, to examine benefits and safety profiles, to ensure that no harm is done based on objective outcomes, and to build on further research. There was discussion about whether such a design is sound and feasible, whether it should be a mixture of primary and secondary prevention, and about power calculations. An underlying issue is the cost and complexity of the trials; even small trials are not inconsequential. There is also a question of a window of opportunity since it will be difficult to convince men to remain off testosterone if treatment offers clear short-term benefits. The emphasis of the IOM report was to look at frailty and disability, sexual dysfunction, cognitive function, vitality and quality of life as endpoints for individuals with some degree of disability. NIA staff will proceed to determine the type of clinical trial to pursue. Two Council members have already expressed interest in participating in such planning; others are welcome to join the effort.
Three NIA-supported National Academy of Sciences (NAS) reports were also highlighted: (1) Health and Safety Needs of Older Workers ; (2) Technology for Adaptive Aging , that focused on how to apply research on innovative technology for the benefit of older people, with collaboration from the National Academy of Engineering. The WGOP had some discussion about how to better involve engineers in research on measurable outcomes. The utility and quality of Small Business Innovation Research (SBIR) grants funded from 1993 to 2002 were examined, including whether more emphasis on cross-disciplinary approaches involving engineering should be encouraged, as well as a discussion of existing datasets that might inform this topic; (3) Whitehall in Washington , a report still under development, was inspired by the Whitehall Study of British civil servants which showed remarkable differences in mortality and health by occupational grade. The WGOP had a lively discussion about whether it makes sense to replicate in some form the Whitehall Study in Washington, D.C. Dr. Kuller added that his own prior research (cf. Federal Women's Study) also found remarkable differences in mortality outcomes according to grade, overwhelming the effects of ethnic and racial differences.
D. Advisory Meetings, Conferences, and Workshops
Finally, Dr. Kuller briefly summarized five presentations about past meetings and upcoming initiatives. Joint Workshop on Hutchinson-Gilford Progeria Syndrome The second workshop on Hutchinson-Gilford Progeria, co-sponsored by the Progeria Research Foundation, the NIA, the National Human Genome Research Institute, and the NIH Office for Rare Diseases, was held in July 2003. Although the number of people with Hutchinson-Gilford Progeria Syndrome is extremely small, the study of this genetic abnormality has led to an understanding of a variety of related genes, and has stimulated a great deal of molecular biology research which may have broad implications for the field of aging. Dr. Kuller described this as a model for how rare diseases may be interesting for understanding common diseases. Meeting of the NIA Task Force on Comorbidity The multidisciplinary NIA Task Force on Comorbidity met in October 2003 to evaluate the current state of knowledge and to identify directions for future research in this area. Some comorbidities are related to common etiology; some are related to adverse treatment effects. It is important to understand how comorbidities are linked and how they affect therapeutic and preventive strategies for older individuals. A proposal for an RFA on Multiple Morbidity in Geriatric Practice was presented to move this initiative forward. Within the discussion of the comorbidity RFA, Dr. Kuller noted that a recurrent issue that needs to be resolved is whether large clinical trials should be funded as grants or contracts. Meeting on Neuroimaging of Alzheimer's Disease NIA is sponsoring a meeting with the Centers for Medicare and Medicaid Services (CMS) in April 2004 to examine issues related to neuroimaging in Alzheimer's Disease (AD). This is a continuation of a series of meetings on whether CMS should be paying for PET scans and other imaging techniques for AD diagnoses. A project underway at NIA on neuroimaging might be a potential source for testing the value of PET scans and other modalities. The Biology of Premenopausal Protection Workshop This advisory workshop will be held in Bethesda, Maryland on May 26-27, 2004 to explore gaps in knowledge of the role of the steroid and peptide reproductive hormone levels across the menstrual cycle within the premenopausal hypothalamic-pituitary-ovarian (H-P-O) axis that may serve to protect premenopausal women from health problems associated with menopause. This meeting is focused on biology as opposed to therapies. Sex Steroid Studies: Bench to Bedside – What is Right? What Is Wrong? This two-day advisory workshop, proposed for Fall 2004, will focus on the basic science, epidemiologic, and available clinical trial data to identify what data are still needed for designing appropriate clinical trials on the use of sex steroids for prevention of cognitive decline in aging women. Of interest are drug and hormone therapies that may be available, differences in how they work, and route of administration. Many women may need short-term hormone therapies, and issues remain about effects of hormone therapy on cognition and overall well being of women. Dr. Miriam Kelty asked Council members for their concurrence to proceed on these planned advisory meetings and the proposed RFA, as they are likely to lead to initiatives involving NIA resources. All proposed initiatives that were brought to the meeting from the WGOP passed by voice vote. E. Approval of the Statement of Understanding
Finally, Dr. Kuller briefly summarized five presentations about past meetings and upcoming initiatives.
Joint Workshop on Hutchinson-Gilford Progeria Syndrome The second workshop on Hutchinson-Gilford Progeria, co-sponsored by the Progeria Research Foundation, the NIA, the National Human Genome Research Institute, and the NIH Office for Rare Diseases, was held in July 2003. Although the number of people with Hutchinson-Gilford Progeria Syndrome is extremely small, the study of this genetic abnormality has led to an understanding of a variety of related genes, and has stimulated a great deal of molecular biology research which may have broad implications for the field of aging. Dr. Kuller described this as a model for how rare diseases may be interesting for understanding common diseases.
Meeting of the NIA Task Force on Comorbidity The multidisciplinary NIA Task Force on Comorbidity met in October 2003 to evaluate the current state of knowledge and to identify directions for future research in this area. Some comorbidities are related to common etiology; some are related to adverse treatment effects. It is important to understand how comorbidities are linked and how they affect therapeutic and preventive strategies for older individuals. A proposal for an RFA on Multiple Morbidity in Geriatric Practice was presented to move this initiative forward. Within the discussion of the comorbidity RFA, Dr. Kuller noted that a recurrent issue that needs to be resolved is whether large clinical trials should be funded as grants or contracts.
Meeting on Neuroimaging of Alzheimer's Disease NIA is sponsoring a meeting with the Centers for Medicare and Medicaid Services (CMS) in April 2004 to examine issues related to neuroimaging in Alzheimer's Disease (AD). This is a continuation of a series of meetings on whether CMS should be paying for PET scans and other imaging techniques for AD diagnoses. A project underway at NIA on neuroimaging might be a potential source for testing the value of PET scans and other modalities.
The Biology of Premenopausal Protection Workshop This advisory workshop will be held in Bethesda, Maryland on May 26-27, 2004 to explore gaps in knowledge of the role of the steroid and peptide reproductive hormone levels across the menstrual cycle within the premenopausal hypothalamic-pituitary-ovarian (H-P-O) axis that may serve to protect premenopausal women from health problems associated with menopause. This meeting is focused on biology as opposed to therapies.
Sex Steroid Studies: Bench to Bedside – What is Right? What Is Wrong? This two-day advisory workshop, proposed for Fall 2004, will focus on the basic science, epidemiologic, and available clinical trial data to identify what data are still needed for designing appropriate clinical trials on the use of sex steroids for prevention of cognitive decline in aging women. Of interest are drug and hormone therapies that may be available, differences in how they work, and route of administration. Many women may need short-term hormone therapies, and issues remain about effects of hormone therapy on cognition and overall well being of women.
Dr. Miriam Kelty asked Council members for their concurrence to proceed on these planned advisory meetings and the proposed RFA, as they are likely to lead to initiatives involving NIA resources. All proposed initiatives that were brought to the meeting from the WGOP passed by voice vote.
E. Approval of the Statement of Understanding
The Statement of Understanding between the Council and Institute staff is acted on once a year to allow the business of the Institute to continue between Council meetings. In response to Council member questions, it was clarified that fewer than 100 requests for administrative supplements are received in any given year, and only a proportion of such requests are granted. As part of the approval process, NIA staff examines the awarded budget, unexpended funds, and negotiates an amount. A motion was made, seconded, and passed to approve the Statement of Understanding with no changes. F. Discussion
The Statement of Understanding between the Council and Institute staff is acted on once a year to allow the business of the Institute to continue between Council meetings. In response to Council member questions, it was clarified that fewer than 100 requests for administrative supplements are received in any given year, and only a proportion of such requests are granted. As part of the approval process, NIA staff examines the awarded budget, unexpended funds, and negotiates an amount. A motion was made, seconded, and passed to approve the Statement of Understanding with no changes.
F. Discussion
Prompted by a question posed by a Council member, discussion ensued about health care costs for the elderly, and costs incurred in the last few years of life. NIA has funded research on the cost implications of extended life expectancy with varying assumptions about levels of disability. Dr. Ronald Lee shared conclusions from his research using Medicare data on costs during the 15 years leading up to death. Although there are more elderly people to whom health care must be provided, the costs for an elderly person are less on average because the proportion near death at any age declines as mortality declines. In practice, these two effects largely cancel each other out in the U.S. over a time span of approximately 75 years. It therefore makes little difference whether mortality declines rapidly or slowly in terms of projected Medicare costs. Dr. Suzman noted several strands of NIA-supported research that bear upon the issue. Researchers at the University of Chicago and elsewhere have found economic returns on the order of trillions of dollars, from the extension of life expectancy. There are also data showing that costs decline with age, and less intensive medical services are used after about age 80 or 85. Dr. Robert Fogel has predicted that over the next 100 years the percentage of GDP spent on health care is likely to rise from 15 percent today (which is the highest of any developed country in the world) to 20-25 percent since he sees health care as one of the last consumption frontiers, raising questions about the impact on the economy. Another strand of related research is by Dr. David Cutler and others showing positive returns from increased spending on health care, although on the margin, much money is ill-spent and wasted. Dr. Kuller observed that paying for care of preventable diseases means there is less money to pay for nonpreventable conditions. He suggested that the NIA message should be that by improving quality of life and preventing disease, NIA research ultimately helps the government pay for the nonpreventable costs of treating elderly patients at the end of life. Dr. Hodes suggested this topic as a good one to present as a Program Highlight at the next Council meeting. This suggestion was well received, with one member adding that there is still some controversy about issues related to life extension. Emphasizing better care for the elderly could reverse the trend of decreasing costs and actually raise costs in the future. G. Statistical Data on Extramural Program Dr. Kelty noted the availability of statistical data on applications assigned to the January 2004 Council round. There were no questions raised about these data.
Prompted by a question posed by a Council member, discussion ensued about health care costs for the elderly, and costs incurred in the last few years of life. NIA has funded research on the cost implications of extended life expectancy with varying assumptions about levels of disability. Dr. Ronald Lee shared conclusions from his research using Medicare data on costs during the 15 years leading up to death. Although there are more elderly people to whom health care must be provided, the costs for an elderly person are less on average because the proportion near death at any age declines as mortality declines. In practice, these two effects largely cancel each other out in the U.S. over a time span of approximately 75 years. It therefore makes little difference whether mortality declines rapidly or slowly in terms of projected Medicare costs.
Dr. Suzman noted several strands of NIA-supported research that bear upon the issue. Researchers at the University of Chicago and elsewhere have found economic returns on the order of trillions of dollars, from the extension of life expectancy. There are also data showing that costs decline with age, and less intensive medical services are used after about age 80 or 85. Dr. Robert Fogel has predicted that over the next 100 years the percentage of GDP spent on health care is likely to rise from 15 percent today (which is the highest of any developed country in the world) to 20-25 percent since he sees health care as one of the last consumption frontiers, raising questions about the impact on the economy. Another strand of related research is by Dr. David Cutler and others showing positive returns from increased spending on health care, although on the margin, much money is ill-spent and wasted.
Dr. Kuller observed that paying for care of preventable diseases means there is less money to pay for nonpreventable conditions. He suggested that the NIA message should be that by improving quality of life and preventing disease, NIA research ultimately helps the government pay for the nonpreventable costs of treating elderly patients at the end of life.
Dr. Hodes suggested this topic as a good one to present as a Program Highlight at the next Council meeting. This suggestion was well received, with one member adding that there is still some controversy about issues related to life extension. Emphasizing better care for the elderly could reverse the trend of decreasing costs and actually raise costs in the future.
G. Statistical Data on Extramural Program
Dr. Kelty noted the availability of statistical data on applications assigned to the January 2004 Council round. There were no questions raised about these data.
A. Biology of Aging: Which Genes Cause Old Skeletal Muscles to Become Weak? Dr. Frank W. Booth, Professor, Department of Physiology, School of Medicine, and Research Investigator, Dalton Cardiovascular Research Center, University of Missouri-Columbia, posed the following questions: Which genes cause old skeletal muscles to become weak? Why are elderly physically frail? Can we prevent premature frailty? Dr. Booth observed that loss of muscle translates to less strength. Skeletal muscle wasting begins at the age of 25 years, with a loss of mass of 4 percent per decade until 50 years of age when mass loss is accelerated to 10 percent per decade. Data collected with support from an NIA grant found 1700 mRNAs were differentially expressed in the soleus muscle when comparisons were made between young and old rats, which were freely mobile or undergoing limb immobilization for 10 days, after which muscles had the opportunity to regrow from atrophy for up to 30 days. Dr. Booth reported that young muscle recovers mass lost by limb immobilization at the 30th day after ending the immobilization; old muscle does not recover lost mass even after 777 days after ending limb immobilization. He further observed unexpected decreases in 48 mRNAs for proteins in the extracellular matrix, a biologically active protein complex that acts like a suspension for a bridge and is thought to play a role in muscle loss. Four mRNAs that differed in their recovery pattern between young and old rats were selected for cloning. The genes were then either overexpressed or silenced in cultured muscle cells to determine if the cells hypertrophied, proliferated more, or became multinucleated muscle fibers faster as a function of the expression of these genes. It was noted that insulin like growth factor probably declines in old muscle, making it difficult for older animals to grow muscle. Weight training in older individuals appears to be more effective in preventing muscle-wasting, as opposed to enlarging the actual size of muscle, and is more effective before reaching a frail state. B. Neuroscience and Neuropsychology of Aging: Alzheimer's Disease Cooperative Study Dr. Leon Thal, an NIA Council member, Professor and Chair, Department of Neurosciences, University of California San Diego (UCSD), and Staff Physician, Neurology Service, San Diego Veterans Medical in La Jolla, California, presented on the Alzheimer's Disease Cooperative Study (ADCS) for which he is the Principal Investigator. The ADCS was established in 1991 through a cooperative agreement between the NIA and UCSD. The vision of the ADCS was to carry out the most scientifically important studies in the field of Alzheimer's Disease (AD) for compounds that would not be developed by industry and to develop innovative new ways of collecting data for AD trials. In its 13-year history, the ADCS has recruited more than 3,600 subjects into 18 trials and has developed new instruments for the collection of data in AD patients focusing particularly on activities of daily living, global functioning, and cognitive measures. These instruments have been distributed to over 500 academic and industrial sponsors. The ADCS has completed and published two major trials with public health impact. In the first trial, high dose vitamin E was demonstrated to delay the time to a composite endpoint of death, institutionalization, loss of basic activities of daily living, or progression of dementia in patients with moderate to moderately advanced AD (Sano, et al., NEJM 1997). Vitamin E is now widely prescribed for AD patients in the United States and elsewhere. In a second study, the ADCS demonstrated that the use of hormone replacement therapy in the form of Premarin failed to slow the rate of decline in post-menopausal, hysterectomized women with mild to moderate AD over the course of one year (Mulnard, et al., JAMA, 2000). This publication led to a significant diminution in prescribing Premarin for the treatment of AD. The ADCS is currently completing an intervention trial in patients with mild cognitive impairment, defined as individuals who have significant memory loss, in the absence of other cognitive deficits. Such individuals are known to develop AD at a rate of approximately 12 percent per year. Results of this intervention trial with vitamin E and Donepezil, a cholinesterase inhibitor, are expected to be available in the summer of 2004. Following Dr. Thal's presentation, there was brief discussion about the uncertain evidence supporting use of Vitamin E as a prophylactic against mild cognitive impairment. The epidemiologic data has shown that a combination of Vitamins E and C seems to decrease prevalence and incidence of dementia (Zandi, et al., Arch Neurol. 61:82-88, 2004). There is an absence of clinical trial data on Vitamin E use, particularly in the general population. Results from the only clinical trial of Vitamin E in a population with mild cognitive impairment are not yet available. A question was also raised about recent reports expressing concerns about statins causing fixed cognitive deficits. Statins are being used by millions of people, and are associated with certain side effects of very low incidence of cognitive deficits, mood disturbances, and muscle aches and pains. There has so far been no systematic answer to the side effect profile, but extant studies suggest that the side effect profile is benign. A final question concerned the correspondence in brain profile of subjects with mild cognitive impairment and those with AD in terms of plaques and tangles. Can current treatments for AD prove effective earlier given that there is already evidence of pathology in the brain? Dr. Thal responded that we do not know. He described his study as a secondary prevention trial as opposed to a primary prevention trial since the individual has already shown symptoms so is assumed to already have disease. The same concerns can be raised with primary prevention trials. If AD is a disease that exists pathologically in the brain 20-30 years before presenting symptoms, then in a primary prevention trial of 5-7 years in length, every subject that converts to AD will also already have pathology. In reality, time will probably change the definition of conditions, so that what is now considered mild cognitive impairment may someday come to be seen as very early AD. Until we have a firmer pathological understanding, we do not want to label people who have MCI as AD because there are societal implications (like the ability to continue to drive), and it is possible to have MCI that does not progress to AD. In many epidemiological studies, there also have been occasions when subjects initially coded as MCI turned out later not to have MCI. C. Geriatrics and Clinical Gerontology: The Genetics of Human Longevity Dr. Nir Barzilai, Director, Institute for Aging Research, Albert Einstein College of Medicine, presented on the unique lipoprotein phenotype and genotype associated with exceptional longevity (Barzilai, et al., JAMA , 290, 15: 2030-2040, 2003), a study supported by the NIA and the Ellison Medical Foundation. Dr. Barzilai is supported by the Geriatrics and Clinical Gerontology Program as well as the Biology of Aging Program at NIA. Extending from earlier discussions, Dr. Barzilai noted that the health care costs in the last two years of life for centenarians was about a third of that for those who died between the ages of 60 and 70. More importantly, the costs for centenarians when they were aged 60-70 were substantially less than other 60- to 70-year-olds. Dr. Barzilai presented his hypothesis that to reach age 100 (which occurs with probability of 1/10,000), one needs longevity assurance genes since at the time the centenarians were born life expectancy was around 40 years. Offspring inherit longevity traits from their parents, and these may be a platform for longevity-associated traits. Dr. Barzilai and his colleagues have collected 1200 samples from over 300 (Ashkenazi) Jewish families (Proband, sometimes siblings, offspring, sometimes spouse of offspring) in their homes. The genetically homogenous population increases the likelihood of genetic discoveries. Longevity appears to be strongly correlated in families of centenarians; there is only a weak interaction with the environment. Compared to controls, offspring of centenarians are healthier and have half the diseases (e.g., hypertension, diabetes, ischemic heart disease, and no strokes). It appears that the age-related disease profile of offspring is just 30 years delayed from their centenarian parents. HDL cholesterol (the cardioprotective or “good” cholesterol) has been shown in Framingham and other studies to decline about 5 mg/dL every 5 years. But the HDL cross-section does not change with age. Plasma HDL levels in families of longevity appear consistent, and HDL levels predict cognitive functioning in centenarians better than ApoE. There are challenges in determining a phenotype for exceptional longevity, and the offspring generation provides an opportune sample for study. Dr. Barzilai observed that lipoprotein particle sizes increase with age and are very high for centenarians. The HDL and LDL (the anthrogenic or “bad” cholesterol) particle sizes are significantly higher in offspring and controls without hypertension, cardiovascular disease, and the metabolic syndrome or insulin resistance. These findings suggest the high heritability in lipoprotein particle sizes (0.4 to 0.7) and that these particles can promote a healthy aging phenotype. There may be several genes involved in lipoprotein that have the capacity to increase size of HDL particles. For the young, exercise interventions change the HDL/LDL ratio by a few percentage points. For the elderly, though, the cardiovascular benefits of exercise are modest and pharmacological interventions have a larger effect. Some studies have shown that lipoporotein size increases with exercise among the elderly but HDL levels are not affected. (Kraus, WE, et al., NEJM 347: 1483-1492, November 7, 2002). D. Behavioral and Social Research: Precursors of Physical Disability – The Women's Health and Aging Study II Dr. Linda Fried, Professor of Medicine, Epidemiology, and Health Policy, Director of the Center on Aging and Health, and Director of the Division of Geriatric Medicine and Gerontology at Johns Hopkins University, presented on precursors of physical disability from the Women's Health and Aging Study II (WHAS II). The goal of the WHAS II is to determine the natural history of early decline in physical function leading to physical disability, and particularly to characterize the novel risk factors and markers of early transitions that might be suitable targets for effective prevention of disability. The WHAS II study is a prospective, observational cohort study of 436 women who were 70-79 years at baseline and were drawn, initially, from among the two-thirds least disabled older women living in the community. The study findings that were reported support two initial study hypotheses. First, there are two major pathways to disability: one involving loss of mobility, and one involving loss of cognition. The two pathways have distinct constellations of risk factors, and predictable order of early decrements unique to each pathway. Novel risk factors for mobility disability discussed include biomediators: hemoglobin level, IGF-1 and IL-6, and the interactions among these. WHAS II data provide evidence that there is a predictable order of decline in different domains of cognition in this cohort of initially high functioning older women followed over six years, and that declines in different domains occur at different rates: Declines in executive function precede declines in mental speed, which precede declines in memory. Cognitive activity predicts decline in cognitive function. It is hypothesized, but not yet observed, that those with decrements in both pathways will be at highest risk of loss of function in household management (i.e. IADL) and basic self care (i.e. ADL tasks), and that the two independent pathways converge at these end stages of functional decline. Second, early change in each pathway can be detected by the implementation of compensations, despite individuals reporting no difficulty. In the mobility pathway, self report of modification of task performance, in the absence of difficulty, independently predicts onset of mobility difficulty (4-fold increased risk) in these initially high functioning older women, over 18 months. Objective performance measures, such as walking speed, contribute independent information beyond this. Mobility compensations do not differ as a function of cognitive status. In the face of cognitive decline, traditional self report of difficulty or dependency, or recognition of modifications conceptually is underestimated. The WHAS II study has developed novel approaches to identify compensations implemented to preserve performance of cognitively-based tasks, in response to cognitive declines. Initial findings are that these compensations are much more frequently reported than difficulty in IADLs, and present a method for conceptually organizing types of compensations which has initial construct and criterion validity. Next steps might include focusing on components that relate to executive functioning.
A. Biology of Aging: Which Genes Cause Old Skeletal Muscles to Become Weak?
Dr. Frank W. Booth, Professor, Department of Physiology, School of Medicine, and Research Investigator, Dalton Cardiovascular Research Center, University of Missouri-Columbia, posed the following questions: Which genes cause old skeletal muscles to become weak? Why are elderly physically frail? Can we prevent premature frailty?
Dr. Booth observed that loss of muscle translates to less strength. Skeletal muscle wasting begins at the age of 25 years, with a loss of mass of 4 percent per decade until 50 years of age when mass loss is accelerated to 10 percent per decade. Data collected with support from an NIA grant found 1700 mRNAs were differentially expressed in the soleus muscle when comparisons were made between young and old rats, which were freely mobile or undergoing limb immobilization for 10 days, after which muscles had the opportunity to regrow from atrophy for up to 30 days. Dr. Booth reported that young muscle recovers mass lost by limb immobilization at the 30th day after ending the immobilization; old muscle does not recover lost mass even after 777 days after ending limb immobilization. He further observed unexpected decreases in 48 mRNAs for proteins in the extracellular matrix, a biologically active protein complex that acts like a suspension for a bridge and is thought to play a role in muscle loss. Four mRNAs that differed in their recovery pattern between young and old rats were selected for cloning. The genes were then either overexpressed or silenced in cultured muscle cells to determine if the cells hypertrophied, proliferated more, or became multinucleated muscle fibers faster as a function of the expression of these genes.
It was noted that insulin like growth factor probably declines in old muscle, making it difficult for older animals to grow muscle. Weight training in older individuals appears to be more effective in preventing muscle-wasting, as opposed to enlarging the actual size of muscle, and is more effective before reaching a frail state.
B. Neuroscience and Neuropsychology of Aging: Alzheimer's Disease Cooperative Study
Dr. Leon Thal, an NIA Council member, Professor and Chair, Department of Neurosciences, University of California San Diego (UCSD), and Staff Physician, Neurology Service, San Diego Veterans Medical in La Jolla, California, presented on the Alzheimer's Disease Cooperative Study (ADCS) for which he is the Principal Investigator.
The ADCS was established in 1991 through a cooperative agreement between the NIA and UCSD. The vision of the ADCS was to carry out the most scientifically important studies in the field of Alzheimer's Disease (AD) for compounds that would not be developed by industry and to develop innovative new ways of collecting data for AD trials. In its 13-year history, the ADCS has recruited more than 3,600 subjects into 18 trials and has developed new instruments for the collection of data in AD patients focusing particularly on activities of daily living, global functioning, and cognitive measures. These instruments have been distributed to over 500 academic and industrial sponsors.
The ADCS has completed and published two major trials with public health impact. In the first trial, high dose vitamin E was demonstrated to delay the time to a composite endpoint of death, institutionalization, loss of basic activities of daily living, or progression of dementia in patients with moderate to moderately advanced AD (Sano, et al., NEJM 1997). Vitamin E is now widely prescribed for AD patients in the United States and elsewhere. In a second study, the ADCS demonstrated that the use of hormone replacement therapy in the form of Premarin failed to slow the rate of decline in post-menopausal, hysterectomized women with mild to moderate AD over the course of one year (Mulnard, et al., JAMA, 2000). This publication led to a significant diminution in prescribing Premarin for the treatment of AD. The ADCS is currently completing an intervention trial in patients with mild cognitive impairment, defined as individuals who have significant memory loss, in the absence of other cognitive deficits. Such individuals are known to develop AD at a rate of approximately 12 percent per year. Results of this intervention trial with vitamin E and Donepezil, a cholinesterase inhibitor, are expected to be available in the summer of 2004.
Following Dr. Thal's presentation, there was brief discussion about the uncertain evidence supporting use of Vitamin E as a prophylactic against mild cognitive impairment. The epidemiologic data has shown that a combination of Vitamins E and C seems to decrease prevalence and incidence of dementia (Zandi, et al., Arch Neurol. 61:82-88, 2004). There is an absence of clinical trial data on Vitamin E use, particularly in the general population. Results from the only clinical trial of Vitamin E in a population with mild cognitive impairment are not yet available.
A question was also raised about recent reports expressing concerns about statins causing fixed cognitive deficits. Statins are being used by millions of people, and are associated with certain side effects of very low incidence of cognitive deficits, mood disturbances, and muscle aches and pains. There has so far been no systematic answer to the side effect profile, but extant studies suggest that the side effect profile is benign.
A final question concerned the correspondence in brain profile of subjects with mild cognitive impairment and those with AD in terms of plaques and tangles. Can current treatments for AD prove effective earlier given that there is already evidence of pathology in the brain? Dr. Thal responded that we do not know. He described his study as a secondary prevention trial as opposed to a primary prevention trial since the individual has already shown symptoms so is assumed to already have disease. The same concerns can be raised with primary prevention trials. If AD is a disease that exists pathologically in the brain 20-30 years before presenting symptoms, then in a primary prevention trial of 5-7 years in length, every subject that converts to AD will also already have pathology. In reality, time will probably change the definition of conditions, so that what is now considered mild cognitive impairment may someday come to be seen as very early AD. Until we have a firmer pathological understanding, we do not want to label people who have MCI as AD because there are societal implications (like the ability to continue to drive), and it is possible to have MCI that does not progress to AD. In many epidemiological studies, there also have been occasions when subjects initially coded as MCI turned out later not to have MCI.
C. Geriatrics and Clinical Gerontology: The Genetics of Human Longevity
Dr. Nir Barzilai, Director, Institute for Aging Research, Albert Einstein College of Medicine, presented on the unique lipoprotein phenotype and genotype associated with exceptional longevity (Barzilai, et al., JAMA , 290, 15: 2030-2040, 2003), a study supported by the NIA and the Ellison Medical Foundation. Dr. Barzilai is supported by the Geriatrics and Clinical Gerontology Program as well as the Biology of Aging Program at NIA. Extending from earlier discussions, Dr. Barzilai noted that the health care costs in the last two years of life for centenarians was about a third of that for those who died between the ages of 60 and 70. More importantly, the costs for centenarians when they were aged 60-70 were substantially less than other 60- to 70-year-olds.
Dr. Barzilai presented his hypothesis that to reach age 100 (which occurs with probability of 1/10,000), one needs longevity assurance genes since at the time the centenarians were born life expectancy was around 40 years. Offspring inherit longevity traits from their parents, and these may be a platform for longevity-associated traits. Dr. Barzilai and his colleagues have collected 1200 samples from over 300 (Ashkenazi) Jewish families (Proband, sometimes siblings, offspring, sometimes spouse of offspring) in their homes. The genetically homogenous population increases the likelihood of genetic discoveries.
Longevity appears to be strongly correlated in families of centenarians; there is only a weak interaction with the environment. Compared to controls, offspring of centenarians are healthier and have half the diseases (e.g., hypertension, diabetes, ischemic heart disease, and no strokes). It appears that the age-related disease profile of offspring is just 30 years delayed from their centenarian parents. HDL cholesterol (the cardioprotective or “good” cholesterol) has been shown in Framingham and other studies to decline about 5 mg/dL every 5 years. But the HDL cross-section does not change with age. Plasma HDL levels in families of longevity appear consistent, and HDL levels predict cognitive functioning in centenarians better than ApoE.
There are challenges in determining a phenotype for exceptional longevity, and the offspring generation provides an opportune sample for study. Dr. Barzilai observed that lipoprotein particle sizes increase with age and are very high for centenarians. The HDL and LDL (the anthrogenic or “bad” cholesterol) particle sizes are significantly higher in offspring and controls without hypertension, cardiovascular disease, and the metabolic syndrome or insulin resistance. These findings suggest the high heritability in lipoprotein particle sizes (0.4 to 0.7) and that these particles can promote a healthy aging phenotype. There may be several genes involved in lipoprotein that have the capacity to increase size of HDL particles.
For the young, exercise interventions change the HDL/LDL ratio by a few percentage points. For the elderly, though, the cardiovascular benefits of exercise are modest and pharmacological interventions have a larger effect. Some studies have shown that lipoporotein size increases with exercise among the elderly but HDL levels are not affected. (Kraus, WE, et al., NEJM 347: 1483-1492, November 7, 2002).
D. Behavioral and Social Research: Precursors of Physical Disability – The Women's Health and Aging Study II
Dr. Linda Fried, Professor of Medicine, Epidemiology, and Health Policy, Director of the Center on Aging and Health, and Director of the Division of Geriatric Medicine and Gerontology at Johns Hopkins University, presented on precursors of physical disability from the Women's Health and Aging Study II (WHAS II). The goal of the WHAS II is to determine the natural history of early decline in physical function leading to physical disability, and particularly to characterize the novel risk factors and markers of early transitions that might be suitable targets for effective prevention of disability. The WHAS II study is a prospective, observational cohort study of 436 women who were 70-79 years at baseline and were drawn, initially, from among the two-thirds least disabled older women living in the community. The study findings that were reported support two initial study hypotheses.
First, there are two major pathways to disability: one involving loss of mobility, and one involving loss of cognition. The two pathways have distinct constellations of risk factors, and predictable order of early decrements unique to each pathway. Novel risk factors for mobility disability discussed include biomediators: hemoglobin level, IGF-1 and IL-6, and the interactions among these. WHAS II data provide evidence that there is a predictable order of decline in different domains of cognition in this cohort of initially high functioning older women followed over six years, and that declines in different domains occur at different rates: Declines in executive function precede declines in mental speed, which precede declines in memory. Cognitive activity predicts decline in cognitive function. It is hypothesized, but not yet observed, that those with decrements in both pathways will be at highest risk of loss of function in household management (i.e. IADL) and basic self care (i.e. ADL tasks), and that the two independent pathways converge at these end stages of functional decline.
Second, early change in each pathway can be detected by the implementation of compensations, despite individuals reporting no difficulty. In the mobility pathway, self report of modification of task performance, in the absence of difficulty, independently predicts onset of mobility difficulty (4-fold increased risk) in these initially high functioning older women, over 18 months. Objective performance measures, such as walking speed, contribute independent information beyond this. Mobility compensations do not differ as a function of cognitive status. In the face of cognitive decline, traditional self report of difficulty or dependency, or recognition of modifications conceptually is underestimated. The WHAS II study has developed novel approaches to identify compensations implemented to preserve performance of cognitively-based tasks, in response to cognitive declines. Initial findings are that these compensations are much more frequently reported than difficulty in IADLs, and present a method for conceptually organizing types of compensations which has initial construct and criterion validity. Next steps might include focusing on components that relate to executive functioning.
Dr. Hodes introduced Dr. Mark McClellan, Commissioner of the Food and Drug Administration, as someone who has had a long association with NIA and a former grantee. Dr. McClellan shares an appreciation for evidence-based rationales that underlie activities of both the NIH and the FDA with the ultimate purpose of improving the welfare, quality of life, and health of Americans. He met with Council to discuss areas of common interest. Dr. McClellan recognized NIA's important role in bringing basic research into drug development, as well as addressing a broad range of societal trends. Current trajectories foreshadow a strain on future health care resources. The burden cannot be overestimated. Currently, about $50 billion per year is spent on medications; about 25 percent of U.S. spending for medication is associated with 15 percent of the population. The problem of affordability persists. Given the burgeoning medical technologies and the challenge of ensuring affordable medicines to older Americans, NIA is well-positioned to play a critical role. There are many opportunities for greater collaborations between the NIA and the FDA to help turn research findings into treatments, and to develop treatments that the public can use. New drugs and medical treatments hold promise for decreasing the onset of diseases, adding value in the form of longer, healthier lives, and lowering costs. In 2002, the sequencing of the human genome was completed, but the number of new drugs approved by the FDA was the lowest it has been in two decades. The number increased about 20 percent in 2003, and the number of investigational new drug (IND) applications and testing has been larger than ever, but there is still a long way to go. There are about 1000 medicines in development specifically designed to reduce disease and improve quality of life for the elderly. Of the products that reach the human testing stage, fewer than one in five results in an application to the FDA. Fewer than one in two reaches the stage of efficacy testing. Over the past decade, it has become increasingly costly to bring drugs to market, at every phase of the process. The entire process is getting more costly; it is expected to take a decade to bring a drug to market at a cost of $800 million to $1.3 billion. Given the great uncertainty, cost and time in the development process, the decisions made in the public policy arena to improve the process are critical. Better methods are needed to determine early on if drugs will be promising, to make trials shorter and less costly, and to develop imaging programs that could potentially be used to guide treatment. Better research into validated biomarkers is also needed, and is something that the FDA is working with NIA to address. The FDA has launched a series of new initiatives and innovative management programs to bring the drug review process up-to-date, and to improve efficiency of the development process. It has been working with outside organizations including NIA and NIH on developing new guidance documents intended to help product development by clarifying issues regarding emerging technologies like pharmacogenomics and novel drug delivery systems, which also ensures that FDA staff are current on the issues. Dr. McClellan recognized that the pharmaceutical manufacturing industry may not be operating efficiently partly because of cumbersome FDA requirements. He therefore is seeking to overhaul FDA regulations to create a framework that encourages companies to adopt continuous quality improvement methods that have worked to reduce costs and improve productivity in other industries. There is also a great deal more to be learned about how to use medications after purchase, including off-label uses and comorbidities. This is a critical part of the development process that has not received adequate attention. NCI is working with FDA on a common standardized format to transmit data and product applications from all of the major NCI-supported clinical research centers. This will be extended to the post-market setting to expedite collection of information about alternative dosing and special populations (like the elderly), and to implement a test bed concept. To realize this vision, the FDA will require bar codes on drugs, which is also a proven technique for reducing errors. It is possible with modern technology to conduct clinical trials at lower cost, with fewer patients, and for shorter durations. The FDA is working with the NLM to speed up dissemination of information on drugs, side effects, costs, etc., that can be updated on a daily basis for use by doctors and patients. The Medicare drug benefit will probably lead to more drugs being used. The goal is to find the best ways to remove barriers to the critical path of getting therapies to the public, to deliver affordability with innovation. Council members raised a number of questions for Dr. McClellan on such issues as comorbidities, use of electronic records, management processes, and cooperative research opportunities with NIA. One Council member observed that a challenge at the practice end is that published clinical practice guidelines are not prepared for an aging population (e.g., drug interactions, how to prioritize medications), and that it would be helpful for the FDA to have input from an NIA task force focused on comorbidity issues. Dr. McClellan responded that the FDA is absolutely willing to participate in the process. It is trying to set standards, encourage use of electronic data systems to document drug interactions, and build infrastructure to make studies more cost effective. The CMS is exploring whether adverse reaction reporting can be required on a wider scale. Even in the best companies, about 90 percent of adverse events go unreported because doctors are too busy. There has been little FDA funding in the past to generate this type of information. Instead, support has come primarily from the private sector, researchers, and health insurance plans, with concern shared by CMS and the Veterans Administration. Although it makes sense to begin with more widespread adoption of electronic record systems, others noted the daunting cost to implement an electronic patient record system relevant to clinical care and usable by researchers, and that only about 5 percent of physician offices have electronic record systems. NCI is investing funds through its grant program to develop this type of data infrastructure, as is AHRQ. Others added that there may be a need to assess whether adequate capacity exists to implement the vision of electronic records. Basic, practical issues need to be addressed. Lack of an interface to allow electronic data exchange is an obstacle. Much of what is required by the FDA cannot be done electronically, although Dr. McClellan said FDA is changing its processes. In medical interventions, physicians must enter ICD-M codes. However, this linkage is not required for medications. It was suggested that physicians write the ICD-M code on prescriptions to provide the diagnosis that led to the prescription. Attention needs to be given to ensure that codes are rich enough to capture conditions, such as HL-7. The FDA focus on electronic standards will help rationalize the categorization of more than 10,000 medical devices for which there currently are no standard codes. The inclusion of patient records is really motivated by health care providers. With electronic prescribing standards in place, it will be easier to conduct studies. There was some discussion about the need to obtain regulatory input from the FDA before a grant application is submitted to preempt the possibility that a protocol being pursued by an academic researcher funded by a grant is subsequently disapproved by the FDA. NIA staff were advised to work closely with FDA staff to become better aware of problems of concern to the FDA. In many countries other than the U.S., costs are negotiated as drugs are approved. Dr. McClellan observed that a great deal of price negotiation occurs between health insurers and drug manufacturers. The FDA approval process is focused on safety and effectiveness, so cost issues do not slow down the approval process. He was confident that there can be ways to meet the costs of developing new treatments instead of every country negotiating the best deal for itself. Domestically, there will continue to be pressure from payers. Generics are extremely inexpensive and often priced lowest in the U.S. because of open competition. Other countries regulate prices across the board, making innovative new drugs less expensive but making generics more expensive than they otherwise would be. This approach is not an efficient way for encouraging innovation. Medicare coverage of drugs suggests an important research opportunity. Dr. McClellan suggested that the NIA should actively look for opportunities to fund research beginning in 2006 when the Medicare drug coverage goes into effect. It is worth thinking hard about what the research agenda should be to learn about medications. It is helpful to collect information about drugs now to serve as a baseline. Although electronic systems are not in the best shape to facilitate this research, there are many health payers (including Medicare) that have or are establishing electronic records systems that may be of help. He expressed confidence that the FDA can coordinate with CMS and NIA on this front. Dr. McClellan also sees a role for FDA to stimulate better early diagnoses as indicators for drugs, techniques, or whole development processes, which could change the whole process. There should be a way to create a knowledge base across companies without violating a company's proprietary interests that helps with validation and with future product development.
Dr. Hodes introduced Dr. Mark McClellan, Commissioner of the Food and Drug Administration, as someone who has had a long association with NIA and a former grantee. Dr. McClellan shares an appreciation for evidence-based rationales that underlie activities of both the NIH and the FDA with the ultimate purpose of improving the welfare, quality of life, and health of Americans. He met with Council to discuss areas of common interest.
Dr. McClellan recognized NIA's important role in bringing basic research into drug development, as well as addressing a broad range of societal trends. Current trajectories foreshadow a strain on future health care resources. The burden cannot be overestimated. Currently, about $50 billion per year is spent on medications; about 25 percent of U.S. spending for medication is associated with 15 percent of the population. The problem of affordability persists. Given the burgeoning medical technologies and the challenge of ensuring affordable medicines to older Americans, NIA is well-positioned to play a critical role. There are many opportunities for greater collaborations between the NIA and the FDA to help turn research findings into treatments, and to develop treatments that the public can use. New drugs and medical treatments hold promise for decreasing the onset of diseases, adding value in the form of longer, healthier lives, and lowering costs.
In 2002, the sequencing of the human genome was completed, but the number of new drugs approved by the FDA was the lowest it has been in two decades. The number increased about 20 percent in 2003, and the number of investigational new drug (IND) applications and testing has been larger than ever, but there is still a long way to go. There are about 1000 medicines in development specifically designed to reduce disease and improve quality of life for the elderly. Of the products that reach the human testing stage, fewer than one in five results in an application to the FDA. Fewer than one in two reaches the stage of efficacy testing. Over the past decade, it has become increasingly costly to bring drugs to market, at every phase of the process. The entire process is getting more costly; it is expected to take a decade to bring a drug to market at a cost of $800 million to $1.3 billion. Given the great uncertainty, cost and time in the development process, the decisions made in the public policy arena to improve the process are critical. Better methods are needed to determine early on if drugs will be promising, to make trials shorter and less costly, and to develop imaging programs that could potentially be used to guide treatment. Better research into validated biomarkers is also needed, and is something that the FDA is working with NIA to address.
The FDA has launched a series of new initiatives and innovative management programs to bring the drug review process up-to-date, and to improve efficiency of the development process. It has been working with outside organizations including NIA and NIH on developing new guidance documents intended to help product development by clarifying issues regarding emerging technologies like pharmacogenomics and novel drug delivery systems, which also ensures that FDA staff are current on the issues. Dr. McClellan recognized that the pharmaceutical manufacturing industry may not be operating efficiently partly because of cumbersome FDA requirements. He therefore is seeking to overhaul FDA regulations to create a framework that encourages companies to adopt continuous quality improvement methods that have worked to reduce costs and improve productivity in other industries. There is also a great deal more to be learned about how to use medications after purchase, including off-label uses and comorbidities. This is a critical part of the development process that has not received adequate attention.
NCI is working with FDA on a common standardized format to transmit data and product applications from all of the major NCI-supported clinical research centers. This will be extended to the post-market setting to expedite collection of information about alternative dosing and special populations (like the elderly), and to implement a test bed concept. To realize this vision, the FDA will require bar codes on drugs, which is also a proven technique for reducing errors. It is possible with modern technology to conduct clinical trials at lower cost, with fewer patients, and for shorter durations. The FDA is working with the NLM to speed up dissemination of information on drugs, side effects, costs, etc., that can be updated on a daily basis for use by doctors and patients. The Medicare drug benefit will probably lead to more drugs being used. The goal is to find the best ways to remove barriers to the critical path of getting therapies to the public, to deliver affordability with innovation.
Council members raised a number of questions for Dr. McClellan on such issues as comorbidities, use of electronic records, management processes, and cooperative research opportunities with NIA.
One Council member observed that a challenge at the practice end is that published clinical practice guidelines are not prepared for an aging population (e.g., drug interactions, how to prioritize medications), and that it would be helpful for the FDA to have input from an NIA task force focused on comorbidity issues. Dr. McClellan responded that the FDA is absolutely willing to participate in the process. It is trying to set standards, encourage use of electronic data systems to document drug interactions, and build infrastructure to make studies more cost effective. The CMS is exploring whether adverse reaction reporting can be required on a wider scale. Even in the best companies, about 90 percent of adverse events go unreported because doctors are too busy. There has been little FDA funding in the past to generate this type of information. Instead, support has come primarily from the private sector, researchers, and health insurance plans, with concern shared by CMS and the Veterans Administration.
Although it makes sense to begin with more widespread adoption of electronic record systems, others noted the daunting cost to implement an electronic patient record system relevant to clinical care and usable by researchers, and that only about 5 percent of physician offices have electronic record systems. NCI is investing funds through its grant program to develop this type of data infrastructure, as is AHRQ. Others added that there may be a need to assess whether adequate capacity exists to implement the vision of electronic records. Basic, practical issues need to be addressed. Lack of an interface to allow electronic data exchange is an obstacle. Much of what is required by the FDA cannot be done electronically, although Dr. McClellan said FDA is changing its processes.
In medical interventions, physicians must enter ICD-M codes. However, this linkage is not required for medications. It was suggested that physicians write the ICD-M code on prescriptions to provide the diagnosis that led to the prescription. Attention needs to be given to ensure that codes are rich enough to capture conditions, such as HL-7. The FDA focus on electronic standards will help rationalize the categorization of more than 10,000 medical devices for which there currently are no standard codes. The inclusion of patient records is really motivated by health care providers. With electronic prescribing standards in place, it will be easier to conduct studies.
There was some discussion about the need to obtain regulatory input from the FDA before a grant application is submitted to preempt the possibility that a protocol being pursued by an academic researcher funded by a grant is subsequently disapproved by the FDA. NIA staff were advised to work closely with FDA staff to become better aware of problems of concern to the FDA.
In many countries other than the U.S., costs are negotiated as drugs are approved. Dr. McClellan observed that a great deal of price negotiation occurs between health insurers and drug manufacturers. The FDA approval process is focused on safety and effectiveness, so cost issues do not slow down the approval process. He was confident that there can be ways to meet the costs of developing new treatments instead of every country negotiating the best deal for itself. Domestically, there will continue to be pressure from payers. Generics are extremely inexpensive and often priced lowest in the U.S. because of open competition. Other countries regulate prices across the board, making innovative new drugs less expensive but making generics more expensive than they otherwise would be. This approach is not an efficient way for encouraging innovation.
Medicare coverage of drugs suggests an important research opportunity. Dr. McClellan suggested that the NIA should actively look for opportunities to fund research beginning in 2006 when the Medicare drug coverage goes into effect. It is worth thinking hard about what the research agenda should be to learn about medications. It is helpful to collect information about drugs now to serve as a baseline. Although electronic systems are not in the best shape to facilitate this research, there are many health payers (including Medicare) that have or are establishing electronic records systems that may be of help. He expressed confidence that the FDA can coordinate with CMS and NIA on this front. Dr. McClellan also sees a role for FDA to stimulate better early diagnoses as indicators for drugs, techniques, or whole development processes, which could change the whole process. There should be a way to create a knowledge base across companies without violating a company's proprietary interests that helps with validation and with future product development.
Dr. Longo introduced the Intramural Research Program (IRP). The IRP reports were presented by Drs. Mahendra Rao, Cathy Wolkow, and Mark P. Mattson, all from the NIA Laboratory of Neurosciences (LNS). Dr. Rao presented research on human embryonic stem (HuES) cells and aging associated genes. He showed that all major pathways that are known to regulate the aging process are active in HuES cells and are rapidly downregulated as cells differentiate. He proposed that HuES cells could represent an ideal model system for examining the functional role of these molecules in regulating the aging process at the cellular level. The findings suggest that time spent before undergoing senescence in stem cells is correlated with life span of individuals. Dr. Wolkow presented on the genetics of longevity and aging with a focus on the worm model. The nematode is advantageous to study because it has a short lifespan, it is easy to identify and create mutations, its complete annotated genome sequence is well understood, and it is carefully described. Lifespan in C. elegans is controlled by an insulin-like signaling pathway that includes the gene, age-1, encoding a homolog of mammalian PI 3-kinase p110 catalytic subunits. Mutations that decrease age-1 activity can double adult lifespan while more severe age-1 mutations result in developmental arrest at the dauer larval stage, a developmental diapause optimized for long-term survival under harsh environmental conditions. Restoring age-1 activity to some or all of the worm's 302 neurons restored wild-type (shorter) lifespan to age-1(-) animals. The number of neurons with age-1 activity appeared critical for longevity, as animals with age-1 activity restored to small numbers of neurons still exhibited the long age-1(-) lifespan. To further understand how aging impacts the C. elegans nervous system, the effects of aging on behavior were assessed. Increased age was associated with defects in chemotaxis and locomotory behavior, although sensory ability was unaffected. In several assays of muscle function and structure, age-associated behavioral declines were associated with increased muscle frailty. However, behavioral declines preceded significant muscle deterioration. Finally, improved neuromuscular synaptic transmission may be one approach for improving performance in aged individuals, as locomotory behavior in aged animals was improved by treatment with a muscarinic acetylcholine receptor agonist that increases acetylcholine release at the C. elegans neuromuscular junction. Dr. Mattson presented research on the impact of dietary restriction regimes on the brain, including the impact on neurodegenerative disorders. There is increasing evidence that, as with other age-related diseases, dietary factors can modify the risk of neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's Disease (PD), and stroke. It has been shown that when mice are maintained on an intermittent fasting (IF) regimen (every other day fasting) their ability to regulate glucose levels (insulin sensitivity) is increased, consistent with a reduced risk for diabetes. Rodents on an IF diet also exhibit reductions in blood pressure and heart rate, and improved cardiovascular adaptation to stress, suggesting that IF reduces the risk of cardiovascular disease and stroke. In a series of studies, the LNS scientists found that IF can protect neurons in the brains of rats and mice in models relevant to AD, PD, and stroke. The neuroprotective effect of IF was associated with improved behavioral outcomes (learning and memory in the AD model), and motor function in the PD and stroke models. Studies of the expression of various genes in brain cells of rodents on IF and control diets revealed that IF induces the expression of a neurotrophic factor called brain-derived neurotrophic factor (BDNF) and several “stress resistance” proteins including heat-shock protein 70 and glucose-regulated protein 78. Cell culture studies had shown that each of these three proteins can protect neurons against insults relevant to AD, PD and stroke suggesting that they are likely to mediate (at least in part) the neuroprotective effects of IF in vivo . In addition to the neuroprotective effects of IF, LNS investigators found that this dietary restriction regimen enhances neurogenesis, the production of new nerve cells from stem cells. Studies of mice deficient in BDNF suggested that the ability of IF to enhance neurogenesis is mediated by BDNF. Collectively, these findings suggest that the mechanism underlying beneficial effects of IF on the brain involves a mild cellular stress response which enhances the ability of the cells to cope with more severe types of stress. Although it is not known whether IF will have similar effects in humans, these data in animals point in that direction. In this regard, a study of the effects of meal frequency on indicators of risk for diabetes and cardiovascular disease has been designed and will soon begin. A second area of diet–brain interactions covered by Dr. Mattson concerns the role of lipids in the pathogenesis of AD. LNS investigators measured the concentrations of various lipids in brain tissue samples from patients with AD and age-matched control subjects. They found that concentrations of cholesterol and another type of lipid called ceramide were greatly increased in samples from vulnerable brain regions from AD patients compared to concentrations of these lipids in samples from the same brain regions of control subjects and to concentrations in samples from non-vulnerable brain regions of AD patients. The increased amounts of cholesterol and ceramide were particularly prominent in cell membranes. The investigators then showed that when cultured neurons are exposed to amyloid beta-peptide levels of cholesterol and ceramide are increased. When the neurons were treated with the antioxidant vitamin E, or with a drug called myriocin that blocks ceramide production, they were resistant to being killed by amyloid beta-peptide. These findings suggest that membrane-associated oxidative stress, induced by aging and amyloid beta-peptide, causes abnormalities in lipid metabolism in neurons that contribute to their dysfunction and degeneration in AD. Reducing levels of cholesterol and ceramides through diet and/or drugs may reduce the risk of AD and might also slow disease progression in symptomatic patients. Dr. Matson added that his team is also doing a small human pilot study in collaboration with USDA to see how meal frequency affects human health. One group will eat three meals per day; the other will eat essentially one meal over a 3 to 4 hour time period. Subjects enrolled in the study are to try to maintain their weight throughout the 6-month study, with 2 months on diet, 2 months not, and 2 months crossed over. The advice that it is healthier to eat smaller, more frequent meals is not justified by any controlled scientific evidence, although such advice is good for diabetics who need to monitor glucose. Skipping meals appears good for rodents, and this pilot study will help determine whether it is also good for humans.
Dr. Longo introduced the Intramural Research Program (IRP). The IRP reports were presented by Drs. Mahendra Rao, Cathy Wolkow, and Mark P. Mattson, all from the NIA Laboratory of Neurosciences (LNS).
Dr. Rao presented research on human embryonic stem (HuES) cells and aging associated genes. He showed that all major pathways that are known to regulate the aging process are active in HuES cells and are rapidly downregulated as cells differentiate. He proposed that HuES cells could represent an ideal model system for examining the functional role of these molecules in regulating the aging process at the cellular level. The findings suggest that time spent before undergoing senescence in stem cells is correlated with life span of individuals.
Dr. Wolkow presented on the genetics of longevity and aging with a focus on the worm model. The nematode is advantageous to study because it has a short lifespan, it is easy to identify and create mutations, its complete annotated genome sequence is well understood, and it is carefully described. Lifespan in C. elegans is controlled by an insulin-like signaling pathway that includes the gene, age-1, encoding a homolog of mammalian PI 3-kinase p110 catalytic subunits. Mutations that decrease age-1 activity can double adult lifespan while more severe age-1 mutations result in developmental arrest at the dauer larval stage, a developmental diapause optimized for long-term survival under harsh environmental conditions. Restoring age-1 activity to some or all of the worm's 302 neurons restored wild-type (shorter) lifespan to age-1(-) animals. The number of neurons with age-1 activity appeared critical for longevity, as animals with age-1 activity restored to small numbers of neurons still exhibited the long age-1(-) lifespan. To further understand how aging impacts the C. elegans nervous system, the effects of aging on behavior were assessed. Increased age was associated with defects in chemotaxis and locomotory behavior, although sensory ability was unaffected. In several assays of muscle function and structure, age-associated behavioral declines were associated with increased muscle frailty. However, behavioral declines preceded significant muscle deterioration. Finally, improved neuromuscular synaptic transmission may be one approach for improving performance in aged individuals, as locomotory behavior in aged animals was improved by treatment with a muscarinic acetylcholine receptor agonist that increases acetylcholine release at the C. elegans neuromuscular junction.
Dr. Mattson presented research on the impact of dietary restriction regimes on the brain, including the impact on neurodegenerative disorders. There is increasing evidence that, as with other age-related diseases, dietary factors can modify the risk of neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's Disease (PD), and stroke. It has been shown that when mice are maintained on an intermittent fasting (IF) regimen (every other day fasting) their ability to regulate glucose levels (insulin sensitivity) is increased, consistent with a reduced risk for diabetes. Rodents on an IF diet also exhibit reductions in blood pressure and heart rate, and improved cardiovascular adaptation to stress, suggesting that IF reduces the risk of cardiovascular disease and stroke. In a series of studies, the LNS scientists found that IF can protect neurons in the brains of rats and mice in models relevant to AD, PD, and stroke. The neuroprotective effect of IF was associated with improved behavioral outcomes (learning and memory in the AD model), and motor function in the PD and stroke models.
Studies of the expression of various genes in brain cells of rodents on IF and control diets revealed that IF induces the expression of a neurotrophic factor called brain-derived neurotrophic factor (BDNF) and several “stress resistance” proteins including heat-shock protein 70 and glucose-regulated protein 78. Cell culture studies had shown that each of these three proteins can protect neurons against insults relevant to AD, PD and stroke suggesting that they are likely to mediate (at least in part) the neuroprotective effects of IF in vivo . In addition to the neuroprotective effects of IF, LNS investigators found that this dietary restriction regimen enhances neurogenesis, the production of new nerve cells from stem cells. Studies of mice deficient in BDNF suggested that the ability of IF to enhance neurogenesis is mediated by BDNF. Collectively, these findings suggest that the mechanism underlying beneficial effects of IF on the brain involves a mild cellular stress response which enhances the ability of the cells to cope with more severe types of stress. Although it is not known whether IF will have similar effects in humans, these data in animals point in that direction. In this regard, a study of the effects of meal frequency on indicators of risk for diabetes and cardiovascular disease has been designed and will soon begin.
A second area of diet–brain interactions covered by Dr. Mattson concerns the role of lipids in the pathogenesis of AD. LNS investigators measured the concentrations of various lipids in brain tissue samples from patients with AD and age-matched control subjects. They found that concentrations of cholesterol and another type of lipid called ceramide were greatly increased in samples from vulnerable brain regions from AD patients compared to concentrations of these lipids in samples from the same brain regions of control subjects and to concentrations in samples from non-vulnerable brain regions of AD patients. The increased amounts of cholesterol and ceramide were particularly prominent in cell membranes. The investigators then showed that when cultured neurons are exposed to amyloid beta-peptide levels of cholesterol and ceramide are increased. When the neurons were treated with the antioxidant vitamin E, or with a drug called myriocin that blocks ceramide production, they were resistant to being killed by amyloid beta-peptide. These findings suggest that membrane-associated oxidative stress, induced by aging and amyloid beta-peptide, causes abnormalities in lipid metabolism in neurons that contribute to their dysfunction and degeneration in AD. Reducing levels of cholesterol and ceramides through diet and/or drugs may reduce the risk of AD and might also slow disease progression in symptomatic patients.
Dr. Matson added that his team is also doing a small human pilot study in collaboration with USDA to see how meal frequency affects human health. One group will eat three meals per day; the other will eat essentially one meal over a 3 to 4 hour time period. Subjects enrolled in the study are to try to maintain their weight throughout the 6-month study, with 2 months on diet, 2 months not, and 2 months crossed over. The advice that it is healthier to eat smaller, more frequent meals is not justified by any controlled scientific evidence, although such advice is good for diabetics who need to monitor glucose. Skipping meals appears good for rodents, and this pilot study will help determine whether it is also good for humans.
The 91st meeting of the National Advisory Council on Aging was adjourned at 3:15 p.m. on February 4, 2004. Dr. Hodes closed the Council session by thanking all speakers and the Council members for their participation. The next meeting is scheduled for May 24-25, 2004.
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 Miriam F. Kelty, Ph.D. with the assistance of Rose Li and Associates, Inc.
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 Miriam F. Kelty, Ph.D. with the assistance of Rose Li and Associates, Inc.
MEMBERSHIP ROSTERNATIONAL ADVISORY COUNCIL ON AGING NATIONAL INSTITUTE ON AGING (Terms end December 31)
Chairperson
Richard J. Hodes , M.D. Director, National Institute on Aging National Institutes of Health Bethesda , MD
Marie A. Bernard , M.D. (2005) Donald W. Reynolds Chair Department of Geriatric Medicine University of Oklahoma College of Medicine Oklahoma City , OK
Elizabeth H. Blackburn , Ph.D. (2006) Professor Dept of Biochemistry & Biophysics University of California San Francisco , CA
Melissa M. Brown , M.D. (2006) Director Center for Value-Based Medicine Flourtown , PA
John T. Cacioppo , Ph.D. (2007) Blake Distinguished Service Professor Department of Psychology University of Chicago and Institute for Mind & Biology Chicago, IL
*David V. Espino , M.D. (2004) Professor and Vice Chair Dept. of Family & Community Medicine Division of Community Geriatrics University of Texas Health Science Center San Antonio , TX
Linda P. Fried , M.D., MPH (2006) Professor, Medicine, Epidemiology & Health Policy Director, Division of Geriatric Medicine & Gerontology Director, Center on Aging and Health The Johns Hopkins Medical Institutions Baltimore , MD
Alan M. Garber , M.D., MPH (2007) Director Center for primary Care and Outcomes Research Center for Health Policy Standford University Standford, CA
F. Michael Gloth , III , M.D., (2005) President Victory Springs Senior Health Care Reisterstown , MD
*Eugene M. Johnson, Jr. , Ph.D. (2005) Norman J. Stupp Professor, Department of Neurology Professor, Dept. of Molecular Biology & Pharmacology Co-Director, Alzheimer's Disease Research Center Washington University School of Medicine St. Louis , MO
*Lewis H. Kuller , M.D., DrPH, MPH (2004) University Professor of Public Health Professor of Epidemiology Department of Epidemiology University of Pittsburgh Graduate School of Public Health Pittsburgh , PA
Ronald D. Lee , Ph.D. (2005) Professor, Department of Demography College of Letters and Science University of California Berkeley , CA
Virginia M.-Y. Lee , Ph.D. (2007) Professor Dept of Pathology & Laboratory Medicine University of Pennsylvania School of Medicine Philadelphia, PA
Spero M. Manson , Ph.D. (2006) Professor of Psychiatry and Head American Indian & Alaska Native Programs University of Colorado Health Sciences Ctr Aurora , CO
Peter W. Nauert, J.D. (2005) Principal Insurance Capital Management Chicago , IL
Stanley B. Prusiner , M.D. (2004) Director and Professor Institute for Neurodegenerative Diseases School of Medicine University of California San Francisco , CA
*Judith A. Riggs , M.A. (2004) Washington , DC
Leon J. Thal , M.D. (2005) Professor and Chair Department of Neurosciences University of California San Diego School of Medicine (and Staff Physician, Neurology Service,
San Diego Veterans Medical) La Jolla , CA
*WGoP Member
Tommy G. Thompson Secretary Department of Health and Human Services Hubert H. Humphrey Building Washington , D.C.
Elias Zerhouni , M.D. Director National Institutes of Health Public Health Service Bethesda, Maryland
James F. Burris , M.D. Deputy Chief Research & Development Officer Office of Research and Development Department of Veterans Affairs Washington, D.C.
John Wren Director, Office of Program Development Administration on Aging, DHHS Washington , D.C.
[ 1 ], [ 2 ] For the record, it is noted that members absented themselves from the meeting when the Council discussed applications (a) from their respective institutions, or (b) in which a conflict of interest may have occurred. This procedure only applied to applications that were discussed individually, not to "en bloc" actions.
[ 3 ] These minutes will be approved formally by the Council at the next meeting on May 24-25, 2004, and corrections or notations will be stated in the minutes of that meeting.
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