COMPARATIVE BIOLOGY: MECHANISMS OF AGING RELEASE DATE: October 30, 2002 RFA: AG-03-003 National Institute on Aging (NIA) (http://www.nih.gov/nia/) LETTER OF INTENT RECEIPT DATE: December 23, 2002 APPLICATION RECEIPT DATE: January 23, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The NIA is soliciting applications that use comparative biology approaches to understand the biological mechanisms that lead to changes in human and other animal cells and tissues with age. The major questions to be addressed under this RFA are: How does increasing age lead to biological changes, especially decrements in cell, tissue and organ function; and what sets the rate of aging such that different organisms have different life expectancies? Studies that take advantage of the differences in aging and life expectancy between species and within species to investigate hypotheses on the mechanisms of aging are encouraged. RESEARCH OBJECTIVES Background This RFA follows on a workshop held by the NIA in February, 2002 on Comparative Biology of Aging. A publication from that meeting can be accessed on the Science of Aging Knowledge Environment (SAGE KE) at http://sageke.sciencemag.org/cgi/content/full/sageke;2002/17/pe5?&view=print We do not yet know why the function of many human tissues and organs increasingly declines with age. Senescence takes place in most organisms, resulting in increasing mortality with age. Humans are among some of the longest-lived organisms but some organisms, such as tortoises, live longer and some, such as the bristle cone pine tree live for thousands of years. At the other end of the spectrum, many organisms have very short life expectancy. Hypotheses of aging have been advanced and provide a framework for study of the causes of biological changes seen with aging. The free radical damage theory of aging implies that accumulation of free radicals, such as reactive oxygen species(ROS) that result from respiration, results in damage to lipids, proteins and/or nucleic acids. This damage accumulates and, eventually, function of tissue is impaired. It has long been assumed that the more oxygen that is metabolized by mitochondria, the more reactive oxygen species (ROS) will be produced. Not yet clear is how mitochondria from some species might metabolize oxygen more efficiently than mitochondria from other species, and thus produce ROS at a lower rate. Comparative approaches should be useful for elucidating the molecular basis for differences in mitochondrial efficiency among species and for testing whether production of ROS and repair of resulting damage are key to determining longevity. Such information might also be useful in understanding differences in oxygen utilization and oxidative stress in different tissues and organs within a species. The telomeres that protect the functional ends of chromosomes have been implicated in the process of cell senescence, the limited replication potential of non-stem cell populations in the body. However, the role of telomeres in determining how long cells can continue to replicate and function before senescing, or how long an organism lives, is far from clear. In some model organisms, single gene changes can result in extended or shortened life expectancy. Thus, there appears to be a genetic component to longevity determination within a species. Although considerable progress has been made identifying genes involved in longevity regulation within species, e.g. fruit flies, nematodes and mice, and similar genes are found across species, relatively little is known about the genes that account for the striking differences in longevity between species. Comparative approaches should prove useful in identifying these genes. A variety of correlations with long life have been noted in several different species; factors such as body size, protective lifestyle (flying as opposed to terrestrial or high vs. low predation environments, for instance), and social lifestyle may all be involved. However, none of the hypothesized influences on aging rate and longevity has been adequately tested and proven to be a cause of changes with age. In addition, the molecular and genetic bases for longer life expectancy that results from environmental influences are not characterized. Comparison between organisms with different life expectancies, or with characteristics that, according to hypotheses on aging, should be predictive of life expectancy, is very likely to be a productive approach to testing hypotheses and advancing new ones that explain aging. However, this productive approach has not been widely used. For example, animals may be phylogenetically closely related, such as the mouse and naked mole rat, but have considerably varying life expectancies, in this case about two years compared to over 20 years, respectively. Alternatively, comparisons between humans and other primates, or between primate species with widely varying life expectancies would also be valuable. Understanding the biological differences between these closely related species at the molecular, cell and tissue levels may help to understand the causes of senescence. Such studies would also help determine whether relationships between biological mechanisms of aging and life expectancy or aging rates observed among non-primate phylogenies also apply to humans and closely related species. It is also unclear that the mechanisms that make a difference in life expectancy among relatively shorter-lived species are the same ones that account for the life expectancies of very long-lived species, e.g., long-lived primates, including humans, as well as long-lived species in other phylogenies. Studies to extend comparisons involving mechanisms of aging to primates would be useful in answering this question. Variation of life expectancies within species can be quite large, and the causes of this variation are likely to be informative. Thus, the honeybee can produce a worker or a queen from the same egg, depending on early feeding of the larva, and possibly other factors. Yet the queen bee lives 5-8 years, while the worker lives less than a year. Some organisms have properties that, according to some aging hypotheses, would seem predictive of short or long life expectancy. The budgerigar is approximately the same body size as a mouse but has much higher lifetime energy consumption. This would seem to predict greater production of reactive oxygen species and, thus, shorter life expectancy. Yet, the budgerigar lives almost ten times as long as a mouse. Finally, within an organism, some cells have a shorter life relative to other cells (for example, a columnar absorptive cell from the intestinal epithelium as opposed to a cardiac myocyte). It is unclear how longer lived cells maintain tissue homeostasis in spite of predicted accumulation of damage with greater age. In each of the above examples, and many others, careful studies that use comparisons to test hypotheses of aging would be valuable to understanding aging mechanisms. Objectives and Scope This RFA is intended to encourage mechanistic, basic research using comparative biology approaches to investigate aging. Research that takes maximal advantage of unique properties of species available for laboratory study is particularly encouraged. Studies should be focused on well-described hypotheses for why functional changes and mortality increase with age, and why rates of change and life expectancy vary among species or strains. Studies may be at the molecular, cellular, tissue, organ, or organism level. Studies comparing humans with other species, including other primate species, are encouraged. Such studies may include physiologic measures and collection of body fluids, tissues, or cells for in vitro use. Studies under this RFA may not include clinical interventions or therapeutic evaluations. Studies focused on models for a particular disease process, as opposed to a general mechanism of aging and altered life expectancy, are not appropriate under this announcement. The examples below illustrate some potential areas of interest but are intended as examples only and are not exclusive. o Studies to identify genes that explain differing life expectancies between species, including species with exceptionally long life expectancies. o Studies on mechanisms of senescence or protection from senescence in stem cells and how stem cell lifespan influences organism lifespan o Studies in multiple species to determine if genes whose expression results in increased longevity in one species also increase longevity in other species. For example, do the mutations in genes that result in longer life span for worms, flies and mice also result in longer life span in other organisms. o Studies on strategies different organisms use to deal with oxidative stress through reduced production of ROS, or through repair, replacement, or prevention of damaged molecules (for example, DNA) and cells and how this strategy results in different life expectancies. o Studies to identify key molecular and genetic changes that dominate as a result of selection for longer lived animals within a species. o Studies of telomere biology between species to determine how telomere and telomerase function correlate with life expectancy of the organism (or specific cell types within an organisms?). o Studies of environmental influences that substantially change the rate of aging or life expectancy within and between species, especially the resulting changes in gene expression and physiology that contribute to this effect. o Studies to define periods of development and adulthood where aging and longevity factors exert their effect. o Studies to understand the cellular and molecular basis of the changes in tissue or organ function with age by comparisons between organisms with different tissue-aging properties o Mechanistic studies that make use of organisms not currently broadly used for aging research but that have special interest to study of aging in light of mechanisms proposed for aging. MECHANISM OF SUPPORT This RFA will use the NIH R01 award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 2003. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see https://grants.nih.gov/grants/funding/modular/modular.htm). FUNDS AVAILABLE The NIA anticipates that a total of $1.5 million will be available in FY 2003 to fund new grants in response to this RFA. An applicant may request a project period up to five years and a budget for direct costs up to $200,000 a year. Because the nature and scope of the proposed research will vary from application to application NIA anticipates that the size and duration of awards will also vary. It is anticipated that 5-7 grants will be supported. Awards are contingent upon availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. At this time it is not known whether this RFA will be reissued. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about general scientific/research issues and regarding projects focused on non-neural tissues to: Jill L. Carrington, Ph.D. Biology of Aging Program National Institute on Aging Gateway Building, Suite 2C231 7201 Wisconsin Avenue Bethesda, MD 20892-9205 Telephone: (301) 496-6402 Email: carringtonj@nia.nih.gov For questions about involvement of humans in studies under this RFA, contact: Evan C. Hadley, M.D. Geriatrics and Clinical Gerontology Program National Institute on Aging, NIH Gateway Building, Suite 3E327 7201 Wisconsin Avenue Bethesda MD 20892-9205 Telephone: (301) 435-3044 Email: ehadley@nih.gov For questions on studies focused on the nervous system under this RFA, contact: Bradley C. Wise, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging Gateway Building, Suite 3C307 7201 Wisconsin Avenue Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: wiseb@nia.nih.gov o Direct your questions about peer review issues to: Mary Nekola, Ph.D. Scientific Review Office National Institute on Aging Gateway Building, Room 2C212 Bethesda, MD 20892-9205 Telephone: (301) 496-9666 Email: nekolam@nia.nih.gov o Direct your questions about financial or grants management matters to: Linda Whipp Grants and Contracts Management Office National Institute on Aging Gateway Building, Room 2N212 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 Email: whippl@nia.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Chief of Review Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2C212, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9666 FAX: 301-402-0066 Email: NekolaM@nia.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at https://grants.nih.gov/grants/funding/phs398/phs398.html includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at https://grants.nih.gov/grants/funding/modular/modular.htm. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center for Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Chief of Review Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2C212, MSC 9205 Bethesda, MD 20892-9205 APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIA. Incomplete applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIA in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o May undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Advisory Council on Aging REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: December 23, 2002 Application Receipt Date: January 23, 2003 Peer Review Date: May, 2003 Council Review: August, 2003 Earliest Anticipated Start Date: September, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_20 01.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at https://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at https://grants.nih.gov/grants/guide/notice- files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.866, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at https://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and to discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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