OXIDATIVE DAMAGE, ANTIOXIDANT DEFENSE, AND AGING

NIH GUIDE, Volume 21, Number 41, November 13, 1992



PA:  PA-93-017



P.T. 34



Keywords:

  Aging/Gerontology 

  Pathophysiology 

  Proteins and Macromolecules 

  Metabolism, Lipid 



National Institute on Aging



PURPOSE



Free radical damage has long been believed to be a risk factor for the

degenerative processes that accompany aging in a variety of animal

species ranging from insects to humans.  The free radical theory of

aging was proposed by Denham Harman in 1956, and much research since

then has been directed towards establishing correlations among

oxidative damage, antioxidant defense systems, aging and life span.

Although a few modest correlations have been observed, efforts to move

beyond correlative evidence, e.g., using antioxidant manipulations in

animal and cell culture models to attempt to extend maximum life spans,

have yielded few definitive results.  Nevertheless, evidence continues

to accumulate about the ubiquity of free radicals and their

considerable destructive potential in living tissues.  It is plausible

that an improved understanding of free radical processes will lead to

the discovery of interventions (dietary, pharmacological or genetic) to

improve health and increase life spans.  Research is needed to

establish the critical relationships among free radical sources,

protective systems and aging phenomena that may be amenable to

intervention.



ELIGIBILITY REQUIREMENTS



Applications may be submitted by foreign and domestic, for-profit and

non-profit, public and private organizations, such as universities,

colleges, hospitals, laboratories, units of State and local

governments, and eligible agencies of the Federal government.

Applications from minority individuals and women are encouraged.



Foreign institutions are not eligible to apply for career awards (K04,

K08, K11) or First Independent Research Support and Transition (FIRST)

(R29) awards, and can apply for National Research Service Training

Awards (F32, F33) only if the applicant is a U.S. citizen.  Applicants

for F32, F33, K04, K08, and K11 awards must be U.S. citizens or

resident aliens.



MECHANISMS OF SUPPORT



The primary mechanisms for support of this program are:



o  Research grant (RO1)

o  FIRST award (R29)

o  Career grants, which include:  Research Career Development Award

(K04); Clinical Investigator Award (K08); Physician Scientist Award,

individual (K11)

o  Fellowships (F32, F33)



Deadlines for applications are as follows:



F-series grants:                            Jan 10, May 10, and Sep 10

New R and K-series grants:                  Feb 1, Jun 1, and Oct 1

Competing continuation and revised grants:  Mar 1, Jul 1, and Nov 1



RESEARCH OBJECTIVES



The National Institute on Aging (NIA) invites investigators to submit

applications for research on oxidative damage and pathobiology as

related to aging and the aging process.  Priority will be given to

research projects that are likely to provide critical insights into

these relationships other than correlative data.  Also, it is

recognized that the National Cancer Institute (NCI) has an interest in

the role of oxidative damage in cancer and the carcinogenesis process,

the National Institute of Environmental Health Sciences (NIEHS) has an

interest in toxic environmental agents, and the National Institute of

Diabetes and Digestive and Kidney Diseases (NIDDK) has an interest in

the role of oxidative damage due to saturated and unsaturated lipids on

normal and abnormal metabolic processes in high eukaryotes and humans.

Applications will be given an institute assignment based on the

Referral Guidelines for Funding Components of PHS.



The following areas of research are of particular interest to the NIA,

but applications need not be limited to the areas listed below.



1.  Improved methods for measuring any of the following in biological

tissues suitable for aging studies: levels of antioxidants in both the

oxidized and reduced state; rate of production of superoxide, hydrogen

peroxide and hydroxyl radical; levels and/or identification of oxidized

products in macromolecules, such as DNA, protein and lipids; rate of

repair of oxidized macromolecules in vivo.



2.  Identification of which enzyme activities involved in antioxidant

defense are rate-limiting, with particular emphasis on age-related

changes.



3.  The role of heavy metal ions, whether bound or free, in age-related

accumulation of oxidative damage in vivo.



4.  Development of interventions that reduce oxidative damage through

either neutralization of oxygen free radicals, reduction of the rate of

production of oxygen free radicals, repair of oxidative damage, or

improvement of antioxidant defense systems, coupled with a

demonstration that this reduced oxidative stress is associated with a

change in age-associated biological processes and/or diseases.



5.  The role of mitochondrial dysfunction in cellular oxidative damage

due to normal metabolism, and how this changes with age.



6.  Elucidation of how genes involved in antioxidant defense systems

are regulated in vivo, with particular emphasis on how the regulation

is altered during aging.



7.  The mechanism of attenuation of oxidative damage by spin trapping

compounds and other chemical and dietary interventions.



8.  Determination of whether and/or how caloric restriction reduces

oxidative damage, and whether or not this is related to life span

extension.



9.  The relationship between oxidative damage and the eventual

development of age-related disease states.



10.  Development of animal model systems, particularly transgenic

animals, to test the effect of altering

oxidative damage or antioxidant defense systems on aging and/or life

span.



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



NIH policy is that applicants for NIH clinical research grants and

cooperative agreements are required to include minorities and women in

study populations so that research findings can be of benefit to all

persons at risk of the disease, disorder or condition under study;

special emphasis must be placed on the need for inclusion of minorities

and women in studies of diseases, disorders and conditions which

disproportionately affect them. This policy is intended to apply to

males and females of all ages.  If women or minorities are excluded or

inadequately represented in clinical research, particularly in proposed

population-based studies, a clear compelling rationale must be

provided.  The composition of the proposed study population must be

described in terms of gender and racial/ethnic group.  In addition,

gender and racial/ethnic issues should be addressed in developing a

research design and sample size appropriate for the scientific

objectives of the study.  This information must be included in the form

PHS 398 (rev. 9/91) in Sections 1-4 of the Research Plan AND summarized

in Section 3, Recruitment of Individuals from Under represented

Racial/ethnic Groups, and Section 5, Human Subjects.  Applicants are

urged to assess carefully the feasibility of including the broadest

possible representation of minority groups.



However, NIH recognizes that it may not be feasible or appropriate in

ALL research projects to include representation of the full array of

United States racial/ethnic minority populations (i.e., Native

Americans including American Indians or Alaskan Natives, Asian/Pacific

Islanders, Blacks, Hispanics).  The rationale for studies on single

minority population groups must be provided.



For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology, prevention

and preventive strategies, diagnosis, or treatment of diseases,

disorders or conditions, including but not limited to clinical trials.



The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.



For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including

minorities.



If the required information is not contained within the application,

the review will be deferred until the information is provided.



Peer reviewers will address specifically whether the research plan in

the application conforms to these policies.  If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed AND the justification for the selected

study population is inadequate, it will be considered a scientific

weakness or deficiency in the study design and will be reflected in

assigning the priority score to the application.  All applications for

clinical research submitted to NIH are required to address these

policies.  NIH funding components will not award grants or cooperative

agreements that do not comply with these policies.



APPLICATION PROCEDURES



Applications for R01, R29, and K Awards are to be submitted on the

grant application form PHS 398 (rev.9/91) and will be accepted at the

standard application deadlines indicated in the application kit.

Applications for F32 and F33 awards are to be submitted on form PHS 416

(rev. 10/91).



Application kits are available at most institutional offices of

sponsored research and may be obtained from the Office of Grants

Inquiries, Division of Research Grants, National Institutes of Health,

Westwood Building, Room 449, Bethesda, MD 20892, telephone (301)

496-7441.  The title and number of the announcement must be typed in

Section 2a on the face page of the application.



The completed original application and five legible copies of PHS 398

or two copies of PHS 416 must be sent or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



To expedite the application's routing within the NIH, please check the

box on the face page of the application indicating that the application

is in response to this announcement and type (next to the checked box)

"Oxidative Damage and Aging."



Applications for F32, F33 and R29 awards must include at least three

letters of reference attached to the face page of the original

application.  Applications submitted without the required number of

reference letters will be considered incomplete and will be returned

without review.



REVIEW CONSIDERATIONS



The review criteria are the traditional considerations underlying

scientific merit.  Applications will be assigned on the basis of

established Public Health Service referral guidelines.  For information

on the special review criteria for the FIRST (R29) award, research

career awards (K series), and fellowships (F32, F33) contact the

program staff listed under INQUIRIES.  Applications will be assigned on

the basis of established PHS referral guidelines.  In accordance with

the standard NIH peer review procedures, research project grant (RO1

and R29) applications, fellowships (F32, F33) and research career

development awards (K04) will be reviewed for scientific and technical

merit by an appropriate study section in the Division of Research

Grants.  Other applications (K08 and K11) will be reviewed by an

appropriate institute review group.  Following scientific/technical

review, the applications will receive a second-level review by the

appropriate advisory council.



AWARD CRITERIA



There are no set-aside funds for funding these applications.

Applications compete for available funds on the basis of scientific

merit with all other applications.  The following will be considered in

making funding decisions:



o  Quality of the proposed project as determined by peer review

o  Availability of funds

o  Program balance among research areas of the announcement



INQUIRIES



Researchers considering an application in response to this announcement

may discuss their project and the range of grant mechanisms available

with NIA staff in advance of formal submission.  This can be done

either through a telephone conversation or a brief letter giving the

descriptive title of the proposed project and identifying the Principal

Investigator and, when known, other key participants.  Applications

related to the health of women and minorities are particularly

encouraged.  Correspondence and inquiries may be directed to:



Huber R. Warner, Ph.D.

Biology of Aging Program

National Institute on Aging

Gateway Building, Room 2C231

7201 Wisconsin Avenue

Bethesda, MD  20892

Telephone:  (301) 496-6402

FAX:  (301) 402-0010



or



Pamela Starke-Reed, Ph.D.

Geriatrics Program

National Institute on Aging

Gateway Building, Room 3E327

7201 Wisconsin Avenue

Bethesda, MD  20892

Telephone:  (301) 496-6761

FAX:  (301) 402-1784



Direct inquiries regarding fiscal matters to:



Joseph Ellis

Grants and Contracts Management Officer

National Institute on Aging

Gateway Building, Room 2N212

Bethesda, MD  20892

Telephone:  (301) 496-1472



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic Assistance

No. 93.866.  Awards are made under authorization of the Public Health

Service Act, Title IV, Part A (Public Law 78-410, as amended by Public

Law 99-158, 42 USC 241 and 285) and administered under PHS grants

policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This

program is not subject to the intergovernmental review requirements of

Executive order 12372 or Health Systems Agency review.



.

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