CALORIC RESTRICTION AND AGING IN NIA NON-HUMAN PRIMATES

Release Date:  June 18, 2001

RFA:  RFA-AG-02-002

National Institute on Aging
 (http://www.nih.gov/nia/)

Letter of Intent Receipt Date:  November 11, 2001
Application Receipt Date:       December 11, 2001

PURPOSE

The purpose of this RFA is to solicit applications that will utilize 
the non-human primate (NHP) resources maintained by the National 
Institute on Aging (NIA) Intramural Research Program (IRP).  The NIA 
IRP has developed colonies of Rhesus monkeys and squirrel monkeys 
(described in the background section under Research Objectives) under 
either chronic or short-term caloric restriction protocols.  These 
monkeys have been studied extensively and characterized by the NIA IRP.  
This RFA is to provide support for extramural investigators to perform 
additional studies on these cohorts of monkeys, thereby extending and 
expanding on the information about the effects of caloric restriction 
on the physiology of aging in NHP.

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 Request for 
Applications (RFA), Caloric Restriction and Aging in NIA Primates, 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/. 

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and 
non-profit organizations, public and private, such as universities, 
colleges, hospitals, laboratories, units of state and local 
governments, and eligible agencies of the Federal government. 
Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as principal investigators.  There 
may be some restrictions imposed on successful applicants from foreign 
institutions based on laws governing export of tissue, cells, or live 
animals.

MECHANISM OF SUPPORT

This RFA will use the cooperative agreement (U01) mechanism. The 
cooperative agreement is an assistance mechanism in which substantial 
involvement of the NIA with the recipient is anticipated during the 
performance of the planned activity. The nature of the NIA's 
involvement is described under SPECIAL REQUIREMENTS. Responsibility for 
the planning, direction, and execution of the proposed project will be 
solely that of the applicant/awardee. 

The total project period for an application submitted in response to 
the present RFA may not exceed five years.  The anticipated award date 
is September 2002. This RFA is a one-time solicitation.  Future 
unsolicited competing continuation applications will compete with all 
investigator-initiated R01 applications and be reviewed according to 
the customary peer review procedures. 

FUNDS AVAILABLE

It is anticipated that a total of $1,000,000 will be available for the 
first year of support for this RFA and that 5-10 awards will be made.  
Because the nature and scope of the research proposed in response to 
this RFA may vary, it is anticipated that the sizes of awards will vary 
also.  Awards and level of support depend on receipt of a sufficient 
number of applications of high scientific merit.  Although this program 
is provided for in the financial plans of the NIA, awards pursuant to 
this RFA are contingent upon the availability of funds for this 
purpose. 

RESEARCH OBJECTIVES

Background

Caloric restriction (CR) is the one paradigm that has been demonstrated 
through extensive experimentation to extend lifespan in a variety of 
species, including flies, yeast and rodents.  In addition to increased 
longevity, CR also has a positive effect on many metabolic and 
physiological variables in rodents, such as immune function, stress 
response, and spontaneous and induced tumor genesis.  However, although 
there is a large body of experimental evidence for the benefits of CR 
in rodents, the mechanism by which CR effects those benefits has yet to 
be elucidated.  It is also unknown at this time the extent to which the 
findings in rodents will be recapitulated in NHP.  There have been 
limited studies on CR in NHP, due in part to the expense of maintaining 
the animals necessary to carry out such studies.  The studies that have 
been done in NHP, primarily examining metabolic variables, have shown a 
remarkable level of agreement with the rodent data.  It is important 
now to expand these studies in NHP to examine a broad range of 
variables to determine if CR has benefits to both lifespan and health-
span in NHP and to investigate the mechanism(s) by which CR acts.
 
The NIA IRP has colonies of Rhesus macaques and squirrel monkeys that 
have been maintained under CR protocols and extensively characterized 
for metabolic endpoints.  CR was instituted at 10% per month until 
reaching 30% CR, the level at which they are maintained.  These animals 
are now available to investigators in the extramural research 
community, as described below.  IRP investigators have already 
generated a significant amount of data on these colonies, and a list of 
publications is available at the following website: 
http://www.grc.nia.nih.gov/branches/leg/rfa.htm.  IRP investigators are 
available to any applicant for collaborative studies.

The Rhesus macaque colony has two segments, a chronic (long-term) CR 
protocol and an acute (short-term) CR protocol.  Under the chronic CR 
protocol, males were started in 1987-88 and females were started in 
1992.  For both genders, there are three (3) groups defined by the age 
at which CR was initiated: juvenile (1-2 years old); adult (3-5 years 
old); and aged (>17 years old).  At the start of the study there were 
10 animals in each cohort defined by gender/age at initiation/diet (CR 
or ad libitum (AL) fed controls), but due to mortality over the course 
of the study, actual numbers of animals available will vary.  This 
group of animals is available primarily for noninvasive studies carried 
out at the NIA facility or in collaboration with NIA IRP investigators, 
with blood, tissue or cell samples transferred to the Principal 
Investigator’s home institution.  Some exceptions may be made depending 
on the applications received.

The Rhesus macaques in the acute CR protocol have undergone shorter CR 
protocols.  There are three groups of animals: males initiated in the 
CR protocol in 1997, at 3-5 years of age; females initiated in the CR 
protocol in 1995 at 4-5 years of age; and males initiated in the CR 
protocol in 1996 at >18 years of age.  Females were re-fed at AL levels 
for several months before returning to 30% CR by 12/1/00.  Each group 
consists of 6 AL and 6 CR monkeys.  These animals are available for 
terminal or invasive studies and may be approved for transfer to the 
Principal Investigator’s home institution. 

A colony of squirrel monkeys has been maintained under a chronic CR 
protocol since 1987.  There are two age groups (males only), those 
initiated in CR as juveniles (1-4 years old) and those initiated as 
adults (5-10 years old).  There are AL control groups for both groups 
and the sample size is approximately 7 per age/diet cohort.  The 
squirrel monkeys are available for non-invasive research performed at 
the NIA facility or in collaboration with NIA IRP investigators.
   
Research Objectives

The research objectives of this RFA are very broad.  The purpose of 
making this resource available is to stimulate research in all areas of 
study relating to the mechanism of action of CR in NHP.  One goal is to 
determine if the health-span and lifespan benefits of CR observed in 
rodents are also observed in NHP.  The second goal is to promote more 
mechanistic studies of CR to identify target systems, processes or 
molecules by which CR exerts its beneficial effects on healthy aging.  
To this end, many diverse areas of research are relevant, including 
investigations into maintenance of immune function with aging, 
behavioral studies, cognitive and motor function, sensory modalities 
including taste and olfaction, endocrine and neuroendocrine status, 
reproductive function, renal function, cardiovascular health, and 
hepatic function.  The role of oxidative stress is another area of 
interest, since there is considerable evidence that oxidative stress is 
a major factor in aging and that CR reduces the level of oxidative 
stress in rodents.

SPECIAL REQUIREMENTS

Due to the limited nature of the resource, significant coordination of 
studies may be necessary to facilitate multiple investigations using 
the same animals.  Therefore, experimental protocols and timing of 
experiments will be coordinated by an Advisory Panel as described 
below.   

Terms and Conditions of Awards

The following terms and conditions will be incorporated into the award 
statement and provided to the Principal Investigator as well as the 
institutional official at the time of the award.  These special Terms 
of Award are in addition to and not in lieu of otherwise applicable OMB 
administrative guidelines, HHS Grant Administrative Regulations at 45 
CFR Parts 74 and 92, and other HHS, PHS and NIH Grant administration 
policy statements. 

The administrative and funding instrument used for this program is a 
cooperative agreement (U01), an “assistance” mechanism (rather than an 
“acquisition” mechanism) in which substantial NIH scientific and/or 
programmatic involvement with the awardee is anticipated during 
performance of the activity.  Under the cooperative agreement, the NIH 
purpose is to support and/or stimulate the recipient’s activity by 
involvement in and otherwise working jointly with the award recipient 
in a partner role, but it is not to assume direction, prime 
responsibility or the dominant role in the activity.  Consistent with 
this concept, the dominant role and prime responsibility for the 
activity resides with the awardee(s) for the project as a whole, 
although specific tasks and activities in carrying out the studies will 
be shared among the awardees and the Advisory Panel, which will be 
responsible for coordinating activities to allow multiple projects to 
efficiently and effectively utilize the primate colony.

1.  Awardee Rights and Responsibilities  
 
Awardees have primary authorities and responsibilities to define 
objectives and approaches, to plan and conduct the research activities, 
and to analyze and publish results, interpretations and conclusions of 
their studies.  NIH intramural investigators who are scientific 
collaborators with awardees will have the same rights and 
responsibilities as other investigators.  
 
Awardees will retain custody of and have primary rights to the data 
developed under these awards, subject to Government rights of access 
consistent with current HHS, PHS, and NIH policies.  However, the 
awardee has the responsibility to submit the data to the Primate Aging 
Database, an NIA-sponsored database in development that will be 
available to all researchers.  Timing of submission of the data will be 
coordinated between the Principal Investigator and the Advisory Panel, 
but will take place no later than the time of publication of the study 
results.  

Due to the significant investment the NIA has made in these animals, 
awardees also have the responsibility to provide excess collected 
tissue or blood to an NIA-approved tissue bank at the culmination of 
the study.  If animals are used for terminal experiments, awardees will 
collect unused tissue, within reasonable limits, at necropsy and send 
it to a tissue bank as directed by the Advisory Panel.

Awardees should attend an annual meeting at the NIA Gerontology 
Research Center in Baltimore MD, for the purpose of discussing 
preliminary results.

2.   NIA Staff Responsibilities  
 
The Program Coordinator will be an Intramural NIA scientist with 
knowledge of the specific rhesus and squirrel monkey colonies.  This 
individual will advise investigators and provide necessary expertise to 
ensure that the study goals can be met given the characteristics of the 
two colonies.  The Program Coordinator is expected to have substantial 
scientific involvement during the course of these studies because of 
the knowledge of the colonies and expertise that will be shared with 
investigators.

The Program Administrator will be an Extramural official with 
responsibility for administering the grant.  This individual will also 
be a liaison member of the Advisory Panel (see below) in order to 
provide essential information concerning progress of the awards, to 
allow the Advisory Panel to make appropriate decisions about the 
continued use and sharing of the resources.

An Advisory Panel will be established comprised of five extramural and 
intramural scientists who have expertise in primate colony management 
and use of NHP in research.  Their role is to make recommendations to 
the NIA that will coordinate the use of the primate colonies among the 
awarded studies.  None of the panel members may be part of a laboratory 
or unit that is seeking to use the resources of the subject primate 
colonies.  The Advisory Panel will be convened at least once a year, 
with additional meetings and/or teleconferences as needed.    

The NIA reserves the right to terminate or curtail the study (or an 
individual award) in the event that significant mortality within the 
primate colonies renders the experimental approach invalid. 
 
3.  Collaborative Responsibilities 
 
The Advisory Panel will provide recommendations coordinating the 
experimental protocols to accommodate the needs of all investigators 
using the same animals.  These animals are used in active research 
projects in the Intramural Research Program and funded studies must be 
compatible with the IRP studies in progress.  Refer to the web site 
(http://www.grc.nia.nih.gov/branches/leg/rfa.htm) for descriptions of 
on-going projects.  Data generated during the course of these studies 
must be made available to the Primate Aging Database.  IRP Animal Care 
and Use Committee approval must be obtained for studies as described on 
the website.  NIA IRP scientific staff are available for collaborative 
studies with active participation in the project execution. 

4.  Arbitration 
 
Any disagreement that may arise on scientific/programmatic matters 
(within the scope of the award), between award recipients and the NIA 
may be brought to arbitration.  An arbitration panel will be composed 
of three members – one selected by the individual awardee, a second 
member selected by NIA, and the third member selected by the two prior 
selected members.  This special arbitration procedure in no way affects 
the awardee's right to appeal an adverse action that is otherwise 
appealable in accordance with the PHS regulations at 42 CFR Part 50, 
Subpart D and HHS regulation at 45 CFR Part 16.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that 
includes a descriptive title of the proposed research, the name, 
address, and telephone number of the Principal Investigator, the 
identities of other key personnel and participating institutions, and 
the number and title of the RFA in response to which the application 
may be submitted. 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 avoid conflict of interest 
in the review.

The letter of intent is to be sent to the program staff listed under 
INQUIRIES by the letter of intent receipt date listed in the heading of 
this RFA.

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.  Reviewers are cautioned that 
their anonymity may be compromised when they directly access an 
Internet site.

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:                
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm 

Applicants may wish to place data collected under this RFA (PA) 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.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants.  These forms are available at most 
institutional offices of sponsored research and from the Division of 
Extramural Outreach and Information Resources, National Institutes of 
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, 
telephone (301) 435-0714, email: GrantsInfo@nih.gov. Applications are 
also available on the Internet at 
http://grants.nih.gov/grants/funding/phs398/phs398.html 

The RFA label available in the PHS 398 (rev. 4/98) 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 sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been 
modified to allow for this change.  Please note that this sample label 
is in pdf format.

Applicants should include in the budget funds to attend an annual 
meeting at the NIA Gerontology Research Center in Baltimore MD.  

If an NIH intramural investigator will be a scientific collaborator in 
the project, a formal letter of collaboration from the intramural 
scientist must be included as part of the grant application. The letter 
should describe the intramural scientist's collaborative work under the 
grant. The grant applicant is responsible for writing the section of 
the grant that describes the proposed collaboration within the grant, 
which the NIH investigator should see and approve.

Submit a signed, original of the application, including the Checklist, 
and three signed photocopies of the application 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, send two additional copies of the 
application to:

Mary Nekola, Ph.D.
Chief, Scientific Review
Scientific Review Office
National Institute on Aging
7201 Wisconsin Avenue, Room 2C212
Bethesda, MD  20892-9205

It is important to send these copies at the same time as the original 
and three copies are sent to the Center for Scientific Review. These 
copies are used to identify conflicts and to help ensure the 
appropriate and timely review of the application.

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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and 
responsiveness by the NIA.  Incomplete and/or non-responsive 
applications will be returned to the applicant without further 
consideration.

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 NIA in accordance with the review criteria 
stated below. As part of the initial merit review, a process may be 
used by the initial review group in which applications receive a 
written critique and 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, assigned a priority 
score, and 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 the application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals.  Each of these criteria will be addressed and 
considered in assigning the overall score, weighting them as 
appropriate for each application.  Note that the 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, 
an investigator 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 this study address an important problem?  If 
the aims of the application are achieved, how will scientific knowledge 
be advanced?  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?  Does the applicant acknowledge potential problem 
areas and consider alternative tactics?

3.  Innovation:  Does the project employ novel concepts, approaches or 
method? Are the aims original and innovative?  Does the project 
challenge existing paradigms or develop new methodologies or 
technologies?

4.  Investigator:  Is the investigator appropriately trained and well 
suited to carry out this work?  Is the work proposed appropriate to the 
experience level of the principal investigator and other researchers 
(if any)?

5.  Environment:  Does the scientific environment in which the 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?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o The reasonableness of the proposed budget and duration in relation to 
the  proposed research.

o 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.

Schedule:

Letter of Intent Receipt Date:  November 11, 2001
Application Receipt Date:       December 11, 2001
Date of Initial Review:         April, 2002
Review by Advisory Council:     May, 2002
Anticipated Award Date:         September 1, 2002

AWARD CRITERIA

Applications recommended by the NIA Advisory Council will be considered 
for award based upon (a) scientific and technical merit; (b) program 
objectives; and (c) availability of funds.

INQUIRIES

Inquiries concerning this RFA are encouraged. The opportunity to 
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding the application process or technical issues 
on the cooperative agreement mechanism to:

Nancy L. Nadon, Ph.D.
Head, Office of Biological Resources and Resource Development
National Institute on Aging
7201 Wisconsin Avenue, GW 2C231
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010 
Email:  nadonn@exmur.nia.nih.gov

Direct scientific inquiries regarding the primate colonies, including 
background information available, the CR protocols, and restrictions to 
research protocols, to:

Mark Lane, Ph.D.
National Institute on Aging
Gerontology Research Center
5600 Nathan Shock Drive
Baltimore MD 21224
Telephone: 301-594-1210
FAX: 301-480-0504
Email:  ml124y@nih.gov 

Direct inquiries regarding fiscal matters and award concerns to:

Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  lw17m@NIH.GOV

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
No. 93.866.  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 and Federal Regulations 42 
CFR 52 and 45 CFR Parts 74 and 92.  This program is not subject to the 
intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review

The PHS strongly encourages all grant and contract recipients to 
provide a smoke-free workplace and promote the non-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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