MOLECULAR AND NEURAL MECHANISMS UNDERLYING THE EFFECTS 0F CALORIC RESTRICTION ON 
HEALTH & LONGEVITY

Release Date:  August 22, 2000
 
RFA:  AG-01-002
 
National Institute on Aging
 (http://www.nih.gov/nia/)

Letter of Intent Receipt Date:  September 30, 2000
Application Receipt Date:       November 20, 2000


PURPOSE
 
The purpose of this RFA is to solicit applications to conduct research 
on the mechanisms underlying the effects of caloric restriction (CR) on 
longevity and health span. Although numerous studies in several species 
over the past three decades have shown that experimental animals 
maintained on CR have a longer lifespan than ad libitum controls, the 
biological process(es) which mediates this effect is unknown. Knowledge 
about the changes induced by CR at genetic, molecular, cellular, 
tissue, systems and behavioral levels are needed in order to explore 
the full range of possible mechanisms.  One approach to learning more 
about the underlying mechanisms takes advantage of the recent advances 
in genetics with the use of transgenic and knockout animals that target 
genes affecting longevity, body weight regulation, food intake, 
metabolism and physical activity. Another approach is to develop and 
test interventions that mimic the effects that CR induces in 
experimental animals.

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), Molecular and Neural Mechanisms Underlying the 
Effects of Caloric Restriction on Health & Longevity, 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.

MECHANISM OF SUPPORT

This RFA will use the research project grant (R01) mechanism.  
Responsibility for the planning, direction and execution of the 
proposed project will be solely that of the applicant/awardee.

FUNDS AVAILABLE

The NIA intends to commit up to $2,000,000 in FY 2001 to fund new 
grants in response to this RFA.  An applicant may request a project 
period of up to 5 years.  Applicants interested in proposing R01 
budgets in excess of $500,000 in direct costs per year should discuss 
the budget with a program official prior to submission (see Application 
Procedures).  Because the nature and scope of the research proposed may 
vary, it is anticipated that the size of each award will also vary.  
Although the financial plans of the NIA provide support for this 
program, awards pursuant to this RFA are contingent upon the 
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 if the RFA will be reissued.


RESEARCH OBJECTIVES

It has been known since 1935 that caloric restriction (CR) extends 
maximum life span in rodents such as rats and mice.  More recent 
results indicate that the development of some age-related pathology is 
also delayed by CR.  Furthermore, CR appears to extend maximum life 
span in every species in which it has been adequately tested.  Trials 
in rhesus monkeys are currently in progress, but it is too soon to 
predict whether CR will have an impact on maximum life span in this 
species, although preliminary results suggest that some changes induced 
by CR in rodents are mimicked in the CR monkeys.  Even if CR can be 
shown to work in non-human primates, it is unclear whether or not the 
general population would voluntarily adhere to a similarly restricted 
nutritional program.  Thus, it is imperative to attempt to develop 
possible mimetic approaches to achieve the same goal.

In March 1999, the NIA and NIDDK (National Institute on Diabetes 
Digestive Diseases and Kidney) co-sponsored the Caloric Restriction 
Clinical Implications Advisory Group.  The Advisory Group reviewed data 
and made recommendations on epidemiologic, experimental therapeutic, 
mechanistic, and human intervention studies relating to the 
relationships of caloric intake, energy balance, and weight gain over 
the lifespan with longevity and morbidity. The proceedings from this 
Advisory Group meeting will be published in the Journals of 
Gerontology: Series A Biological and Medical Sciences, with an 
anticipated publication date in mid 2000. Notice of publication will be 
posted on the NIA Website at http://www.nih.gov/nia/news/. 

Potential applicants interested in conducting research on human aspects 
of caloric restriction are encouraged to review the companion NIA RFA, 
(RFA AG-01-001), “Sustained Caloric Restriction in Non-Obese Persons: 
Physiologic Effects and Comparisons/Interactions with Physical 
Activity”. 

In spite of considerable research on CR funded by the NIA, a mechanism 
has yet to be established for how CR works.  It is known that CR 
increases resistance to stress and reduces oxidative damage to cellular 
macromolecules, but causative links have not been established.

Although most attention has focused on mitochondrial and other 
metabolic factors, free radicals and neuronal damage, and physical 
activity and body composition, less is known about the role(s) played 
by neuroendocrine/neuropeptide/neurotransmitter systems of the brain.  
Lowered body weight, in comparison to the body weight of ad libitum fed 
animals, may be an important component of the life span-enhancing 
effect of CR.  It is well-known that manipulations (e.g., destruction, 
chemical injection, etc.) of specific regions of the central nervous 
system (CNS) can result in profound, long-term changes in body weight.  
For example, destruction of one area of the hypothalamus (ventromedial 
nucleus) will produce an obese animal, whereas destruction of another 
area nearby (lateral hypothalamus) can lead to an animal which fails to 
eat.  Thus, there is a strong link between the function of certain CNS 
areas and the regulation of body weight and food intake.  CR could have 
its effect at several levels:  hypothalamus, pituitary, target tissue; 
and on multiple functions: synthesis, release, action, metabolism as 
well as target tissue sensitivity (receptor function).  

There are both species and strain differences (rats and mice have been 
studied), and few studies have been able to assess the entire life 
span.  CR effects may differ when the manipulation is chronic vs. 
acute, in males vs. females, when CR is initiated at different ages or 
at different stages of reproduction in the case of females.  In 
addition, the percentage of ad libitum intake used for CR is not 
consistent among studies.  The type of feeding schedules may influence 
the release of critical hormones, peptides or transmitters; receiving 
one large meal per day could have different metabolic consequences from 
receiving several smaller meals that are spaced to more closely 
simulate the animal’s natural feeding rhythm. Thus, these variables 
with regard to CR and CNS function require further investigation.

The major objectives of this RFA include, but are not limited to, 
applications designed to address one or more of the following in 
mammalian and/or non-mammalian systems (including unicellular 
organisms):

o  Identification of the critical metabolic changes associated with CR

o  Investigation of which of the many changes (metabolic and/or non-
metabolic) induced by CR are critical to life span extension

o  Understanding of the role played by reduction of oxidative stress in 
life span extension by CR

o  Investigation of the role played by reduction of blood glucose 
levels in life span extension by CR

o  Development of mimetics which induce life span extension in the 
absence of dietary restriction

o  Elucidation of the neuroendocrine, neuropeptide and neurotransmitter 
changes induced by CR

o  Use of genetically altered mice to mimic changes induced by CR

o  Characterization of age-related changes that are affected by CR by 
use of high throughput technology such as microarrays

o  Studies of the association between CR and changes in responsiveness 
to sensory characteristics such as taste and smell

o  Studies of longevity and body weight regulation in transgenic and 
knockout animal models in which the manipulated gene has been shown to 
influence food intake, metabolism or physical activity

o  Studies of changes in sensitivity of CR animals to pharmacological 
agents known to have short- or long-term effect on food intake, body 
weight control, physical activity or metabolism

o  Investigation of cognitive changes in CR animals and in genetically-
manipulated animals with modified lifespan

SPECIAL REQUIREMENTS

Applicants should state their willingness to participate in one-day 
annual meetings to track the progress of their studies and to promote 
exchange of experiences and ideas. Attendees to these meetings will 
include the grantees funded under this RFA as well as grantees funded 
under the companion NIA RFA “Sustained Caloric Restriction in Non-Obese 
Persons: Physiologic Effects and Comparisons/Interactions with Physical 
Activity” (RFA AG-01-001) as an exchange of data and ideas between 
researchers conducting basic/molecular studies and clinical research on 
the effects of caloric restriction will be invaluable in guiding future 
studies in this area.  Funds for travel to the Washington D.C. area for 
the Principal Investigator (and up to two co-investigators, if 
appropriate) should be included in the budget for each year.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

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 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification are 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 research involving human subjects should 
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete 
copy of the updated Guidelines are available 
at  
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  
The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.

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.

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 one of the program staff listed 
under INQUIRIES by the letter of intent receipt date listed in the 
heading of this RFA.

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; 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; and on the internet 
at: http://grants.nih.gov/grants/forms.htm 

The RFA label found in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application.  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 at 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been 
modified to allow for this change. Please note this is in pdf format.

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 NIA.  Incomplete applications will be returned to the 
applicant. 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 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 NIA in accordance with the review criteria stated below. As 
part of the initial merit review, all applications will receive a 
written critique and may undergo a process in which only those 
applications deemed to have the highest scientific merit, generally the 
top half of 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 the study address an important problem related 
to the research objectives of this RFA?  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 adequacy of plans to include both genders, minorities and their 
subgroups as appropriate for the scientific goals of the research. 
Plans for the recruitment and retention of subjects will also be 
evaluated.

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.

The personnel category will be reviewed for appropriate staffing based 
on the requested percent effort.  The direct costs budget request will 
be reviewed for consistency with the proposed methods and specific 
aims. The duration of support will be reviewed to determine if it is 
appropriate to ensure successful completion of the requested scope of 
the project.

Schedule:

Letter of Intent Receipt Date:  September 30, 2000
Application Receipt Date:       November 20, 2000
Date of Initial Review:         February 2001
Review by Advisory Council:     May 2001
Anticipated Award Date:         July 1, 2001

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  Balance among the projects in addressing different experimental 
approaches and their complementarity to other ongoing efforts

o  Extent to which the proposed research supports the goals of the NIA

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

Direct inquiries regarding programmatic issues to:
 
David B. Finkelstein, Ph.D.
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD 20892
TEL:	301/496-6402
FAX:	301/402-0010
Email:  FinkelsD@exmur.nia.nih.gov 

or

Judith A. Finkelstein, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Building, Suite 3C307
Bethesda, MD 20892
TEL:	301/496-9350
FAX:	301/496-1494
Email:	FinkelsJ@exmur.nia.nih.gov

Direct inquiries regarding fiscal matters to:

Mr. Joseph Ellis
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD 20892
TEL:	301/496-1472
FAX:	301/402-3672
Email:	EllisJ@exmur.nia.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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