RELEASE DATE:  May 13, 2003

PA NUMBER:  PAS-03-122

March 2, 2006  (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through using 
the electronic SF424 (R&R) application. Parent R03 (PA-06-180) and R21 (PA-06-181) 
funding opportunity announcements have been issued for the submission date of 
June 1, 2006 and submission dates thereafter. Applications relating to R33 and R34 
activities must be in response to NIH Institute/Center (IC)-specific announcements.

EXPIRATION DATE for R21 Non-AIDS Applications: March 2, 2006
EXPIRATION DATE for R21 AIDS and AIDS-Related Applications: May 2, 2006 
EXPIRATION DATE for All R01 Applications: May 22, 2006, unless reissued.
National Institute on Aging (NIA)



o Purpose of the PA
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 Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


The aim of this program is to foster biomedical research that will 
enhance our understanding of the complex biology and pathophysiology 
underlying the geriatric syndrome of frailty.  A second goal is to 
foster development and testing of novel interventions targeting pathways 
believed to play an important mechanistic role in the development and 
progression of frailty.  This PA is intended to foster clinical 
research, including integrative biomedical research, some of which will 
incorporate the tools of molecular and cellular biology in the study of 
function and clinical outcome, and studies in appropriate animal models.  
A long-term goal is to provide the groundwork for the possible 
prevention of frailty in older persons.  



The term "frailty" has been used clinically as a global concept to 
describe a condition, common in the very old, of impaired strength, 
endurance, and balance, vulnerability to trauma and other stressors, and 
high risk for morbidity, disability, and mortality.  It may add clinical 
value in prognosis and decision-making because frail older persons may 
have additional adverse pathophysiologic or functional changes not 
captured fully by disease and disability definitions.  If distinct 
pathophysiologic or functional changes can be shown to contribute to the 
clinical features of frailty, it may be possible to develop and test 
interventions that may provide additional benefits beyond those obtained 
from treatments from currently recognized diseases in old age. 

Operational definitions of frailty could greatly enhance research on its 
causes and consequences by providing precision and consistency within 
and among studies.  Recently, a definition of frailty as a syndrome has 
been proposed, by which individuals are considered frail if they meet 
operationally defined criteria for at least three of the following five 
attributes: unintentional weight loss, muscle weakness, slow walking 
speed, exhaustion, and low physical activity (Fried et al.; J Gerontol 
Med Sci; 2001; 56A(3): M146-M156).  Using this definition, the condition 
of frailty was found to overlap only partially with the presence of 
comorbidity or disability.  A substantial proportion of frail older 
persons did not meet common criteria for either comorbidity or 
disability.  Frailty, as defined above, has independent predictive value 
for mortality, increases in disability in activities of daily living, 
and hospitalization, even after adjusting for disease diagnoses and 
other factors. 

There is also evidence that frailty thus defined may result from 
pathologic processes acting independently from the effects of diseases 
present in the elderly.  Recent reports indicate that frailty is 
associated with elevated circulating levels of markers of inflammation 
(C-reactive protein) and coagulation (fibrinogen and factor VIII) 
(Walston et al.; Arch Intern Med; 2002; 162: 2333-2341).  These markers 
were linked to frailty even in the absence of two of the most prevalent 
comorbid conditions in older persons, cardiovascular disease and 

Other operational definitions of frailty, using differing or additional 
criteria, may also be useful in capturing additional clinically 
important aspects of the weakness, vulnerability to stress, and other 
decrements implied by the general concept of frailty, and in identifying 
important pathophysiologic processes.  Research focused on individual 
components of syndromic definitions of frailty (e.g., weight loss, 
exhaustion) may also be useful in clarifying its pathophysiology.   

A variety of factors may contribute to frailty or to one or more of its 
specific features.  These include inflammatory, musculoskeletal, 
cardiorespiratory, metabolic, hematologic, neurologic, immunologic and 
endocrine functions.  Few of these have been studied in regard to 
frailty.  Inflammatory factors, such as interleukin-6 (IL-6), tumor 
necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP), have 
been the focus of several studies.  These studies found associations 
between elevations in inflammatory markers and low muscle strength, 
exhaustion, slow walking speed, and low physical activity.  Pathways 
mediated by angiotensin converting enzyme (ACE) may be important in the 
pathophysiology of frailty.  Studies on ACE inhibitors in frail older 
women suggest that they may protect against muscle weakness.  ACE 
inhibitors have been suggested to play an important role in factors that 
could contribute to frailty, including inflammation, fibrinolysis, 
oxidative stress, and endothelial dysfunction.  Dysregulation of dynamic 
interactions among physiologic systems may also play an important role 
in frailty (Lipsitz LA; J Gerontol A Biol Sci Med Sci; 2002; 57(3): 

Most studies to date on potential factors contributing to frailty have 
been associational and have not clearly established cause-and-effect 
relationships.  For example, an important research question that needs 
to be answered is whether elevated levels of inflammatory factors 
actually contribute to the development and progression of frailty, or 
whether they rise as a consequence of some aspect of frailty, or in 
response to another, yet to be identified, factor that contributes to 

Controlled intervention studies can be valuable in clarifying the causal 
role of factors associated with frailty, as well as in determining 
effects of interventions on frailty itself or its components.  Both 
types of information are useful preliminary data for possible larger 
clinical prevention or therapeutic trials.  There is evidence that some 
available interventions affect factors that may contribute to frailty.  
Physical activity has effects on chronic inflammation as well as 
strength.  Statins and ACE inhibitors have effects on markers of chronic 
inflammation.  ACE inhibitors may also affect muscle strength and other 
systems that may be involved in the pathophysiology of frailty. 
Thiazolidinedione oral hypoglycemic agents have effects on muscle and 
inflammation.  The effects of different types of anti-inflammatory 
agents on components of frailty have not yet been thoroughly examined. 

Animal models have begun to be developed that could greatly enhance 
opportunities for research on frailty.  For example, an aging rodent 
model has been used to assess the longitudinal changes in physical 
performance and their relationship to longevity (Carter et al.; J 
Gerontol Biol Sci; 2002; 57A(5): B193-B197). 
Knowledge to be achieved

NIA encourages submission of R01 applications for projects to elucidate 
the pathophysiologic basis of frailty.  Studies may address frailty 
defined as a syndrome, as described in the preceding section, or on one 
or more components of such a syndrome (e.g., weight loss or exhaustion), 
or alternative phenotypic definitions of frailty. 

Proposed projects may include observational studies (including 
prospective studies), mechanistic studies, small-scale human 
intervention studies, and studies in animal models.  Studies designed to 
allow conclusions regarding pathophysiologic effects, beyond mere 
associations, are very strongly encouraged.  An integrative approach to 
frailty, through collaboration between basic and clinical scientists, is 
highly desirable.  

Topics of interest include, but are not limited to:

o Role of inflammatory factors in frailty, including their role in 
muscle weakness, weight loss, low physical activity, and other 
biological and behavioral phenotypes related to frailty.  Studies on 
circulating factors and factors in specific tissues are encouraged.  
Studies on interactions of inflammatory factors with other cellular 
processes (e.g., apoptosis) and physiologic processes (e.g., endocrine 
and metabolic regulation) are encouraged;  

o Effects of angiotensin converting enzyme and drugs and other factors 
modulating its actions on the development of components of frailty;

o Roles of musculoskeletal, cardiorespiratory, metabolic, bioenergetic,  
hematologic, neurologic, immunologic, and endocrine factors and their 
interactions.  Roles of factors related to regulation of mood and affect 
(e.g., neuroendocrine factors involved in depression) and other 
psychological factors are also of interest;

o Role of cell loss, apoptosis, and loss of stem cells (e.g., muscle 
satellite cells)in specific tissues in the development of frailty or on 
one or more of its components; 

o Contributions to frailty by mechanisms postulated to be important in 
aging processes; e.g., oxidative damage; 

o Effects of genetic polymorphisms on risk for frailty or on one or more 
of its components, and on responses to interventions to ameliorate 
frailty or one of its components;  

o Explorations of the role in frailty of dysfunctional regulation of 
dynamics of physiologic responses to stressors or other perturbations; 

o Interrelationships between individual phenotypes of frailty or 
components of frailty, defined as a syndrome, such as:  synergistic 
effects on outcomes; identifying common causal mechanisms underlying 
several components; and/or mutually reinforcing relationships between 
components (e.g., positive feedback loops); 

o Development and use of appropriate aging animal models to study 
etiologic and pathophysiologic pathways postulated to play important 
roles in frailty, and to conduct pre-clinical testing of novel 

o Small-scale human intervention studies (e.g., both drug, endocrine, or 
lifestyle) to better characterize the importance of various biologic 
pathways in frailty including: identifying potential targets for 
therapeutic intervention; and to identify promising intervention studies 
for larger, more definitive trials; and  

o Longitudinal human studies to clarify the sequence of changes leading 
to frailty and its clinical consequences, including interactions with 
effects of specific chronic diseases.       

These topics are neither prioritized nor meant to be restrictive.  
Principal Investigators are encouraged to submit applications in any 
area of research responsive to the general research objectives of the PA.


This PA will use the NIH research project grant (R01) award mechanism 
and the exploratory/developmental research project award (R21)mechanism 
of support.  As an applicant, you will be solely responsible for 
planning, directing, and executing the proposed project.  The total 
project period for an application submitted in response to this PA may 
not exceed five years.

Applicants pursing an exploratory/developmental research project award 
(R21) should follow the guidelines described in the program announcement 

This PA uses just-in-time concepts.  It also uses the modular as well as 
the non-modular budgeting formats (see
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  Otherwise follow 
the instructions for non-modular research grant applications.  This 
program does not require cost sharing as defined in the current NIH 
Grants Policy Statement at


NIA intends to commit $1.8 million in total costs for the first year of 
funding for applications submitted in response to this PA for the 
following three receipt dates: October 1, 2003, February 1, 2004, and 
June 1, 2004.  Applications received after the June 1, 2004 receipt date 
(except for amended applications submitted for the July 1, 2004 receipt 
date) will not compete for set-aside funding.  These applications will 
compete for funding with all other applications assigned to NIA.  Awards 
made will be contingent upon availability of funds and the receipt of a 
sufficient number of applications of outstanding scientific and 
technical merit.  


You may submit an application 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
o Faith-based or community-based organizations 


Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with his or her 
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.  


We encourage your inquiries concerning this PA and welcome the 
opportunity to answer questions from potential applicants.  Inquiries 
may fall into two areas:  scientific/research and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

Andre J. Premen, Ph.D.
Geriatrics & Clinical Gerontology Program 
National Institute on Aging 
Gateway Building, Room 3C-307
Bethesda, MD  20892-9205
Telephone: (301) 496-6761
FAX: (301) 402-1784

o Direct your questions about financial or grants management matters to:

Ms. Linda Whipp
Grants Management Officer
Grants and Contracts Management Office 
National Institute on Aging 
Gateway Building, Room 2N212
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672


Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email: 

APPLICATION RECEIPT DATES: Applications submitted in response to this PA 
will be accepted at the standard application deadlines, which are 
available at
Application deadlines are also indicated in the PHS 398 application kit.

requesting up to $250,000 per year in direct costs 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 
includes step-by-step guidance for preparing modular grants.  Additional 
information on modular grants is available at

YEAR: Applications requesting $500,000 or more in direct costs for any 
year must include a cover letter identifying the NIH staff member within 
one of the NIH institutes or centers who has agreed to accept assignment 
of the application.   

Applicants requesting more than $500,000 must carry out the following 

1) Contact the IC program staff member at least six weeks before 
submitting the application, i.e., as you are developing plans for the 

2) Obtain agreement from the IC staff member that the IC will accept 
your application for consideration for award; and
3) Identify, in a cover letter sent with the application, the staff 
member and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended or 
revised version of these grant application types.  Additional 
information on this policy is available in the NIH Guide for Grants and 
Contracts, October 19, 2001 at
SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten 
original of the application, including the checklist, and five 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)

APPLICATION PROCESSING:  Applications must be mailed on or before the 
receipt dates described at
The Center for Scientific Review (CSR) will not accept any application 
in response to this PA 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 a substantial revision of an application already 
reviewed, but such an application must include an Introduction 
addressing the previous critique.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review 
group convened in accordance with the standard NIH peer review 
procedures will evaluate applications 
for scientific and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to 
have the highest scientific merit, generally the top half of 
applications under review, will be discussed and assigned a priority score
o Receive a second level review by National Advisory Council on Aging


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, an 
investigator may propose to carry out important work that by its nature 
is not innovative but is essential to move a field forward.

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?

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?

INNOVATION:  Does the project employ novel concepts, approaches or 
methods?  Are the aims original and innovative?  Does the project 
challenge existing paradigms or develop new methodologies or 

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 

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?

ADDITIONAL REVIEW CRITERIA:  In addition to the above criteria, the 
following items will be considered in the determination of scientific 
merit and the priority score:

human subjects and protections from research risk relating to their 
participation in the proposed research will be assessed.  (See criteria 
included in the section on Federal Citations, below).

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 will be assessed.  Plans for the recruitment and 
retention of subjects will also be evaluated. (See Inclusion Criteria in 
the sections on Federal Citations, below).

are to be used in the project, the five items described under Section f 
of the PHS 398 research grant application instructions (rev. 5/2001) 
will be assessed.


BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.

Applications submitted in response to a PA will compete for available 
funds with all other recommended applications.  The following will be 
considered in making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities


HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated 
with reference to the risks to the subjects, the adequacy of protection 
against these risks, the potential benefits of the research to the 
subjects and others, and the importance of the knowledge gained or to be 
gained. .

components involving Phase I and II clinical trials must include 
provisions for assessment of patient eligibility and status, rigorous 
data management, quality assurance, and auditing procedures.  In 
addition, it is NIH policy that all clinical trials require data and 
safety monitoring, with the method and degree of monitoring being 
commensurate with the risks (NIH Policy for Data Safety and Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998:

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 "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 
a complete copy of the updated Guidelines is available at http://  
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 

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

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

Applicants may wish to place data collected under this 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.

The Department of Health and Human Services (DHHS) issued final 
modification to the "Standards for Privacy of Individually Identifiable 
Health Information", the "Privacy Rule," on August 14, 2002.  The 
Privacy Rule is a federal regulation under the Health Insurance 
Portability and Accountability Act (HIPAA) of 1996 that governs the 
protection of individually identifiable health information, and is 
administered and enforced by the DHHS Office for Civil Rights (OCR). 
Those who must comply with the Privacy Rule (classified under the Rule 
as "covered entities") must do so by April 14, 2003 (with the exception 
of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule 
reside with the researcher and his/her institution. The OCR website 
( provides information on the Privacy Rule, 
including a complete Regulation Text and a set of decision tools on "Am 
I a covered entity?"  Information on the impact of the HIPAA Privacy 
Rule on NIH processes involving the review, funding, and progress 
monitoring of grants, cooperative agreements, and research contracts can be 
found at

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 PA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at and is not subject 
to the intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.  Awards are made under the authorization 
of Sections 301 and 405 of the Public Health Service Act as amended (42 
USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR 
Parts 74 and 92.  All awards are subject to the terms and conditions, 
cost principles, and other considerations described in the NIH Grants 
Policy Statement.  The NIH Grants Policy Statement can be found at 

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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NIH Funding Opportunities and Notices

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