Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

No late applications will be accepted for this Funding Opportunity Announcement.

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

This Funding Opportunity Announcement (FOA) calls for the renewal and further development of the Interventions Testing Program (ITP). The ITP tests potential intervention strategies that may delay aging in mammals under standardized conditions.The interventions' effects on aging are measured by lifespan extension and/or delayed onset/severity of late life pathologies. The ITP uses lifespan as a primary outcome. Secondary outcomes currently include geropathology assessement at 22 months of age and pathology at time of death, functional phenotypes (e.g., measures of strength) and measurements of animal vitals (e.g., weight) at intervals across the lifespan.

The ITP, the animal model of choice (the "four-way cross" UM-HET3 mouse), and the two-tier review process to select the compounds for testing (by the Access Panel and the Steering Committee, see section VI) are described in greater detail on the ITP webpage. Pilot studies of compound stability, toxicity, and bioavailability are performed before new compounds are entered into the testing pipeline. Testing by the ITP follows two Stages: Stage I and Stage II. In Stage I studies, a single dose of a candidate compound is administered chronically from an established adult age. In Stage II studies, multiple doses, different administration regimens, multiple compounds, or a combination thereof are tested based on promising data from Stage I studies. The animal model, the review process for selecting compounds for testing, pilot studies, Stage I and Stage II interventions will remain unchanged and will continue to be used by the ITP. The ITP uses lifespan as a primary outcome. Secondary outcomes currently include geropathology assessement at 22 months of age and pathology at time of death, functional phenotypes (e.g., measures of strength) and measurements of animal vitals (e.g., weight) at intervals across the lifespan.

The ITP, the animal model of choice (the "four-way cross" UM-HET3 mouse), and the two-tier review process to select the compounds for testing (by the Access Panel and the Steering Committee, see section VI) are described in greater detail on the ITP webpage. Pilot studies of compound stability, toxicity, and bioavailability are performed before new compounds are entered into the testing pipeline. Testing by the ITP follows two Stages: Stage I and Stage II. In Stage I studies, a single dose of a candidate compound is administered chronically from an established adult age. In Stage II studies, multiple doses, different administration regimens, multiple compounds, or a combination thereof are tested based on promising data from Stage I studies. The animal model, the review process for selecting compounds for testing, pilot studies, Stage I and Stage II interventions will remain unchanged and will continue to be used by the ITP.

The Standard Operating Procedures (SOPs) for lifespan measurements in the ITP were developed, refined, and implemented during the previous funding cycles of the program. Similarly, statistical procedures were developed and reviewed during previous cycles. Those include: approaches for blinding and randomization as well as discussion of issues such as power analysis, sample size estimates based on anticipated variability in primary or secondary outcome(s) of interest, potential inclusion of interim analyses, and criteria for accounting for losses of animals to follow-up during the intervention studies. The ITP will continue to follow the already established SOPs and statistical procedures for longevity studies.

Purpose and Research Objectives

The ITP aims to achieve the following goals through its renewal:

1. Continue the testing of compounds for effects on lifespan in the four-way cross mice UM-HET3 using well-established protocols and SOPs. The protocol details for lifespan studies, statistical analyses, and Stage I and II interventions have been evaluated in the review of applications submitted in response to the original and subsequent renewals of the ITP. Several articles detailing the protocols and testing results have been published. Only newly introduced major changes/modifications will be evaluated in response to this FOA.
2. Continue pilot studies of optimal drug formulation, stability, and bioavailability for new compounds. Optimal drug formulation and tests of compound stability during preparation and storage should continue for compounds proposed for lifespan studies in Stage I. Pilot testing should include studies of blood levels, potential toxicity, and likely optimal dose based on hepatic response or other biological markers.
3. Expand geropathology analyses at a minimum of one time point after starting the intervention and continue pathology studies at time of death. Evaluation of age-related pathological changes and post-mortem organ/tissue examination for diagnosis aimed at assessing and quantifying the impact of tested compounds on the aging of tissues and organs and on chronic diseases of aging (those typically observed in the control cohorts of UM-HET3 mice).
4. Introduce transcriptomic analyses (i.e., "bulk" RNA sequencing). The detection of changes in gene expression in selected organs at selected timepoint(s) after starting an intervention will help determine the gene regulatory and molecular pathways at the tissue and/or organ level affected by aging and modified by the interventions.
5. Expand tissue collection for ancillary studies. The interventions tested by the ITP may result in perturbations of processes at the molecular, tissue, and organ level that can be associated with aging. Therefore, tissues from treated and matched untreated mice are collected by the ITP and are a highly valuable resource for ancillary studies aimed at elucidating the biology of aging, geropathology, pathways involved in aging, and other questions regarding diseases of aging. Ancillary studies could incorporate a broad range of experimental platforms (e.g., genomics, proteomics, metabolomics, spatial omics, advanced microscopy) and could focus on one or more tissues/organs. Currently, tissues from treated and control animals are made available to the research community through the Collaborative Interactions Program (CIP) that was initiated in a previous iteration of the ITP. Starting with this new funding cycle, all biospecimens will be recorded and managed through the Interventions Biospecimens Repository (IBR, see below).

Interventions Biospecimens Repository (IBR)

To broaden the reach of the ITP to a larger group of investigators within the scientific community and to be able to track the discoveries made possible by the unique resources generated by the ITP, a new procedure will be introduced to track and distribute mouse tissues collected by the ITP. This will be based on the establishment of the Interventions Biospecimens Repository (IBR). The IBR will include tissue samples stored both from prior collections and from future studies. Each of the three testing Centers will be responsible for maintaining and updating the collection of biospecimens isolated from mice in their testing cohort. A comprehensive electronic inventory of the Biospecimen Repository will be replicated at the following locations: each of the ITP Centers, the ITP Data Coordinating Center (DCC), and the NIA. Therefore, each ITP Center will hold a physical inventory of the biospecimens they collected and maintain the corresponding electronic inventory that will be shared with the other Centers, the ITP DCC, and the NIA. This will facilitate the streamlining of tissues distributed from the three ITP Centers to other investigators. Coordination of the comprehensive electronic inventory will be the responsibility of the ITP DCC and will be monitored by the NIA Project Scientist. A description of the Project Scientist’s responsibilities can be found in Section VI: Award Administration Information under the Cooperative Agreement Terms and Conditions of Award.

The requests for samples are handled by the NIA and will not be described in the applications submitted in response to this FOA. Samples from the IBR may be requested in response to an annual notice in the NIH Guide. Requests will be submitted to the NIA Project Scientist and will be evaluated by a Review Panel of Program Officers at the NIA, led by the Project Scientist. As appropriate, Program Officers from other NIH Institutes may be asked to provide input if the requests are made by an investigator supported by that NIH Institute. The Review Panel will provide a summary of the discussion and their recommendation to the investigator making the request and to the ITP Principal Investigators. The panel will assess the scientific merit of the requests, ensure that investigators making these requests have sufficient funds to utilize the samples, and ensure that the ITP is duly acknowledged in the publications derived from the use of samples from the IBR. Data generated from such studies will be submitted to the ITP DCC for archiving and public access under standard NIH policies for data sharing. Investigators seeking to obtain biospecimens not part of the IBR, will have to contact a Principal Investigator of the ITP and the NIA Project Scientist.

The ITP shares documentation (e.g., SOPs, protocols, statistical procedures for lifespan studies), data (e.g., compound pilot studies, lifespan, animal vitals, geropathology reports, transcriptomics) and information on the resources (e.g., the IBR) in real time among the three ITP Centers and between the Centers and the ITP DCC. Documentation, data, and information on available tissues are publicly shared post-publication through the website developed and managed by the ITP DCC. The data repository for the tissues is coordinated by the ITP DCC and mirrored at each ITP Center and at the NIA ITP site.

Cooperative Relationships and Data Sharing

Recipients are expected to work closely and collaboratively with the NIA in achieving the goals stated in the FOA.

A plan for sharing and disseminating to the scientific community the results and resources generated by the ITP is required. This plan must include the deposition of the SOPs, protocols, statistical procedures adopted by the ITP, the data (e.g., longevity, geropathology, transcriptomics), and information on the IBR in the ITP DCC database and, upon publication, in a public portal developed by the ITP DCC.

The NIA will appoint a NIA Project Scientist. All Principal Investigators must participate in a monthly teleconference with the NIA assigned Project Scientist.

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Government

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see 2.3.9.4 Similar, Essentially Identical, or Identical Applications)

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

R&R Subaward Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy: Lifespan studies. Applicants should provide only a general description of planned lifespan studies, including, but not limited to, acquisition of data such as weight and veterinarian heath report records. The details of protocols for lifespan studies, statistical power analyses, and of Stage I and II designs have been evaluated in the review of applications submitted in response to the previous iterations of the ITP. Several publications detailing the protocols and testing results have been published. Therefore, applicants may refer to and summarize protocols, statistical analyses, and Stages of the study to the extent they help understanding of the program and assessment of the other research activities of the program or if changes are introduced. Changes/modifications to existing protocols should be identified as such and described for evaluation in the renewal application.

Applicants must describe in detail plans for analysis of lifespan data from Stage I and Stage II studies. Plans for survival data analysis should include more than one statistical approach. NIH Biosketches for the statistical experts, and descriptions of their involvement in conduct of the studies and data analysis within the ITP should be included in the renewal applications.

Compound pilot studies. The research strategy should describe the methods selected to develop the formulations of compounds for testing. Strategy and timeline must be included for establishing drug stability during production, shipping, and storage. Experiments must be proposed that are sufficient to support the selection of initial dosage, including, but not limited to, determination of oral bioavailability, drug concentrations in the blood and other organs, as well as changes in the expression of target genes at least in the liver. Procedures for the assessment of drug toxicity must be described. Go/no-go critera regarding compound(s) to be tested in Stage I must be discussed.

Geropathology assessment. Standardized procedures for a cross-sectional geropathology assessment made at least one time point after starting the intervention and pathology assessment at the time of death should be described. Applicants should provide details regarding schedules and protocols for the collection of biospecimens (e.g., tissues, blood samples) as well as the preservation, storage, and geropathology assessment of treated and untreated mice used in lifespan studies. Applicants must propose and explain the rationale behind the protocols of choice for geropathology assessment, including number of mice evaluated, organ/tissue type, age(s) at collection, staining and field sampling methods, and tissue-specific grading systems used by veterinary pathologist(s). Description of statistical analyses on quantitative geropathology data should be included. A brief description of post-mortem pathology evaluations should also be included.

Transcriptomics. Applicants must describe protocols for cross-sectional transcriptomic analysis ( bulk RNA sequencing), at least at one time point after starting the intervention, comparing age-associated gene expression changes in treated and untreated mice in the lifespan studies. The rationale for the selection of target organs and tissues, the time(s) at which they are collected, and the number of animals included per condition analyzed in the transcriptomic study must be described. Detailed protocols for organ/tissue collection, storage, RNA processing, sequencing, and plans for transcriptome analysis must be included. The sequencing approach and data analyses must be detailed. Approaches to harmonize mRNA sample preparation and storage protocols among the three testing sites must be described. Discussion of the experimental design and data analysis should be included. A single site or contractor may be chosen as a sequencing core and plans for communicating with that core should be described.

Tissue collection for ancillary studies (Interventions Biospecimens Repository (IBR)). Biospecimens were collected and stored in previous iterations of the ITP. Samples were distributed through the Collaborative Interactions Program (CIP). With this cycle, a more formal Interventions Biospecimens Repository (IBR) will be established. Applicants should describe ongoing practices of biospecimen collection and storage as well as modifications to be implemented. Each procedure should be clearly identified as current or new. Applicants must identify and provide the rationale behind the biological materials to be harvested from animals in the ITP, specifying the age(s) in a life course study for collection, indicating whether during Stage I and/or Stage II, which tissues or organs are selected for the repository, and the protocols for processing and storage. When establishing the size of cohorts of mice treated with effective compounds and controls for biospecimen collection, past records of organ/tissue requests should be taken into consideration. Tissues should be collected using appropriately described methods of tissue preservation (e.g., flash frozen, frozen blocks, various fixation methods) and, based on current state-of-the-science, applicants should identify the compatible analytical/experimental platforms that could be used in follow-up studies (which will be pursued via application to the NIA see Purpose and Research Objectives, above). Because the electronic inventory of collected and available tissues in the IBR will be accessible through the ITP sites, the ITP DCC, and the NIA website, a description of plans for making available to the ITP DCC and the NIA the list updated in real time of tissues in the IBR must be included in the application.

Applicants must describe how documentation of protocols, statistical approaches and stages of the studies as well as lifespan data will be made available to the ITP DCC and the NIA. Applicants should include plans and methods for sharing with the ITP DCC data from the pilot studies, including drug stability, blood levels and studies of optimal dose. Plans for providing the ITP DCC with information on samples for geropathology/pathology and all results from geropathology/pathology (including, when appropriate, images), and plans for sharing transcriptome data with the ITP DCC must be included.

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential fieldof the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by the National Institute on Aging (NIA), NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to notify the NIA Referral Office by email to [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) will not be evaluated at time of review.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance, and organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this FOA:

How detailed and adequate is the plan for statistical analysis of lifespan data from Stage I and II studies?

How adequate are the strategy and timeline to test drug stability during production, shipping, and storage?

How well described and adequate are the tests proposed to establish oral bioavailability and toxicity of a new compound and to inform the selection of the optimal dose of an intervention for Stage I and Stage II studies?

How adequate are the go/no-go criteria to be applied at the end of the pilot studies?

How appropriate is the explanation for the choice of age(s), organs/tissues, and number of animals for cross-sectional collection of biospecimens for the geropathology assessment?

How detailed and accurate are the grading systems proposed for the geropathology assessment?

How appropriate is the explanation for the choice of age(s), organs/tissues and number of animals for cross-sectional collection of biospecimens for transcriptome analysis ("bulk" RNA sequencing)?

How adequate and robust is the plan for cross-sectional transcriptome analysis, including plans for harmonization of mRNA sample preparation, storage, and sequencing?

How adequate is the plan for collection of tissues for the Interventions Biospecimens Repository?

How detailed, robust and timely is the plan for sharing of data, electronic inventory of tissue samples, and documentation with the DCC?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment, and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

For Renewals, the committee will consider the progress made in the last funding period.

Revisions

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) will not be evaluated at time of review.

Reviewers will comment on whether the Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIA, in accordance with NIH peer review policy and procedures, using the stated review criteria above. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council on Aging (NACA). The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federalwide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex (including gender identity, sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.
• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including reasonable accommodations and making services accessible to them, see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.
• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.
• For guidance on administering programs in compliance with applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75 and 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Development, implementation, and evaluation of the ITP. The PDs/PIs will: attend meetings and serve as a voting members of the Steering Committee; participate in monthly metings with the NIA representative; be responsible for accepting and implementing the goals, priorities, procedures, and policies agreed upon by the Steering Committee, and for close coordination and cooperation with the other components of the Testing Program, the Steering Committee, the application sponsors, and NIA staff; implement testing protocols of compounds approved by the Steering Committee; participate in the analysis and publication (preparation of manuscripts) of all results from the ITP testing; as members of the Steering Committee, select individuals to serve on the Access Panel; and distribute biospecimens from the Interventions Biospecimen Repository to approved investigators.
• Recipients will retain custody of and have primary rights to the data generated under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• The NIA will designate program staff, including a Program Officer and a Grants Management Specialist, to provide stewardship and administrative oversight of the cooperative agreement. The Program Officer and Grants Management Specialist will be named in the Notice of Grant Award.
• An NIA Health Scientist Administrator will be the NIA Project Scientist for this award. The NIA Project Scientist will be substantially involved in this project above and beyond the normal stewardship of an NIA Program Official. The NIA Project Scientist will exercise substantial scientific and programmatic involvement to assist, guide, coordinate and participate in the conduct of the Testing Program activities.
• The NIA Project Scientist will: coordinate monthly teleconferences with the PDs/PIs; attend and participate in all meetings of the Steering Committee as a voting member; provide liaison between the Steering Committee and the NIA/NIH; assist the Steering Committee in developing and drafting operating policies, and policies for dealing with recurring situations that require a coordinated action; coordinate with the Access Panel for the review of compound applications; participate in design, implementation, and evaluation of the program; participate in analysis and publication of the results of testing in the ITP; monitor the electronic inventories of the Interventions Biospecimens Repository; receive requests by other investigators for tissues from the Interventions Biospecimens Repository; gather and chair the panel of NIA Program Officers that reviews requests for tissues from the Interventions Biospecimens Repository; communicate to the investigator making a request for tissue a summary of the discussion and recommendations by the review panel; and inform the the ITP PIs of the approved requests so that they can coordinate the distribution of biospecimens.

Areas of Joint Responsibility include:

• STEERING COMMITTEE: This committee will be the main governing body of the ITP and ITP DCC. Its voting members will include the PD/PI of each award of the ITP sites as well as the PI from the ITP DCC, the NIA Project Scientist, and at least four biogerontologists covering a broad range of expertise who are not affiliated with the Testing Program. These additional members will be chosen by the PDs/PIs and the NIA Project Scientist. The NIA Project Scientist will not chair the committee. The primary roles of the Steering Committee are to prioritize the interventions recommended by the Access Panel; develop consensus on testing protocols to be employed in Stage II studies and decide which Stage I studies will proceed to Stage II studies. In carrying out these responsibilities, the Steering Committee should seek advice from outside experts as needed and is encouraged to include in their discussions as appropriate the investigator(s) who either discovered or developed the potential intervention. These individuals, when present at committee meetings, will be temporary non-voting members of the committee. The Steering Committee will meet virtually once a year, or as needed. Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.
• ACCESS PANEL: The function of the Access Panel is to review promising interventions to be tested in Stage I trials; these nominations may be made by anyone either within or outside of the Testing Program. Nominations should be accompanied by sufficient information, either published or unpublished, to permit the Access Panel to evaluate the potential efficacy of the intervention in mice. The Access Panel shall consist of one representative (not the PD/PI) from each testing site, and at least three other scientists nominated by the Steering Committee from the biogerontology research community. The NIA Project Scientist will be a non-voting representative on this Panel. An intervention recommended for testing would require a majority vote of this Panel. In evaluating the merit of a proposed intervention, the Access Panel should solicit relevant information from a wide range of experts and use both published and unpublished data. Where appropriate, the Panel is encouraged to consult with the investigator(s) who discovered or developed a potential intervention. Recommendations from this panel will be prioritized by the Steering Committee. The Panel will meet once a year virtually and email among the panel members as needed. Proceedings of the Access Panel's meetings will be forwarded to the Steering Committee in writing, accompanied by appropriate supporting materials, and a priority rating.

Dispute Resolution:

• Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

• It is the goal of NIA to further advance research by making resources, data, and reagents generated in whole or in part using funds from this U01 award widely available to the research community with minimal restrictions.
• A plan for sharing and disseminating all the ITP published data to the scientific community through the ITP DCC is required. This plan should include the deposition of all data in the public repository (website) developed by the ITP DCC. All applications, regardless of the amount of direct costs requested for any one year, should address how they will share unique reagents, protocols, and Standard Operating Procedures (SOPs) necessary for replicating testing.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Tiziana Cogliati, Ph.D.
National Institute on Aging (NIA)
Telephone: 240-397-4596
Email: [email protected]

Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-402-7700
Email: [email protected]

Traci Lafferty
National Institute on Aging (NIA)
Telephone: 301-496-8987
Email: [email protected]

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

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 Part 52 and 45 CFR Part 75 and 2 CFR Part 200.