Aging Mammalian Tissues In Vitro (R21 Clinical Trial Not Allowed)

Aging Mammalian Tissues In Vitro (R21 Clinical Trial Not Allowed) is sponsored by National Institutes of Health (NIH). This opportunity supports mission-aligned projects and measurable outcomes.

Expired RFA-AG-26-014: Aging Mammalian Tissues In Vitro (R21 Clinical Trial Not Allowed) This notice has expired. For NIH, in limited situations, applications may be accepted on a case-by-case basis for a short period after expiration to accommodate NIH late or continuous submission policies . Contact the eRA Service Desk for any submission issues.

Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations Funding Opportunity Title Aging Mammalian Tissues In Vitro (R21 Clinical Trial Not Allowed) R21 Exploratory/Developmental Research Grant April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 .

August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy.

See Notice NOT-OD-22-189 . Funding Opportunity Number (FON) Companion Funding Opportunity See Part 2, Section III. 3.

Additional Information on Eligibility. Assistance Listing Number(s) Funding Opportunity Purpose This notice of funding opportunity (NOFO) invites applications that propose interdisciplinary research that aims to develop complex mammalian 3-dimensional (3D) in vitro microphysiological systems (MPS) to model aging and recapitulate aging processes/phenotypes observed in the whole organism in vivo .

This NOFO is primarily focused on human cell-derived MPS (e.g., tissue chip, organ-on-chip, tissue organoids). However, systems developed using cells of nonhuman mammalian origin are acceptable for benchmarking, system validation, or when their relevance to understanding human aging biology is justified.

Supported projects will be expected to advance the adoption of MPS in aging biology research and as new human-relevant tools for drug discovery. This NOFO uses the R21 activity code, which is intended for exploratory research at the early and conceptual stages of project development. Preliminary data are not required.

An essential feature of responsive applications is the adoption of a multidisciplinary approach that includes expertise in aging biology and from disciplines such as stem cell biology, tissue and organ physiology, microfluidics, bioengineering, computational biology, pharmacology, and biostatistics.

Funding Opportunity Goal(s) To encourage biomedical, social, and behavioral research and research training directed toward greater understanding of the aging process and the diseases, special problems, and needs of people as they age.

Open Date (Earliest Submission Date) Letter of Intent Due Date(s) Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed 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.

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) 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 1. Overview Information Part 2. Full Text of Announcement Section I.

Notice of Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV.

Application and Submission Information Section V. Application Review Information Section VI. Award Administration Information Section VII.

Agency Contacts Section VIII. Other Information Part 2. Full Text of Announcement Section I.

Notice of Funding Opportunity Description Although animal models are extremely valuable in aging research, they do not always phenocopy human aging, and they provide limited insight into human-specific mechanisms underlying aging. Furthermore, for some aging-related diseases and conditions, there are no suitable animal models available.

Human-based in vitro models that complement animal and clinical studies may be used to gain a deeper understanding of the mechanisms underlying the aging process, and the etiology and progression of various age-related conditions. Advantages of in vitro models include the option for genetic manipulation, controlled cellular environmental conditions, and the ability to study responses to perturbations.

The advent of technologies for culturing 3D human MPS opens opportunities to model aging with multi-cellular in vitro systems. These systems are amenable to pathophysiology mechanistic studies, discovering and testing of interventions, and investigations into human heterogeneity.

MPS are systems that use microscale cell culture platforms for in vitro modeling of functional features of a specific tissue or organ by exposing cells to a microenvironment that mimics the physiological aspects important for their function or pathophysiological condition. Examples of MPS include, but are not limited to, tissue-chip, organ-on-chip, and organoid.

While there are successful examples using MPS for disease modeling, their use to model aging and age-related conditions and phenotypes has not yet been fully developed. Current approaches include the use of donor's induced pluripotent stem cell (iPSC)-derived differentiated cells organized into 3D tissues or self-assembled organoids.

During reprogramming to generate iPSCs, most of the “historic” memory of the donor cell is erased and an age-induction step (e.g., using stressors or modifying the physical/nutritional environment) is necessary to re-establish an aging phenotype. For neuronal and few other tissues, the aging signature of the donor has been successfully retained (albeit with variable efficiency and yield) by direct reprogramming of somatic cells.

Research Objectives and Scope This NOFO solicits projects to develop human MPS that recapitulate aging in vitro with the goal to robustly and reproducibly model how human tissues and organs age in vivo .

Projects that will develop MPS based on nonhuman mammalian cells are acceptable if used for benchmarking and system validation in parallel with the corresponding human MPS and/or when the similarity between the nonhuman tissue/organ and its human counterpart justifies the relevance of the nonhuman system to understanding human aging biology.

These interdisciplinary projects are expected to advance the validation and adoption of MPS for aging research or as new human-relevant tools for drug discovery. Multidisciplinary teams must comprise expertise in aging biology and additional disciplines such as stem cell biology, tissue and organ physiology, microfluidics, bioengineering, computational biology, pharmacology, and biostatistics.

This NOFO supports innovative multidisciplinary approaches, high risk, high impact designs to develop mammalian MPS that recapitulate one or more aging processes/phenotypes as novel models to investigate human aging. Preliminary data are not required. All tissues and organ types are acceptable as long as the target aging phenotype(s) are clearly defined and appropriate.

In the absence of consensus on biomarkers of aging, applicants must provide justification for the use of reliable/rigorous aging-sensitive phenotypes (e.g., hallmarks of aging or disease-specific biomarkers) as surrogate biomarkers. Of particular interest are projects that propose benchmarking MPS against whole organism or clinically relevant human data.

The scope of the research must address the challenge to faithfully and reproducibly recapitulate aging processes/phenotypes in vitro . It may include the design of new tools/assays to analyze molecular and cellular phenotypes in vitro at end-points or over the duration of the experiment.

It must define the constraints within which investigation of aging can be pursued and what questions are best addressed using the proposed in vitro system(s). It should discuss what characteristics of the proposed MPS will facilitate its establishment and wide adoption as a tool to study aging and how it will complement research in live animals and clinical studies.

The proposed mammalian 3D in vitro tissue systems must be relevant for human aging research. They will recapitulate the minimal tissue complexity and microenvironment to elicit physiological features comparable to the in vivo human aged tissue or organ type. Such tissue constructs will be utilized to investigate molecular and cellular aging phenotypes retained from the donor or induced with different experimental approaches.

When the source of cells are human donors, they should allow for the identification of mechanisms/pathways of aging that are unique to humans and, where possible, include subjects that are representative of the heterogeneity in the population. When nonhuman mammalian species are used as the cell source, they should facilitate benchmarking against corresponding in vivo aging whole organisms.

The proposed MPS may be based on cells derived from human donors (e.g., from biopsies, therapeutic surgical interventions, or post-mortem) or from iPSC-derived cells/tissues. When derived from nonhuman primary cells or iPSCs, the choice must be justified by the relevance of the model to human aging.

Examples of in vitro model systems include, but are not limited to: Human organoids, tissue/organ-on-chip that recapitulate molecular, cellular or physiological features of aging Tissues comprising multiple cell types organized in functional units that are characteristic of the human tissue and its aging phenotype(s) Multi-organ systems to investigate human organ-to-organ communication and the emergence of aging phenotypes MPS generated using cells from human donors with genetic predisposition to or manifesting diseases of aging, or premature aging syndromes Applications addressing, but not limited to, the following topics with the goal to recapitulate one or more phenotypes of aging are responsive to this NOFO: Development of a new in vitro system Increasing the complexity of an existing system Validating protocols for recapitulating aging in vitro Non-Responsiveness Criteria Applications addressing the following topics are not responsive to this NOFO and will be withdrawn prior to review: Developing MPS (1) that are not informative about cell, tissue or organ aging, (2) that do not include more than one cell type, (3) using mammalian cells/tissues that are not directly relevant to human aging, and (4) that employ tissue explants/organotypic cultures A central focus on scaling assays or adapting for use in compound screening Strategies directed toward cell therapy or regenerative medicine Utilization of existing technologies that are not well justified to advance the state of the art to address aging-relevant questions See Section VIII.

Other Information for award authorities and regulations. Section II. Award Information Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO. Not Allowed: Only accepting applications that do not propose clinical trials.

Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards NIA intends to commit $2. 4M in FY 2026 to fund 10 awards.

Application budgets are limited to $275,000 in direct costs over the two-year period, with a maximum of $200,000 in direct costs allowed in any single year. Requested budgets need to reflect the actual needs of the proposed project. The scope of the proposed project should determine the project period.

The maximum period is 2 years. NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO. Section III.

Eligibility Information Higher Education Institutions - Includes all types Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education 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 (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized).

Eligible Agencies of the Federal Government U.S. Territory or Possession 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 Non-domestic (non-U.S.) Entities (Foreign Organizations) 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 allowed. Applicant organizations must complete and maintain the following registrations as described in the How to Apply- 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications for additional information.

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 registrations; 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.

Eligible Individuals (Program Director/Principal Investigator) 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 their organization to develop an application for support.

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 How to Apply-Application Guide. This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1. 2 Definition of Terms .

3. Additional Information on Eligibility 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 NIH Grants Policy Statement Section 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 NIH Grants Policy Statement 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 NOFO. 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 How to Apply - Application Guide except where instructed in this notice of funding opportunity 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 How to Apply- Application Guide and the Table of Page Limits must be followed. Instructions for Application Submission The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed. SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply- Application Guide must be followed. SF424(R&R) Other Project Information All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed. Multidisciplinary teams must comprise expertise in aging biology and additional disciplines such as stem cell biology, tissue and organ physiology, microfluidics, bioengineering, computational biology, pharmacology, and biostatistics. All instructions in the How to Apply- Application Guide must be followed.

All instructions in the How to Apply-Application Guide must be followed. PHS 398 Cover Page Supplement All instructions in the How to Apply- Application Guide must be followed.

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions: The primary focus of applications responding to this NOFO should be developing human MPS that recapitulate one or more aging phenotypes as novel models to study aging. Development of other mammalian nonhuman MPS is only responsive to this NOFO if informative to modeling human aging.

All applications must define the present state of technology, address how current challenges (especially faithful and reproducible mimicking of aging phenotypes) will be overcome by the proposed MPS, and discuss what parameters will be evaluated to assess success.

The proposed in vitro system must maintain tissues in 3D in a controlled environment for a minimal length of time to provide biologically relevant outputs (e.g., molecular, cellular, physiological, etc.) mimicking aging or diseases associated with aging.

Of particular interest are MPS that replicate in vivo aging physiological processes less accessible to direct investigation in human and that are amenable to real-time detection of phenotypic changes (e.g., through sensors and data acquisition). Performance of the system should be characterized and validated using clearly defined metrics.

Applications must include milestones, quantifiable deliverables and criteria to define success in establishing an in vitro human-relevant model of aging. The research strategy must address the following four elements: 1) Definition of the 3D in vitro system Description of the MPS that recapitulates human molecular, cellular, and/or physiological aging phenotypes.

Discussion of how the challenges of faithfully and reproducibly recapitulating aging processes/phenotypes are addressed by the proposed MPS. Definition of the constraints and what questions are best addressed by the proposed MPS. When human-based, the system should be developed from cell/tissues from human donors and/or human induced pluripotent stem cell (iPSC)-derived cells/tissues.

When nonhuman cell-based, the system must be derived using primary cells or iPSCs from a mammalian species. A justification must be included to support the relevance of the model to understanding human aging. The MPS must include more than one cell type to closely resemble the tissue of origin and may include the vasculature and/or immune and/or neuronal cells to better recapitulate tissue physiology and aging.

The strategy must include considerations about control of tissue environment (e.g., oxygen tension, access to nutrients). 2) Explanation of the approach(es) adopted to attain aging. Possible strategies include but are not limited to: Incorporating an aging component into a pre-existing MPS of one or more tissue types or organs.

Directing tissue maturation and aging by increasing cell complexity and tissue connectivity. Introducing stressors, inducing DNA/cell damage, environmental stimuli, or exposing the tissue to progeroid factors. Incorporating in the system cells harvested from aging donors, directly reprogrammed if necessary.

Establishing the system with cells carrying genetic mutations that confer accelerated aging phenotypes. 3) Define what aging phenotypes (e.g. molecular, cellular, functional) will be measured Provide justification for the use of the aging-sensitive phenotypes of choice relevant to the proposed MPS.

The research strategy may include development of sensors (e.g., molecular, devices) and software for data acquisition, real-time long-term detection and analysis and/or high-throughput measurements that are justified by the need to benchmark aging in vitro .

Benchmark performance of the MPS against applicable in vivo known human aging parameters (e.g., -omics profiles, physiological parameters or aging-related disease phenotypes) or in vivo animal model(s) with direct relevance to human that are widely accepted by the research community. Provide evidence of modulation of one or more measurable biological hallmark of aging or markers of disease of aging.

This research approach is most successful when tools, cell lines, engineering designs, etc., are shared. Therefore, the successful investigators will participate in a consortium to develop new tools for MPS applications in aging research, with set periodic meetings, forums and shared resources. Successful investigators will also be invited to join the National Center for Advancing Translational Sciences (NCATS) Tissue Chip Consortium .

Resource Sharing Plan : Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide.

All instructions in the How to Apply-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. Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information 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 How to Apply- 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 How to Apply- Application Guide must be followed.

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 How to Apply- Application Guide must be followed. PHS Assignment Request Form All instructions in the How to Apply- Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM) See Part 2. 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 4. Submission Dates and Times Part I.

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 Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications .

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 How to Apply-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 Section 7. 9.

1 Selected Items of Cost. 7. Other Submission Requirements and Information Applications must be submitted electronically following the instructions described in the How to Apply 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. All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of 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 NOFO 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 How to Apply 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 NIA, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200. 113 and NIH Grants Policy Statement Section 4.

1. 35 . Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected] .

Post Submission Materials Applicants are required to follow the instructions for post-submission materials, as described in the policy Section V. Application Review Information 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.

For this particular announcement, note the following: The R21 Exploratory/Developmental Research Grant activity code supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 application need not have extensive background material or preliminary information.

Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

Since this NOFO encourages innovative approaches with major methodological challenges, the level of risk is generally expected to be higher than for conventional R21 applications. As a result, reviewers should primarily assess merit based on the technical achievements and capabilities of the proposed cell-based models relative to current state of the art.

Applications may focus on technology development that is at the early conceptual stage. Development of a prototype in vitro MPS that is sufficient to generate preliminary data and that has the potential to be further developed in future efforts for validation as in vitro model of aging should be considered of high significance.

Projects need not include investigation of specific biological questions using the proposed in vitro system to attain high significance. Benchmarking (i.e., comparison of the MPS with other models or human data) is required, whereas validation (i.e., assurance of the accuracy) of the in vitro system is welcome but not necessary at this stage.

In the absence of data in the literature showing that a proposed in vitro system has already been tested and failed, the expectation should be that recapitulating aging in vitro could be accomplished in principle if the rationale and approach are sound.

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 scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. Factor 1.

Importance of the Research (Significance and Innovation) Evaluate the importance of the proposed research in the context of current scientific challenges and opportunities, either for advancing knowledge within the field, or more broadly. Assess whether the application addresses an important gap in knowledge in the field, would