Phenotypic and Functional Studies on FOXO3 Human Longevity Variants to Inform Potential Therapeutic Target Identification Research (R01 Clinical Trial Optional) | PAR 18 026

Opportunity Information: Apply for PAR 18 026

This NIH grant opportunity (PAR-18-026) is an R01 funding announcement focused on research that uses human-based systems to understand how naturally occurring FOXO3 gene variants linked to exceptional longevity influence aging-related biology, and how that knowledge could be turned into practical therapeutic target ideas for promoting healthy aging. The scope is explicitly centered on in vivo studies in humans as well as in vitro work using human cells and tissues, with the expectation that projects will connect FOXO3 longevity-associated genetics to measurable phenotypes, underlying cellular functions, and actionable pathways. The announcement is labeled "Clinical Trial Optional," meaning applicants may propose clinical trials if appropriate, but a trial is not required as long as the work fits the human-focused and translational aims.

At the core of the FOA is the idea that FOXO3 is a key node in pathways that regulate stress resistance, metabolism, and other processes thought to influence lifespan and healthspan. Rather than funding general aging studies, this program targets projects that specifically examine human FOXO3 longevity variants and the biology they affect. Therapeutic target identification is a major emphasis: the potential targets are not limited to FOXO3 itself but also include upstream regulators and downstream effectors within FOXO3-mediated signaling networks. In practical terms, proposals should aim to clarify which molecular components in these pathways are most responsible for beneficial longevity-associated effects and therefore might be good candidates for drug development or other interventions.

The FOA highlights three broad and overlapping research directions. First are studies that examine the in vivo phenotypic effects of human FOXO3 variants. These could include identifying how variant carriers differ in clinically relevant traits tied to healthy aging, such as resilience to age-related decline, cardiometabolic profiles, immune function, cognitive outcomes, frailty-related measures, or other physiological markers, as long as the work is grounded in human participants and links back to FOXO3 genotype. Second are studies that dig into how these variants change cellular functions and the pathways that mediate them, using human cells or tissues to map functional consequences, pathway activity, and mechanisms. Third are studies that move from mechanism to translation by identifying and evaluating candidate therapeutic targets, including target validation efforts and testing candidate compounds or interventions that engage FOXO3 functional pathways in ways that could plausibly mimic or leverage the protective effects seen in longevity-associated variants.

Because the stated goal is to inform therapeutic target identification and potential intervention testing for healthy aging, competitive projects would typically be expected to go beyond association and provide functional evidence. That can mean showing how a specific FOXO3 variant shifts pathway signaling, alters transcriptional programs, changes stress-response phenotypes in relevant human cell types, or influences biomarkers in variant carriers in ways that are consistent with healthier aging. Similarly, intervention-oriented projects would be expected to justify why a particular upstream regulator, downstream effector, or pathway component is a promising target, and then provide data or a plan to evaluate whether modulating it produces beneficial, FOXO3-pathway-consistent effects in human systems.

The administering agency is the National Institutes of Health, and the activity category is health (CFDA 93.866). The mechanism is an NIH R01 research project grant, which generally supports substantial, hypothesis-driven research programs. The original closing date listed in the source data is 2018-05-07, and the FOA was created on 2017-11-01; applicants would need to verify current availability, deadlines, and any reissued versions of the announcement through NIH since older FOAs are sometimes expired, updated, or replaced.

Eligibility is broad and includes many common U.S. applicant organizations such as public and private institutions of higher education, nonprofits (with and without 501(c)(3) status), for-profit organizations (other than small businesses), small businesses, and various levels of government (state, county, city/township, special districts), as well as independent school districts and public housing authorities/Indian housing authorities. It also includes federally recognized Native American tribal governments and other Native American tribal organizations. The FOA also explicitly calls out additional eligible applicant types, including Alaska Native and Native Hawaiian Serving Institutions, AANAPISISs, Hispanic-serving Institutions, Historically Black Colleges and Universities, Tribally Controlled Colleges and Universities, faith-based or community-based organizations, eligible federal agencies, U.S. territories or possessions, regional organizations, and even non-domestic (non-U.S.) entities (foreign organizations) and Indian/Native American Tribal Governments that are not federally recognized. This wide eligibility reflects NIH's interest in drawing from diverse institutional settings and populations, which can be especially relevant for studying genetic variants and aging phenotypes across different cohorts.

Overall, the opportunity is designed for teams that can combine human genetics, deep phenotyping, and functional biology in human systems to translate FOXO3 longevity variant biology into concrete therapeutic hypotheses. The most aligned applications are likely to be those that (1) start from FOXO3 variant status in humans, (2) connect that status to meaningful aging-related phenotypes and mechanistic cellular readouts, and (3) use those mechanistic insights to prioritize, validate, and possibly test interventions targeting FOXO3 or its pathway components with the long-term goal of improving healthspan.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Phenotypic and Functional Studies on FOXO3 Human Longevity Variants to Inform Potential Therapeutic Target Identification Research (R01 Clinical Trial Optional)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.866.
• This funding opportunity was created on 2017-11-01.
• Applicants must submit their applications by 2018-05-07. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

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