Trial at a Glance
VITAL-H is the first large-scale clinical trial designed to evaluate whether FDA-approved drugs can delay age-related functional decline in healthy adults. Led by the Barshop Institute at UT Health San Antonio, this five-year Phase 3 trial will test rapamycin, dapagliflozin, and semaglutide against placebo in 726 adults aged 60–65. It represents the most rigorous attempt yet to translate decades of geroscience research into an FDA-recognized regulatory framework for healthspan interventions.
"Over the past 50 years, global life expectancy has increased substantially, yet the age of onset of age-related diseases and disabilities has remained largely unchanged. This work is focused on changing that trajectory." — Elena Volpi, MD, PhD, PI of VITAL-H
Why This Matters
Over 90% of adults over 65 have at least one chronic condition. 80% have two or more. Despite advances in understanding the biology of aging, no FDA-approved interventions exist to delay functional decline in healthy adults. VITAL-H aims to change this by establishing the first regulatory-grade framework for healthspan drugs — treating aging itself, not just individual diseases.
The Geroscience Hypothesis
Aging modifies a small number of core biological mechanisms that drive most age-related diseases. If we target those mechanisms — mTOR, metabolic dysregulation, chronic inflammation — a single intervention could influence many outcomes simultaneously. This "one drug, many diseases" approach is fundamentally different from the disease-by-disease model of modern medicine.
Historical Context
PROSPR Funding Distribution
Age-Related Chronic Conditions (65+)
Three FDA-Approved Drugs Under Test
Each drug targets a distinct hallmark of aging, is orally administered, and has extensive post-marketing safety data. At low doses, their anti-aging effects may extend well beyond their original therapeutic indications.
Rapamycin
mTOR Inhibitor (Sirolimus)
Originally developed as an immunosuppressant for transplant patients. At low doses, inhibits mTORC1 — the master nutrient sensor — enhancing cellular cleanup (autophagy), reducing chronic inflammation, and mimicking caloric restriction's pro-longevity effects. First small molecule shown to extend mammalian lifespan.
Dapagliflozin
SGLT2 Inhibitor (Farxiga)
Blocks glucose reabsorption in the kidney, inducing mild metabolic stress that triggers beneficial adaptations. Reduces oxidative stress, improves mitochondrial function, and acts as a senotherapeutic — clearing senescent cells. Dramatic cardiovascular and renal protection observed across multiple landmark trials (DECLARE, DAPA-HF, DAPA-CKD).
Semaglutide
GLP-1 Receptor Agonist (Ozempic)
The blockbuster GLP-1 receptor agonist addresses multiple hallmarks of aging beyond its diabetes/obesity indications. Reduces systemic inflammation (CRP ↓40–60%), improves insulin sensitivity, protects cardiovascular function, and may preserve cognitive health. The SELECT trial showed 20% CV risk reduction independent of diabetes status. Phase 3 Alzheimer's trials (EVOKE) underway.
How Three Drugs Target the Hallmarks of Aging
Drug Aging Hallmark Coverage
Evidence Strength by Drug
Trial Design
VITAL-H is a Phase 3, randomized, placebo-controlled, four-arm trial using a hybrid decentralized design. It enrolls 726 generally healthy adults ages 60–65 from South Texas — a region whose demographics closely mirror projected future US population composition.
Decentralized Design Innovation
VITAL-H pioneers a hybrid decentralized model for aging research. Instead of requiring all visits at a single academic center, participants complete assessments across multiple community sites throughout San Antonio, dramatically improving accessibility and enrollment diversity.
Wearable-First Data Collection
Participants wear a health-tracking ring that continuously monitors physical activity, heart health metrics, and sleep quality — enabling real-time, objective measurement of functional trajectories without frequent clinic visits.
Why South Texas?
South Texas's demographic composition closely mirrors the projected US population in coming decades, making results broadly generalizable. The region's ethnic diversity, health disparities, and established research infrastructure at UT Health San Antonio create an ideal setting for nationally relevant healthspan research.
Partner Clinical Sites
Traditional vs VITAL-H Trial Design
| Feature | Traditional | VITAL-H |
|---|---|---|
| Enrollment age | 65–80+ (post-disease) | 60–65 (pre-decline) |
| Endpoints | Disease incidence | Functional capacity |
| Duration needed | 10–20 years | 1–3 years |
| Assessment | Clinic-only | Hybrid + wearable |
| Data capture | Periodic snapshots | Continuous + in-person |
| Generalizability | Narrow demographics | Nationally representative |
WHO Intrinsic Capacity Framework
Intrinsic Capacity (IC) is the WHO's composite measure of an individual's physical and mental capabilities — a holistic metric for healthy aging that goes beyond counting diseases. VITAL-H aims to be the first trial to validate IC as an FDA-recognized regulatory-grade endpoint, which would open the door for future healthspan drug approvals.
"We want the FDA to recognize intrinsic capacity as a meaningful, regulatory-grade endpoint." — Elena Volpi, MD, PhD
The Five Domains of Intrinsic Capacity
Cognitive
Memory, attention, executive function, processing speed
Locomotor
Gait speed, grip strength, balance, mobility
Psychological
Mood, resilience, motivation, well-being
Vitality
Energy, metabolism, hormonal balance, nutrition
Sensory
Vision, hearing, vestibular function
Why IC Matters for Drug Regulation
Currently, the FDA has no approved endpoint for "aging" itself. Drugs must target specific diseases (e.g., diabetes, heart failure). Intrinsic Capacity reframes aging as a measurable functional trajectory rather than an inevitable accumulation of disease. If validated, IC would enable:
- Regulatory pathway for healthspan drugs (not just disease treatments)
- Shorter trial durations (functional change detectable in 1–3 years)
- Composite endpoint capturing multi-system aging effects
- Scalable, decentralized assessment with digital health tools
- Patient-centered outcomes aligned with real-world quality of life
PROSPR-IC Score (Stanford)
The Stanford University PROSPR team is developing the PROSPR-IC Score — a harmonized healthspan score derived from vast existing longitudinal health datasets across multiple institutions. This score will:
- Integrate data from multiple longitudinal aging studies
- Generate a standardized, quantitative IC composite
- Be validated in a 1-year lifestyle intervention
- Use in-home digital health assessment technology
- Draw on VITAL-H data for drug intervention validation
IC Decline Trajectory: Untreated vs Treated
Drug Coverage Across IC Domains
How IC Is Assessed in VITAL-H
| Domain | Assessment Tools | Wearable Data | Frequency |
|---|---|---|---|
| Cognitive | MoCA, digit span, trail making | Sleep architecture metrics | Baseline, 6mo, 12mo |
| Locomotor | Gait speed, SPPB, grip strength | Daily step count, activity patterns | Continuous + quarterly |
| Psychological | GDS, WHO-5, resilience scale | HRV, sleep quality | Baseline, 6mo, 12mo |
| Vitality | BMI, albumin, hemoglobin, CRP | Resting HR, energy expenditure | Quarterly labs + continuous |
| Sensory | Visual acuity, pure-tone audiometry | — | Baseline, 12mo |
Drug Arena — Head-to-Head Comparison
All three VITAL-H drugs are FDA-approved for non-aging indications but show compelling preclinical and early clinical evidence for healthspan extension. Here they are, side by side.
| Property | Rapamycin | Dapagliflozin | Semaglutide |
|---|---|---|---|
| Drug Class | mTOR inhibitor | SGLT2 inhibitor | GLP-1 receptor agonist |
| Brand Name | Rapamune / Sirolimus | Farxiga | Ozempic / Wegovy / Rybelsus |
| FDA Approval | 1999 | 2014 | 2017 |
| Original Indication | Organ transplant (immunosuppression) | Type 2 diabetes | Type 2 diabetes / Obesity |
| Primary Target | mTORC1 complex | SGLT2 transporter (kidney) | GLP-1 receptor |
| Aging Mechanism | ↑ Autophagy, ↓ inflammaging, ↓ senescence | ↓ Oxidative stress, ↑ mito function, senolytic | ↓ Systemic inflammation, ↑ metabolic health |
| Mouse Lifespan | +9–14% | Emerging data | Emerging data |
| CV Benefit | Indirect | −18% CV death | −20% MACE |
| Renal Benefit | Limited | −39% CKD | Emerging |
| Neuro/Cognitive | Preclinical | Limited data | EVOKE Ph3 ongoing |
| Weight Effect | Neutral | Mild loss (glycosuria) | −15% body weight |
| Anti-Inflammatory | Strong (mTOR) | ROS ↓, NO ↑ | CRP −40–60% |
| Route | Oral, daily | Oral, daily | Oral (Rybelsus), daily |
| Key Safety Note | Immunosuppression at high doses | UTI risk, dehydration | GI side effects, muscle loss concern |
| Cost (retail/mo) | ~$20 generic | ~$500 brand | ~$1,000+ brand |
| ITP Validated? | Yes (2009) | No | No |
Multi-Organ Benefit Profile
Safety & Tolerability Profile
Complementary vs Overlapping Mechanisms
VITAL-H's three drugs target largely non-overlapping pathways, which is by design. This enables the trial to compare three distinct geroscience strategies head-to-head:
Rapamycin Strategy
Nutrient sensing axis. Mimic caloric restriction via mTOR inhibition. Enhance cellular quality control (autophagy). The oldest and most validated geroscience intervention.
Dapagliflozin Strategy
Metabolic stress adaptation. Induce mild metabolic challenge via glycosuria. Improve mitochondrial efficiency and clear senescent cells. Proven organ protection across heart, kidneys.
Semaglutide Strategy
Systemic inflammation control. Multi-organ anti-inflammatory via GLP-1 signaling. Address obesity-inflammation-aging nexus. Broadest clinical evidence base across organ systems.
PROSPR Program — The 7 Teams
VITAL-H is part of ARPA-H's Proactive Solutions for Prolonging Resilience (PROSPR) program — a $144M, 5-year initiative across 7 research teams. PROSPR aims to create a new "healthspan industry" by identifying biomarkers, developing assessment tools, and testing therapeutics that target the biology of aging directly.
"PROSPR is designed to identify therapeutics that show the aging process is not an inevitable slide into disability." — Andrew Brack, PhD, ARPA-H PROSPR Program Manager
Stanford University
UT Health San Antonio — VITAL-H
Columbia University Mailman SPH
Apollo Alpha
Cambrian BioPharma
Linnaeus Therapeutics
University of Rochester
PROSPR Team Approach Taxonomy
Aging Pathway Coverage by Team
VITAL-H's Unique Position in PROSPR
References
- UT Health San Antonio. "Barshop Institute to receive up to $38 million from ARPA-H, anchoring UT San Antonio as a national leader in aging and healthy longevity science." Press Release, Feb 24, 2026. news.uthscsa.edu
- UT Health San Antonio. "UT San Antonio to lead $38 million national trial testing drugs to extend healthspan." Mar 4, 2026. news.uthscsa.edu
- ARPA-H. "Research teams to add more healthy years to Americans' lives as they age." Feb 24, 2026. arpa-h.gov
- Harrison DE, Strong R, Sharp ZD, et al. "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice." Nature. 2009;460(7253):392-395. doi:10.1038/nature08221
- Blagosklonny MV. "Rapamycin for longevity: opinion article." Aging (Albany NY). 2019;11(19):8048-8067. doi:10.18632/aging.102355
- Mannick JB, Del Giudice G, Sabber M, et al. "mTOR inhibition improves immune function in the elderly." Science Translational Medicine. 2014;6(268):268ra179.
- McMurray JJV, Solomon SD, Inzucchi SE, et al. "Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF)." New England Journal of Medicine. 2019;381(21):1995-2008.
- Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. "Dapagliflozin in Patients with Chronic Kidney Disease (DAPA-CKD)." New England Journal of Medicine. 2020;383(15):1436-1446.
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. "Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT)." New England Journal of Medicine. 2023;389(24):2221-2232.
- "GLP-1 Receptor Agonists to expand the healthy lifespan: Current and future potentials." Aging Cell. 2023;22(5):e13831. PMC10186594.
- "Are GLP-1s the first longevity drugs?" Nature Biotechnology. 2025;43:1234-1237. doi:10.1038/s41587-025-02932-1
- Cesari M, Araujo de Carvalho I, Amuthavalli Thiyagarajan J, et al. "Evidence for the Domains Supporting the Construct of Intrinsic Capacity." J Gerontol A Biol Sci Med Sci. 2018;73(12):1653-1660.
- Beard JR, Jotheeswaran AT, Cesari M, et al. "The Structure and Predictive Value of Intrinsic Capacity in a Longitudinal Study of Ageing." BMJ Open. 2019;9(11):e026119.
- World Health Organization. "Decade of Healthy Ageing: Baseline Report." WHO, 2020.
- "Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms." Int J Mol Sci. 2022;23(20):12325. PMC9604287.
- "SGLT2 inhibitors as a novel senotherapeutic approach." npj Aging. 2025;11:27. doi:10.1038/s41514-025-00227-y
- Longevity Technology. "ARPA-H pours millions into healthspan-focused human trials." Feb 24, 2026. longevity.technology
- CDC. "Chronic Conditions Among Older Adults." MMWR / PCD. 2025. cdc.gov
- "Rapamycin for longevity: the pros, the cons, and future perspectives." Frontiers in Aging. 2025;6:1628187. doi:10.3389/fragi.2025.1628187
- "SGLT2 inhibitor downregulates ANGPTL4 to mitigate pathological aging of cardiomyocytes." Cardiovascular Diabetology. 2024;23:520. doi:10.1186/s12933-024-02520-8