ARPA-H puts $144 million into healthspan-focused human trials (mTOR inhibitor)

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This is really good news for the longevity field:

Multiple biotechs and academic institutions among recipients of funding for trials of therapeutics designed to extend healthspan.

The US Government, via its Advanced Research Projects Agency for Health (ARPA-H) initiative, is putting up to $144 million into multiple projects aimed at extending healthspan – the years people live in good health. Through its PROSPR program, ARPA-H is funding seven research teams working to treat aging as a tractable biological process, and proving, in humans, that intervening earlier can help people stay healthier for longer.

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Longevity biotech Cambrian has been awarded up to $30.8 million to support human trials of a daily, oral, next-generation rapamycin analog intended to selectively inhibit mTORC1. The company views dysregulated mTORC1 signaling as a key driver of the metabolic decline that accumulates with age, and it is tying its program to “intrinsic capacity,” a composite measure of physical and metabolic resilience that declines over time.

“We founded Cambrian to lay the groundwork for treating some of today’s most debilitating diseases at the molecular level, before they cause disease,” said Cambrian CEO James Peyer. “Improving intrinsic capacity is the perfect expression of that mission, yet no drug development effort has ever attempted to target it. PROSPR is the first. Efforts like this are what allow us to push into new frontiers of medicine.”

and…

The University of Texas Health Science Center at San Antonio is being funded to pursue a regulatory path for testing therapeutics for aging by running a phase 3 hybrid trial that repurposes three FDA-approved drugs (an SGLT2 inhibitor, rapamycin, and semaglutide) into a trial structure explicitly oriented around aging-related outcomes.

Related:

What PROSPR is actually building

PROSPR is a five-year, three-part program structured in three interlocking Technical Areas:

TA1 is building what they call the PROSPR Intrinsic Capacity (IC) score, a composite measure of physical, cognitive, metabolic, and functional health that can be assessed longitudinally using wearables and minimal biosampling. The goal is to develop and validate this as an FDA-recognized surrogate endpoint: something you can measure in as little as six months that predicts where someone’s health trajectory is headed over the long term. This is the measurement infrastructure the whole field needs, and it doesn’t exist yet.

TA2 is running intervention trials using already-approved drugs with strong safety records and evidence of geroprotective effects, testing whether they can move the IC score in people in their early sixties. These trials simultaneously generate human evidence for those drugs and stress-test the IC score as an endpoint.

TA3 is where Cambrian sits. Its purpose is to help validate the drugs that could actually become the very first gerotherapeutics. No approved drug today is both safe enough and effective enough to serve as a gerotherapeutic useful to most people. But once the IC score is validated, it creates a path to approve next-generation medicines that have grown up with the novel insights of the geroscience field, purpose-built to target the biology of aging, with the safety profiles needed for long-term preventative use in healthy people. And those are the kinds of drugs Cambrian has created.

Why TORnado — and why mTOR is the right target

mTOR is the best-validated pharmaceutical target in all of aging biology. Inhibiting the mTOR pathway extends healthy lifespan in yeast, worms, flies, and mice, across sexes, across genetic backgrounds, and even when treatment is started in middle age. This kind of cross-species, cross-sex consistency is extraordinarily rare in geroscience. mTOR hyperactivation is also a documented feature of human tissue aging, driving age-related decline.

Rapamycin and its analogs are the best-performing drugs for extending healthy lifespan in animal models, and on top of that, they have shown promise in animal models across cardiovascular disease, cancer, neurodegeneration, immunosenescence, and more. The science is compelling.

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#2

Linnaeus has been awarded up to $22 million to advance a drug targeting the G protein-coupled estrogen receptor (GPER) into human trials for healthspan preservation. I

Related:

G Protein-Coupled Estrogen Receptor (GPER) in Healthspan Preservation

Biological Rationale and Pathway Identification

The G protein-coupled estrogen receptor (GPER), also known as GPR30, mediates rapid, non-genomic estrogenic effects across multiple systems, including the cardiovascular, central nervous, and metabolic networks. The fundamental hypothesis driving GPER longevity research is that premenopausal females possess significant biological resilience against age-related cardiometabolic and neurodegenerative diseases—an advantage that rapidly attenuates following the cessation of endogenous estrogen production.

Targeting GPER aims to uncouple the geroprotective effects of estrogen signaling from the feminizing and potentially oncogenic effects mediated by classical nuclear estrogen receptors (ERα and ERβ). By selectively activating GPER, researchers speculate it is possible to maintain physiological homeostasis, metabolic flexibility, and vascular health post-menopause, and potentially offer similar systemic resilience to males without the adverse effects of traditional systemic hormone replacement therapy.

Leading Compounds and Interventions

Research has shifted from broad endogenous estrogen observation to the development of highly selective synthetic agonists.

  • LNS8801: This orally bioavailable, highly selective GPER agonist is currently the most advanced compound in translational healthspan research.

    • Verified Facts: Originally developed for oncology, Phase 1/2 human trials demonstrated an exceptional safety and tolerability profile. Collateral clinical data showed statistically significant improvements in cardiometabolic biomarkers, including reductions in LDL cholesterol, systolic blood pressure, and HbA1c, alongside weight loss.

    • Current Trajectory: In February 2026, Linnaeus Therapeutics received up to $22 million from ARPA-H to fund a multiphase translational program. This program is specifically designed to assess if LNS8801 can preserve “Intrinsic Capacity” and extend healthspan in healthy older adults.

  • G-1: A nonsteroidal, high-affinity GPER agonist utilized extensively in preclinical models.

    • Verified Facts: In aged, ovariectomized rat models, late-life administration of G-1 reversed adverse cardiac remodeling, reduced interstitial fibrosis, and improved myocardial relaxation. It also demonstrates renal protection by increasing the estimated glomerular filtration rate and reducing proteinuria.
    • Limitations: G-1 remains primarily a preclinical investigative tool and lacks the human safety and pharmacokinetic validation of LNS8801.

Scholarly Debates and Controversies

  • Receptor Hierarchy in Aging: There is an active scholarly debate regarding the relative importance of GPER versus ERα in physiological aging. While some studies emphasize ERα as the primary driver of health preservation in advanced age, GPER’s independent role as a plasma membrane-based receptor in mediating endogenous estrogen effects in vivo is sometimes contested due to conflicting results in receptor knockout models.
  • The Oncogenic Paradox: GPER expression and its downstream effects are highly context-dependent. Literature reveals a dichotomy: in certain models, GPER activation inhibits proliferation and induces apoptosis (e.g., via ER stress and pro-death unfolded protein response signaling), while in specific tumor microenvironments, high GPER expression has been associated with pro-tumor signaling. The tissue-specific mechanics of GPER agonism remain incompletely mapped and represent a persistent theoretical risk.
  • Neurological Efficacy: While GPER is highly expressed in the central nervous system (hippocampus, cortex), there is ongoing dispute regarding whether its isolated activation is sufficient to mitigate age-associated memory impairment without the synergistic genomic action of classical ERs.

Knowledge Gaps and Required Data

To transition GPER agonism from informed speculation to a validated geroprotective intervention, the following data are required:

  1. Longitudinal Human Data: The upcoming ARPA-H funded trials must prove that the surrogate biomarker improvements seen in LNS8801 oncology trials translate into durable, measurable delays in functional and cognitive decline in healthy aging populations.
  2. Sex-Dimorphic Responses: Granular data is needed to determine if GPER agonism yields equivalent healthspan extensions in male cohorts, who possess different baseline expressions of GPER and distinct renin-angiotensin-aldosterone system (RAAS) pathway activity.
  3. Surrogate Biomarker Validation: The field requires validated, age-specific biomarkers that accurately map GPER target engagement to a deceleration in biological aging clocks over a compressed 1-to-3-year clinical trial window.