Translating Aging

Matthew "Oki" O'Connor is the CEO of Scientific Affairs at Cyclarity Therapeutics, a clinical-stage biotech building a new class of medicines designed not to slow the accumulation of vascular damage but to reverse it. Oki and Chris first crossed paths as postdocs at Lawrence Berkeley National Lab in the mid-2000s — Oki was in Irina Conboy's lab, not far from the late Judy Campisi's group, where Chris was then working on cellular senescence. After Berkeley, Oki spent nearly a decade running the research program at the SENS Research Foundation, the organization most identified with the "damage repair" framing of aging biology, before co-founding Cyclarity (then known as Underdog Pharmaceuticals) in 2019 to translate one of SENS's most drug-tractable ideas into an actual molecule.When Oki was last on the show in March of 2023 (Episode 36), Cyclarity was deep in IND-enabling work and its lead asset, UDP-003, had only ever seen the inside of a mouse artery. At the end of that conversation, Chris asked what Oki hoped to be discussing the next time he visited. He answered, bluntly, that he wanted to be presenting human data. Last month, at the AHA Vascular Discovery Sessions, Cyclarity reported the results of their first-in-human Phase 1 trial of UDP-003 — a designed cyclodextrin that selectively binds 7-ketocholesterol, the oxidized cholesterol species that drives foam cell formation and arterial plaque. He's back to discuss what the drug actually did when it went hunting for 7KC inside a living human being.In this episode, Chris and Oki cover the unmet need that lipid-lowering drugs — statins, PCSK9 inhibitors, the coming Lp(a) agents — still don't address: none of them remove the damage already sitting in an artery wall. Oki explains the basic chemistry of 7-ketocholesterol and why macrophages, lacking the machinery to recycle it, collapse into foam cells and seed the necrotic core of advanced plaque. They walk through the engineering of UDP-003 as a dimeric beta-cyclodextrin "double cone" tuned for a single oxidized cholesterol species, the design of the 72-volunteer Australian Phase 1, and the exploratory pharmacodynamic readout that has the field's attention: dose-dependent urinary excretion of 7KC, stoichiometric with drug, cleared within a day. The conversation then turns to the 150-patient Phase 2 plan in coronary artery disease patients with plaque imaging as the primary biological readout, the funding math that stands between Cyclarity and that trial, the platform's reach into NASH, vascular dementia, AMD, and aging itself, and how all of this descends from the SENS damage-repair philosophy that Oki has been carrying since LBL.The Finer Details:- Why current standard of care is not enough — statins, PCSK9 inhibitors, GLP-1s, and the soon-to-arrive Lp(a) lowering agents all act by slowing the accumulation of arterial damage, not by reversing what's already there; despite 30 years on the market, statins have never demonstrated an all-cause mortality benefit in a clinical trial, and even the best statin imaging data shows only 1–2% plaque volume regression at very high doses in a subset of patients- The scale of the problem — atherosclerosis is estimated to contribute to roughly 40% of all human deaths once heart attack, stroke, and a surprisingly large COPD contribution are risk-adjusted in, on top of an enormous morbidity tail that includes angina, peripheral artery disease (up to and including amputation), and a growing case for vascular dementia as an undercounted driver of cognitive decline- The biology of 7-ketocholesterol — when an oxygen free radical reacts with cholesterol, it preferentially attacks the 7 position, and a second oxidation step locks the molecule into 7KC, a stable toxic species cells were essentially never equipped to recycle; it builds up in long-lived cells like macrophages, eventually shutting down their ability to traffic lipids back to the liver via HDL and converting them into foam cells that seed soft plaque and, over years, the necrotic core of advanced lesions- The molecular design of UDP-003 — cyclodextrins are naturally occurring carbohydrate rings; the beta size fits half a cholesterol molecule, and Cyclarity's in silico work showed that two beta-cyclodextrins facing wide-side to wide-side form a "double cone" that can fully encapsulate a single cholesterol; engineered correctly, that wrapper can be made selective for 7KC over native membrane cholesterol, which is what gives the drug its therapeutic window- The Phase 1 trial design and result — a traditional 72-volunteer safety study in Australia, split between single ascending dose and multiple ascending dose arms, escalating up to six doses at what Cyclarity believes will be the efficacious level; no serious adverse events, no bioaccumulation, drug excreted essentially completely in the urine (as predicted preclinically), and — the headline exploratory endpoint — dose-dependent urinary 7-ketocholesterol appearing on the same timescale as the drug, consistent with one molecule of UDP-003 binding one molecule of 7KC and leaving the body together- What the urinary 7KC readout can and cannot tell you — the easiest 7KC to mobilize is the free pool in circulation, but there is not nearly enough of it floating in the bloodstream to account for what came out in urine, which means the drug is reaching deeper compartments; how much is coming from vessel wall plaque versus liver versus other peripheral tissues will require the imaging endpoints of Phase 2 to answer- The Phase 2 plan — 150 coronary artery disease patients (the coronary being, as Oki puts it, the artery most likely to kill you), with baseline plaque imaging, a year of dosing, and a repeat scan; safety and PK continue, inflammatory biomarkers come on, and plaque volume change is the prize — for context, a 1% change in plaque volume is associated with roughly a 20% change in next-year risk of heart attack or stroke- The funding math and the platform — Cyclarity has raised $33M to date and needs roughly $45M more to run the Phase 2, with Phase 3 cardiovascular outcomes trials running into the hundreds of millions and likely requiring a pharma partner; beyond atherosclerosis, 7KC is elevated in NASH livers, in Alzheimer's brains, and in the retinal cells that die in age-related macular degeneration, and the underlying chemistry — designed binders that drag a specific toxic molecule out of the body — is meant to generalize into a pipeline against other accumulated damage species, the direct intellectual descendant of the SENS damage-repair programQuotes:"Atherosclerosis, or the plaque that builds up in your blood vessels in your arteries, is estimated to cause approximately 40% of all human death.""When [the macrophage] eats up too much oxidized cholesterol, it just accumulates it… And that's when you get this transition to these kind of monster blob cells called foam cells.""One molecule of our drug is supposed to bind one molecule of 7-ketocholesterol and then go away and never be seen again. You excrete both of them together.""A 1% change in plaque volume is associated with a 20% risk in the next year of your probability of having a heart attack or a stroke.""You pick one target at a time, you do it well, and you take it all the way to the clinic and hopefully prove that you can actually cure patients, help them get better, help their plaque shrink away, and prove that this approach can work."Links:Cyclarity Therapeutics: https://cyclarity.com

Marco Quarta is co-founder and Chief Scientific Officer of Rubedo Life Sciences, a precision-therapeutics company developing medicines that target the pathological cell states that drive age-associated disease. Marco's first appearance on the show was three years ago, in February 2023 (Episode 35), when Rubedo was a much earlier-stage company committed to the then-contrarian premise that "the senescent cell" is not a single entity but a heterogeneous family of cell states that needs to be deconvoluted at the single-cell level. In March 2026, Rubedo reported preliminary Phase 1b/2a clinical data for its lead candidate, RLS-1496, a first-in-class topical GPX4 modulator. Marco returns to the show to discuss what survived contact with human biology.In this episode, Chris and Marco unpack the readout from Rubedo's basket trial across four skin indications — psoriasis, atopic dermatitis, actinic keratosis, and photoaged skin — and the biology that underlies it. RLS-1496 came clean on safety in all four indications, with significant efficacy signals despite small patient numbers and short (20–30 day) treatment courses. More provocatively, the clinical and translational data have pushed Marco to redefine what kind of drug this actually is. Rather than a next-generation senolytic, GPX4 modulation appears to act as a state-gating intervention: it triggers ferroptosis in deeply senescent cells that have already crossed a redox threshold, while inducing a hormetic "redox reset" in stressed-but-recoverable cells that restores them to a healthier state. Marco proposes a new category to capture this dual action — adaptive senotherapeutics, or senoadaptive drugs — distinct from senolytics and senomorphics.The conversation traces the arc from Rubedo's founding thesis to a clinically validated platform (ALEMBIC, the AI-enabled single-cell multiomics engine that surfaced GPX4 as a target), through the strategic logic of leading with skin, into the broader question every longevity-biotech founder eventually has to answer: when does a disease-by-disease franchise become a credible preventive geroscience platform? Marco lays out the GLP-1 analogy explicitly — an anchor indication and a label-expansion roadmap that could carry GPX4 modulation from dermatology into respiratory, neurodegenerative, and metabolic disease, and ultimately into the use case where biomarkers of cellular senescence flag patients for therapy decades before disease becomes clinically apparent.The Finer Details:How Marco's 2023 contrarian view — that "senescent cells" hide a tissue- and state-specific reality — has been reinforced by the clinic, and how Rubedo's framing has shifted from "targeting senescent cells" to "targeting pathological cell states"The biology of GPX4 as a lipid-peroxidation gatekeeper, why senescent cells have intrinsic vulnerabilities (p16, p21, CDK4/6 inhibition) that make them ferroptosis-sensitive, and how Rubedo's approach differs from oncology-focused GPX4 programs at Takeda and othersThe "senoadaptive" mechanism — RLS-1496 eliminates GPX4-dependent senescent cells via ferroptosis while triggering NRF2/Keap1-driven redox reset, autophagy, and epigenetic remodeling in recoverable cells, restoring tissue trajectory from degenerative to regenerativeWhy Rubedo led with skin: clean regulatory path, accessible tissue, the ability to read out aging biology anddisease in the same trial, and a label-expansion runway into systemic indicationsPhase 1b (Europe) and Phase 2a (US) basket-trial results across psoriasis, atopic dermatitis, photoaged skin, and actinic keratosis: clean safety in 4/4 indications and significant efficacy signals — itch reduction in atopic dermatitis, decreased lesional thickness in psoriasis, target-engagement-correlated clinical improvement in photoaged skinThe richness of the translational dataset: biopsies, tape-stripping, spatial transcriptomics, proteomics, multiplex histomics, plasma biomarkers — all feeding back into ALEMBIC to refine the platformWhy actinic keratosis is the most strategically important indication — an age-related, chronic-inflammatory, precancerous condition where Rubedo can simultaneously test disease modification and biological-age reversalThe Rubedo–Beiersdorf partnership and the cosmetic vertical as a parallel commercial axisPipeline beyond skin: targeting aberrant basaloid stem cells in IPF and other pulmonary indications using different modalities (prodrugs, PROTACs, ADCs) to achieve cell-state selectivityThe longer-arc vision: senescence biomarkers as a "prediabetes-style" early signal, with senoadaptive drugs deployed decades before disease — and what a GLP-1-scale franchise might look like for GPX4 modulationQuotes:"There is not such a thing as a senescent cell — like there is not a cancer cell. And that was the initial idea. I'm glad that over time the field evolved. Now this is an accepted concept in the senotherapeutic space.""We are really talking about a dual function of RLS-1496 that can modulate the cell state depending on the adaptive response. That's why we call this — de facto — a new class of senotherapeutics. We call them adaptive senotherapeutics, or senoadaptive drugs — not a senolytic or a senomorphic, but working by modulating the cell state.""The best animal model for human therapies is human. As much as you can do preclinical work in animal models, it's always an approximation. We were able to test this directly in patients for safety, and in 4 out of 4 indications, we didn't have any safety signal.""Imagine you're taking care of a growing tree, and this tree has some dead leaves and some are a little bit stressed. If you shake the tree, the dead leaves will fall; the healthy leaves will not, because they're healthy and they resist the shake. But that shake actually gives the stressed leaves space and breathing room, and helps them to regain vitality. That's a little bit what GPX4 modulation does.""Senotherapeutics is a large, growing field — an untapped therapeutic opportunity. There is no such thing as a pan-senolytic or a pan-senotherapeutic, like there is no pan-oncotherapeutic. You need to understand the context. But these will all be part of the arsenal for true longevity medicine.""I don't see this as prevention of disease. The way I see therapies like ours, and the way the field of longevity is developing, is treating diseases decades before they develop. That's not a new concept — that's what we're doing in diabetes. You can be diagnosed with prediabetes today and reverse those biomarkers with lifestyle changes or metformin, and maybe never develop diabetes. That's exactly what we're doing here.""First of all, celebrating the first approved drugs from Rubedo — I don't think we're too far from that. But that's also a beginning, because you learn from the big momentum the GLP-1 agonists created: how a drug can start in one indication, create a new field, and prove that you can go beyond that. I hope in a few years we come back and talk about the next GLP-1 — this could be GPX4 modulators, or the senoadaptive drugs that are first in our pipeline."Links:Rubedo Life Sciences: https://www.rubedolife.comMarco Quarta's previous appearance on Translating Aging: Ep 35 — Targeting Pathologic Cells to Preserve Biological Youth