Hedging bets on healthier aging
This post shares a bit about the translational geroscience portfolio I nurtured into being at the University of Oxford between early 2019 and mid-2021.
Building a longevity bioscience portfolio.
In 2019, I joined the University of Oxford as Scientific Liaison on a project aiming to accelerate the development of drugs targeting biological drivers of aging. My primary responsibility was to seed and develop a ~$1.2MM portfolio of longevity research projects which a) touched on a variety of biological drivers of aging, b) represented projects in the ‘unfundable’ zone between basic science research and clinical validation, and c) spanned the drug discovery pipeline or supported the drug discovery process (e.g., new tech for screening platforms).
The overarching project was part of a broader program to nurture collaborations across sectors - academia, industry, government, non-profits. Merging that with drug discovery for aging involved digging deep not only into the scientific and drug discovery challenges of translating early-stage geroscience research, but also into the types of resource exchange initiatives that would accelerate the route to clinic for promising interventions.
The team operated in startup-ish style with a short timeline (mid-2021 end date), limited operating resources, and a small distributed team. Our ability to be nimble and act independently (and with urgency) was ‘balanced’ by having five distributed UK institutions* as core stakeholders, each of which was an invaluable resource and partner.
*The five institutions: University of Oxford, The Francis Crick Institute, University of Birmingham, University of Dundee, Medicines Discovery Catapult.
Sowing seeds
In early 2019, the pool of academic researchers familiar with longevity science was extremely limited. Identifying researchers - in academia, biotech startups, or non profit research organizations - whose interests and research might align with the longevity hypothesis was essential to seeding the portfolio. Promising initial conversations evolved into collaborations on shaping research proposals to fit both the longevity research mandate and the researchers’ scientific interests.
Oxford’s Pro Vice Chancellor of Innovation, Chas Bountra, headed up the overarching project; Chas had done a long stint leading drug discovery efforts in industry, which contributed to our distributed institutional stakeholders mapping out a virtual drug discovery pipeline, from early stage discovery at Oxford and the Crick, to interventions development and testing at Dundee and MDC, to clinical trials at Birmingham. In any case, drug discovery was the focus, and all stages of the pipeline were fair game for the portfolio.
Tending the fields
The Bridge Portfolio that was thoughtfully and carefully nurtured into being emerged as an interesting mix - one that reflected the fascinating tension between geroscience folks who (mostly) don’t default to a disease-centric mindset and drug discovery folks who do.
As it happens, it’s a crucial distinction. To be brought to market, medicines require approval from a regulatory agency. That approval generally demands a demonstration of both safety and efficacy for human use. Efficacy is the tricky point here: Ideally, a disease’s known biomarkers or physiological symptoms are monitored over the course of a clinical trial. Should the final data indicate statistically significant improvements in relation to the trial endpoints, there’s a strong case for claiming that the trialled therapeutic is efficacious.
In the absence of a specific disease target, though, how does one construct a compelling case for efficacy? Longevity, per se, does not have the benefit of long-established, accepted biomarkers, and associated physiological changes tend to be slowly-varying (on the order of decades), not to mention nebulous. To circumvent this challenge altogether, the disease-centric camp arranges a clinical trial around a disease impacted by one or more of the biological pathways targeted by the longevity intervention. Success in terms of efficacy for that disease establishes a route to regulatory approval, which simultaneously opens the door to off label use as a broader-spectrum longevity intervention.
The other camp has extra work cut out for them up front in terms of redesigning the pathway to regulatory approval: biomarkers for ‘aging’ have yet to be established for regulatory purposes, and setting ’lifespan’ as a clinical trial endpoint doesn’t align with the fixed-timeline nature of clinical trials. A modified regulatory process is the goal, potentially leveraging nascent biomarkers of aging and/or physiological metrics for ‘healthy’ aging that align with clinical trial timelines. 2024.11 update: Nir Barzilai’s ARDD2024 talk is highly relevant.
Advisory Board members representing our drug-discovery-oriented stakeholders had the final say on funding decisions. Advocating for those decisions to stay true to the longevity hypothesis (vs defaulting to disease treatment objectives) required deft navigation to enable the Board to stretch their traditional drug discovery expertise to accommodate this new frontier. Those efforts offered fascinating insight into the significant challenges longevity interventions face in a broader context.
Harvest
The majority of Bridge projects continued beyond the tenure of the program via new sources of funding. Drug discovery is a long process and one to two years is generally too short a time frame for significant results, particularly at the exploratory stage. Generally, preliminary results were aligned with findings in the broader longevity research ecosystem, and directionally novel projects helped extend the research landscape.
One particularly notable Bridge Portfolio outcome was Dr. Ghada Alsaleh eventually extending her project to space! To examine the links between biological impacts astronauts experience during space missions and earth-based aging, Ghada established Oxford’s Space Innovation Lab. Space seems to provide an accelerated aging environment; if it does so in a way that aligns sufficiently with earth-based aging, the timeline for developing interventions could be reduced by conducting experiments in orbit. In November, 2024, her lab’s first samples were delivered to the International Space Station.
Bridge portfolio group meetings also generated new research collaborations. Those meetings were either free-form discussions, or anchored by invited speakers such as Richard Miller of the Glenn Center for Aging Research, who also leads one of the institutions participating in the Interventions Testing Program (ITP), funded by the National Institute on Aging. (The ITP sponsors a group of institutions to run mouse facilities at which interventional agents (e.g., drugs, neutraceuticals) are evaluated for their capacity to support successful aging.)
To highlight portfolio projects, I recorded overviews for release at the UK Spine 2020 annual conference. At a somewhat higher level, I detailed the motivation behind the portfolio in a post on the Oxford project website.
Bridge Portfolio projects are listed below. If you’d like more information about an individual project, or to follow up on progress, please reach out - I’ll be happy to connect you with the researcher.
Bridge Portfolio: Longevity drug discovery projects
Autophagy activation via TFEB
Targeting autophagy via TFEB activation - Ghada Alsaleh (Oxford)
Rapamycin: impact on muscle/sarcopenia in an older cohort
Impacts of mTOR inhibition on aged human muscle - Philip Atherton (Nottingham)
WRN reactivation
Identifying factors that restore DNA repair in aging cells via WRN reactivation - Lynne Cox (Oxford)
Protein misfolding: oligomers as biomarkers of aging
Visualizing protein misfolding in brain aging - Sonia Gandhi (Crick)
Biomarkers of healthy and multimorbid aging
Biological insights and biomarkers in healthy, multimorbid, and frail elders - Thomas Jackson (Birmingham)
Senolytics
Preclinical validation of novel candidate senolytics - Satomi Miwa (Newcastle) & Thomas von Zglinicki (Newcastle)
Monitoring mitochondrial function in response to interventions
Raman spectroscopy to determine mitochondrial function and mitochondrial drug accumulation in aging model systems - Karl Morten (Oxford)
Repositioning drugs safely for targeting aging
Drug repositioning and combination therapies for healthy aging - John Overington (Medicines Discovery Catapult - now at ExScientiaAI)
Hypoxia, aging, and treatment with oxygen nanobubbles
Oxygen nanobubbles for tissue hypoxia - Duncan Richards (Oxford)
Mitigating inflammaging
Identification of lipid mediators provided by autophagy that polarize anti-inflammatory macrophages - Katja Simon (Oxford)
Reactivating T cells to counter immune aging
Identification of novel epigenetic targets to reactivate exhausted and senescent T cells - Annette von Delft (Oxford)
