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
Context
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. 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 and knowledge 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
My primary responsibility was to seed and develop a ~$1.2M portfolio 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).
At the time, the pool of academic researchers familiar with longevity science was limited. Thus, my challenge was to identify researchers whose interests and current research might align with the longevity hypothesis, initiate a conversation to explore possibilities, and collaboratively shape a research proposal to fit both the longevity research mandate and the researchers’ scientific interests.
Oxford’s Pro Vice Chancellor of Innovation, Chas Bountra, was our PI; Chas had done a long stint leading drug discovery efforts in industry, which likely contributed to our distributed stakeholders mapping out a virtual drug discovery pipeline. And, so, drug discovery was our focus, though all stages of the pipeline were fair game.
Tending the fields
The Bridge Portfolio I 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. 2025.01 update: Nir Barzilai’s ARDD2024 talk is highly relevant.
In any case, the management group representing our drug-discovery-oriented stakeholders had the final say on funding decisions and, for my part, advocating for staying true to the geroscience hypothesis (vs defaulting to disease treatment objectives) was an education on the challenges geroscience and 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 discovery stage. Generally, preliminary results were aligned with findings in the broader longevity research ecosystem, and directionally novel projects helped extend the research landscape.
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.
For each portfolio project, I recorded a video overview; these were released at the UK Spine 2020 annual conference. At a somewhat higher level, I described 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
WRN reactivation
Identifying factors that restore DNA repair in aging cells via WRN reactivation
Autophagy activation via TFEB
Targeting autophagy via TFEB activation
Mitigating inflammaging
Identification of lipid mediators provided by autophagy that polarize anti-inflammatory macrophages
Monitoring mitochondrial function in response to interventions
Senolytics
Preclinical validation of novel candidate senolytics
Rapamycin: impact on muscle/sarcopenia in an older cohort
Impacts of mTOR inhibition on aged human muscle
Reactivating T cells to counter immune aging
Identification of novel epigenetic targets to reactivate exhausted and senescent T cells
Biomarkers of healthy and multimorbid aging
Biological insights and biomarkers in healthy, multimorbid, and frail elders
Protein misfolding: oligomers as biomarkers of aging
Visualizing protein misfolding in brain aging
Hypoxia, aging, and treatment with oxygen nanobubbles
Oxygen nanobubbles for tissue hypoxia
Repositioning drugs safely for targeting aging
Drug repositioning and combination therapies for healthy aging
