Fight Aging!

Here find an interview with the founder of Rubedo, a senolytic drug discovery company, also one of the co-founders of Turn Bio, one of the first cellular reprogramming companies. Of note, Rubedo recently released more information on their lead program. The senolytic space is expanding considerably in terms of potential target mechanisms. It begins to resemble the cancer research community, which pioneered development of many of the early senolytic drugs, and indeed one might expect this to continue. The two fields share a similar goal, meaning the selective destruction of specific cells that exhibit complex, incompletely mapped characteristics, where those characteristics likely differ in important ways by tissue type, and will naturally tend to proceed along analogous paths to one another.

We just announced our target: it's GPX4. Our compound RLS1496 is a proprietary GPX4 modulator. We developed a molecule that can modulate GPX4 and target vulnerabilities in senescent cells while sparing healthy cells, and its effects extend beyond skin. GPX4 is central to ferroptosis, a distinct form of cell death different from apoptosis or necroptosis. Though this pathway was only discovered about ten years ago, it's generating a lot of interest.

This target has been studied mostly in the context of oncology so far. Now, people are looking at cardiovascular conditions, inflammation, and fibrosis. Our own next step will be systemic applications targeting inflammation and metabolic disorders. We also have other programs with different targets - for instance, our lung interstitial disease program, supported by the California Institute for Regenerative Medicine (CIRM), targets lung stem cells that become senescent. These cells trigger a cascade leading to fibrosis as in idiopathic pulmonary fibrosis, and tissue degeneration leading to COPD or pulmonary hypertension. We'll start with lung fibrosis before expanding to other indications.

In oncology, ferroptosis has been explored as a therapeutic opportunity studying aggressive cancer cells that resist traditional treatments. Researchers are trying to use synthetic lethality approaches to sensitize treatment-resistant cancer cells to ferroptosis, with GPX4 as a target. This presents challenges because cancer cells proliferate rapidly, develop resistance, and require carefully engineered synthetic lethality. What we discovered is that certain senescent cells are naturally vulnerable to ferroptosis. But senescent cells have an advantage over cancer cells - they don't divide or grow. This means we can use more flexible dosing schedules and don't need to eliminate every single cell immediately. We can gradually reduce their population over time.

We've found that by modulating GPX4 in specific ways, we can trigger ferroptosis in senescent cells while sparing healthy cells, giving us a therapeutic window. Our compound, RLS1496, is a potent GPX4 modulator that can achieve this effect at single-digit nanomolar concentrations. Studies have shown that reducing GPX4 levels throughout life in mice (not completely removing it, which is lethal at birth) increases lifespan by 7-10%, and these mice develop fewer tumors and are generally healthier. While this suggests a broader role in longevity, we're currently focusing on targeting specific pathological senescent cell populations.

Link: https://www.lifespan.io/news/marco-quarta-on-cellular-senescence-in-aging/