Could senolytics change the treatment landscape of age-related diseases?

Georgina: My first degree was in sports science, where I specialised in physiology. I then completed a PhD in skeletal muscle and cardiac regeneration, focusing on how the heart and skeletal muscle repair and regenerate themselves. That led me to research stem cells, exercise training, and the administration of growth factors to encourage muscle regeneration.

At one point, we were testing stem cell therapy in the heart, but the effects were modest. We realised that most of the patients we treated after a heart attack were older, and aging fundamentally changes how tissues respond and regenerate. That’s what led me to study the mechanisms and hallmarks of aging. My current research focuses on targeting those biological hallmarks to improve tissue regeneration in the heart and skeletal muscle.

Nicky: It’s been a while since I studied cell biology, and I’m sure many of our listeners might feel the same. Could you start by explaining what cellular senescence is and why it’s become such an important target in aging research?

Georgina: Cellular senescence is one of the biological hallmarks of aging. It’s a state where cells stop dividing but refuse to die, becoming highly pro-survival. Senescence can be triggered by various stresses or damage, and it actually has beneficial roles—preventing cancer and promoting wound healing by limiting the proliferation of damaged cells.

However, as we age, senescent cells accumulate because the immune system’s ability to clear them—known as immunosenescence—declines. These cells also secrete pro-inflammatory factors, creating a chronic inflammatory environment that can damage neighbouring cells. This buildup contributes to age-related diseases and, potentially, the aging process itself.

Nicky: I’ve heard it described as the paradox of senescence—protective in some ways but harmful in others. How do researchers approach targeting senescent cells while preserving their beneficial effects?

Georgina: That’s one of the biggest challenges. Senescence plays both beneficial and detrimental roles, and these depend on the tissue, organ, and disease stage. Therapies need to be context-dependent—designed to minimise harm while harnessing the protective aspects.

There are a few strategies. Senolytics are drugs that clear senescent cells and reduce their harmful effects. Another approach targets their secretome—known as the senescence-associated secretory phenotype, or SASP—which contains pro-inflammatory factors. By inhibiting specific harmful SASP components, we might preserve beneficial ones.

We also need to consider off-target effects and whether senolytics should be used in combination with other therapies, such as cancer treatments, to clear harmful senescent cells after therapy-induced senescence.

Nicky: So how do senolytic drugs actually work?

Georgina: Senescent cells resist programmed cell death, which is why they accumulate. Senolytics, first described by Dr. Jim Kirkland’s group in the US, target the pro-survival signalling pathways that keep these cells alive. By disabling those pathways, senolytics induce the senescent cells to die.

Nicky: Since aging is such a long-term process, how do you design clinical trials to measure the effects of senolytics?

Georgina: Most current trials don’t target aging itself but specific age-related diseases where senescent cells accumulate—such as idiopathic pulmonary fibrosis, chronic kidney disease, Alzheimer’s disease, and frailty.

Researchers measure biomarkers of healthspan—like cognition, tissue function, and inflammation—and use omics-based analyses and machine learning to assess biological age and treatment impact.

The first large coordinated effort came from Dr. Kirkland’s Translational Geroscience Network, which is conducting multicentre senolytic trials aiming to extend healthspan and delay age-related disease onset.

Nicky: And are these clinical trials underway now?

Georgina: Yes. The early preclinical studies were very promising, and several clinical trials are now in progress. Smaller phase 1 studies have shown that senolytics like dasatinib and quercetin can improve physical function and reduce senescent cell burden in skin and fat biopsies.

There have also been studies in Alzheimer’s disease showing these compounds are safe and well tolerated. However, not all trials have been successful—some senolytics haven’t shown benefits compared to placebo. So, the field is still learning which compounds are most effective.

Nicky: Do you think we’ll see more senolytic drugs being tested?

Georgina: Definitely. The next step is increasing specificity—understanding how senescent cells differ across tissues and targeting them selectively. Clearing all senescent cells isn’t ideal, especially in tissues like the heart or brain that have limited regenerative capacity.

We also need to understand the different “types” of senescent cells—their varying degrees of senescence and SASP profiles—so therapies can be refined for safety and precision.

Nicky: I came across the term “hit-and-run” strategy in relation to senolytics. Could you explain that?

Georgina: Yes, that’s the dosing approach. Senolytics are given intermittently, not continuously. Since senescent cells take time to build up, giving the drugs in short bursts eliminates many of them before they reach harmful levels, while reducing side effects from continuous exposure.

Nicky: That makes sense. Focusing on your specialty—cardiac repair and aging—what are some of the most exciting findings so far?

Georgina: We’ve shown that by age 70, around 50% of the heart’s resident stem and progenitor cells become senescent, reducing the heart’s ability to repair itself. Treating aged animals with senolytics like dasatinib and quercetin improves cardiac remodelling, reduces fibrosis, normalises muscle cell size, and restores heart function.

Senescent cells also contribute to cardiovascular diseases like atherosclerosis by promoting inflammation in blood vessels, so senolytics could have a big impact in this area.

Nicky: That’s really promising. What are the next steps in your research?

Georgina: We’re studying how senescent cells in the heart differ from those in other tissues, particularly their SASP profiles, and exploring ways to combine senolytics with regenerative therapies like cell therapy. The goal is to improve the heart’s microenvironment to make regeneration more effective.

Nicky: I also came across the term “senomorphics,” which target the SASP rather than the senescent cells themselves. Is that part of your research too?

Georgina: Yes. Senolytics and senomorphics are both types of “senotherapeutics.” Senomorphics don’t kill senescent cells; instead, they dampen the SASP to reduce inflammation. Drugs like metformin and rapamycin are examples. They act more broadly as anti-inflammatory agents rather than being senescent cell-specific.

Nicky: And in terms of safety—what do we know so far about senolytics?

Georgina: So far, results are encouraging. Many senolytics are repurposed drugs or naturally occurring compounds, which gives us safety data to build on. The intermittent dosing also reduces risk.

Early senolytics like navitoclax caused platelet toxicity, so they’ve largely been replaced by dasatinib and quercetin, which have shown good safety profiles in early trials. We’ll know more once larger phase 2 studies are complete.

Nicky: When might we expect results from some of those larger trials?

Georgina: Many are ongoing or still recruiting. Some results may emerge in the next couple of years. Progress can be slow, but the field is moving forward, and collaboration is growing globally. Translating strong preclinical data into humans is always challenging, but it’s an exciting time for research.

Nicky: Beyond senolytics, what other developments in longevity medicine excite you most?

Georgina: I’m intrigued by the role of senescence in cancer and whether targeting it could improve treatment. I’m also very focused on regenerative medicine—finding biologics that can enhance tissue repair.

But ultimately, lifestyle is still the best “anti-aging therapy.” Exercise, diet, social connection—all of these are powerful in maintaining health. As Jim Kirkland once said, senolytics are like “exercise in a pill,” but nothing beats actual exercise!

Nicky: I couldn’t agree more. I’m a keen runner myself, and it’s such an important message—sometimes the simplest interventions, like exercise and diet, have the biggest impact.

When researching this episode, I also came across studies on fasting and its effects on senescence. What’s the current understanding there?

Georgina: Caloric restriction has been shown to reduce senescent cell burden and improve healthspan in animals, but it’s hard to sustain in humans. Intermittent fasting can help, but long-term adherence is the challenge. Still, it’s an interesting and active area of research.

Nicky: One last question—CAR T-cell therapy has revolutionised cancer treatment. I’ve seen some research suggesting it might be combined with senolytics. What’s your view?

Georgina: Yes, it’s a very exciting area. Researchers are now developing CAR T-cells that can specifically target and eliminate senescent cells. Since the immune system naturally clears senescent cells, leveraging that mechanism makes sense. I’m actually involved in a project exploring this approach—it could become a highly selective senolytic strategy in the future.

Nicky: That sounds incredibly promising. There’s clearly so much to look forward to as this field evolves. Georgina, thank you so much for your time today.

Georgina: Thank you—it’s been a pleasure.

Nicky: And thank you to our listeners for joining us. I hope you enjoyed this episode as much as I did. Don’t forget to subscribe on Spotify, Apple Podcasts, or Podbean to catch our latest episodes. Goodbye for now.

Note: This transcript has been edited by AI to improve flow and clarity.>