Beyond Longevity

Why do joints fail as we age, and why, after decades of research, is there still no drug that reliably stops osteoarthritis from progressing? Daphna Stern speaks with Maria Kyriazi, a DPhil researcher at the University of Oxford studying ageing and osteoarthritis. Still in her twenties, Maria gives us a view of science that we do not often hear. She talks openly about experiments that fail after months of work, almost having to give up her Oxford DPhil because she could not fund it, and the pressures young scientists face to produce and publish exciting results. They also discuss why osteoarthritis is far more complicated than the old idea of “wear and tear”, what ageing changes inside our joints, why promising research has repeatedly failed to become effective treatments, and whether we might eventually be able to treat the disease itself rather than simply manage the pain. About the guest Maria Kyriazi is a DPhil student in Molecular and Cellular Medicine at the University of Oxford, where she researches the age-related mechanisms involved in osteoarthritis. Originally from Athens, she came to the UK to study Biomedical Genetics at Newcastle University before completing an MRes in Ageing and Health and moving into doctoral research at Oxford. In October 2026, Maria received the Korenchevsky Prize for her research into ageing and osteoarthritis at the British Society for Research on Ageing annual scientific meeting. She previously won the Young Star Award at the Greek International Women Awards. She is a Mellon Longevity Graduate Scholar at Oriel College and an Onassis Foundation Scholar. Her research examines how ageing processes, including autophagy and cellular senescence, change within the joint and may contribute to the development of osteoarthritis. Maria Kyriazi — Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences Alsaleh Group | Ageing in the musculoskeletal system and beyond earth — Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences 00:00 Why study ageing and osteoarthritis? 01:38 How did Maria get from Athens to Oxford? 06:32 Why study ageing itself? 09:59 What actually happens in osteoarthritis? 14:00 Is osteoarthritis caused by ageing or injury? 17:06 What happens when cellular recycling starts to fail? 19:40 Why have osteoarthritis treatments repeatedly failed? 22:12 What does scientific failure really look like? 30:32 Why is it so difficult to fund a scientific career? 39:30 Does funding pressure encourage scientists to oversell results? 41:57 How do young scientists protect research integrity? 44:52 Could we eventually treat osteoarthritis itself? 49:02 Rapid-fire questions 51:43 Closing reflections

xercise in a Pill? How Muscle Could Protect Memory, with Professor Constanza J Cortes Episode Summary Could your body get some of the benefits of a workout without you doing the exercise? And could a drug like that help prevent memory loss or treat Alzheimer’s? Host Daphna Stern speaks with Professor Constanza J Cortes, a neuroscientist at the University of Southern California, about how exercise could help preserve memory as we age. Professor Cortes’ goal is to develop treatments for people who cannot exercise enough because of pain, illness or limited mobility. Her research starts with muscle. During exercise, muscles release chemical messengers that travel around the body, including to the brain. Professor Cortes is testing whether a drug, sometimes described as an exercise mimetic, could reproduce some of those signals without the need to exercise. Her team has already improved memory and other brain outcomes in mouse models of Alzheimer’s by changing what happens in their muscles. But her latest research also raises an important question: does a brain affected by Alzheimer’s still respond to exercise in the same way as a healthy brain? In mouse studies, exercise triggered some of the expected molecular changes but did not lead to the same improvements in memory or broader protection of the brain. We discuss how much of exercise a drug could realistically reproduce, whether healthy people could benefit, what still needs testing in humans, differences between how male and female muscle responds to exercise, and her ambition to have a treatment in the clinic within 10 years. About the Guest Professor Constanza J Cortes is an Assistant Professor of Gerontology at the University of Southern California and leads the Cortes Lab at the USC Leonard Davis School of Gerontology. Her research focuses on exercise, brain ageing, Alzheimer’s disease and the signals that pass between skeletal muscle and the brain. She is principal investigator of a National Institute on Aging-funded research programme investigating exercise-associated signalling against brain ageing and Alzheimer’s disease. Her work also examines sex differences in how the body responds to exercise. In 2026, she received the Women in AGE Scientific Achievement Award in recognition of her contributions to ageing research. Research Mentioned in This Episode Skeletal muscle TFEB signalling promotes central nervous system function and reduces neuroinflammation during ageing and neurodegenerative disease Cell Reports, 2023 Research showing how activating TFEB in skeletal muscle can reproduce some effects associated with exercise and influence the ageing brain. https://pubmed.ncbi.nlm.nih.gov/37952157/ Activation of the muscle-to-brain axis ameliorates neurocognitive deficits in an Alzheimer’s disease mouse model via enhancing neurotrophic and synaptic signalling 2024 Research identifying prosaposin (PSAP) as part of the muscle-to-brain signalling pathway and examining PS18 as a potential way to reproduce some of its effects. https://pubmed.ncbi.nlm.nih.gov/39269584/ Long-term voluntary exercise reveals limited translation of hippocampal molecular responses into neuroprotection in 5xFAD mice bioRxiv preprint, 2026 Research examining why an Alzheimer’s disease brain may respond differently to prolonged exercise, despite showing some molecular signs of an exercise response. https://pubmed.ncbi.nlm.nih.gov/42817989/ Single-nuclei RNA-sequencing uncovers sexually divergent exercise signatures partially mimicked by TFEB overexpression in mouse skeletal muscle bioRxiv preprint, 2026 Research showing substantial differences between male and female skeletal muscle responses to exercise and TFEB activation. https://pubmed.ncbi.nlm.nih.gov/41659513/ Further Reading National Geographic: Why exercise can help keep the brain healthy https://www.nationalgeographic.com/magazine/article/new-clues-are-revealing-why-exercise-can-keep-the-brain-healthy USC Leonard Davis School of Gerontology: Professor Cortes on understanding the effects of exercise on the brain https://gero.usc.edu/2023/04/13/assistant-professor-constanza-cortes-understanding-the-effects-of-exercise-on-the-brain USC: Constanza Cortes receives the 2026 Women in AGE Scientific Achievement Award https://gero.usc.edu/2026/10/01/constanza-cortes-phd-receives-women-in-age-scientific-achievement-award The Cortes Lab at USC https://gero.usc.edu/labs/corteslab Timestamps * 00:00 Introduction and episode overview * 01:37 Welcome and Professor Cortes’s background * 02:30 Why the ageing brain became her focus * 03:58 Does exercise work differently in the ageing brain? * 05:39 How does muscle communicate with the brain? * 07:22 What do muscles tell the brain when you run? * 09:35 Can muscle signals released during exercise improve memory? * 11:28 Could PS18 mimic exercise’s effects on the brain? * 12:25 The ongoing study in ageing mice * 14:25 What is PSAP, and what does it normally do in the body? * 16:03 Does the PSAP in blood really come from muscle? * 17:56 What changes inside muscle when we exercise? * 20:22 Which benefit of exercise would she most want to turn into a treatment? * 22:04 Could an exercise mimetic prevent Alzheimer’s or treat it? * 23:19 Could a healthy person benefit? * 25:05 Can changing muscle protect the brain in Alzheimer’s? * 27:21 Why running did not rescue memory in Alzheimer’s mice * 29:07 Can the diseased brain still hear the signal? * 30:01 Do fewer Alzheimer’s plaques necessarily mean better memory? * 31:29 What can people with Alzheimer’s do today? * 32:36 What needs proving before human studies * 33:47 How much does AI help her research? * 37:32 What the first human study needs to show * 39:19 When the biomarkers improve but the person does not feel better * 43:10 When could an exercise pill reach the market? * 44:22 What “exercise in a pill” really means * 46:23 Concerns about off-label use * 48:08 The unanswered question: sex differences in exercise * 50:20 Where will the research be in 10 years? * 51:58 Rapid-fire questions * 53:16 Closing thoughts

Everyone talks about living longer. Far fewer people ask what happens if we reach those extra decades without purpose, identity, relevance or a clear idea of what we actually want to do with them. In this episode of Beyond Longevity, I speak with Paul Long, a third-generation storyteller, former major-market television reporter, anchor and special projects producer, and Emmy-winning content creator. He went on to run his own production company before making a major pivot in his own life. Paul now runs New Way Forward, a platform helping people rethink the second half of life, not just financially, but around purpose, health, relevance, contribution and continued income. His starting point is simple: the traditional path of work, retirement and gradual withdrawal no longer makes much sense if people may have decades of active life ahead of them. We discuss why retirement can leave people struggling once the initial honeymoon period wears off, why losing identity and relevance may matter as much as losing income, and why financial planning alone does not prepare people for what comes next. We also look at who tends to reach this point, whether reinvention is realistic when someone is already in survival mode, and what society needs to change as people live longer. Paul shares practical tools he uses himself, including an adapted Wheel of Life exercise and writing a letter from your 95-year-old self. And rather than advocating one dramatic leap, he explains why small, repeated actions may be a much more realistic way to build a different life. About the guest Paul Long began his career in television news, working as a major-market reporter, anchor and special projects producer. He later became an Emmy-winning content creator, receiving an Emmy for Best Documentary for A Passing of the Torch, and founded his own production company, producing work for major companies. Around 2006, Paul began seriously questioning what he wanted the next stage of his own life to look like. That process eventually led to New Way Forward, where he now shares the ideas, tools and lessons he has gathered on purpose, health, income and reinvention in the second half of life. New Way Forward is still in launch mode, with content across YouTube, LinkedIn, Substack and its own website. Site: www.NewWayFWD.com YouTube: https://www.youtube.com/@newwayfwd/videos LinkedIn: https://www.linkedin.com/in/paul-long-nwf/ Substack: https://newwayfwd.substack.com/ Chapters 00:00 Who Is Paul Long? 01:42 What Is New Way Forward? 03:11 Why Does Awareness Come Before Answers? 07:15 Who Starts Looking for a New Direction? 11:42 What Can the Wheel of Life Tell You? 15:02 How Do You Find the Common Thread in Your Life? 17:47 What Forces Us to Reinvent Our Lives? 22:11 The Different Versions of Paul Long 24:09 Why Can Retirement Leave People Unhappy? 29:08 Why Does Relevance Matter as We Age? 30:29 Why Does Pleasure Fade So Quickly? 30:40 What Creates Lasting Satisfaction? 32:23 Who Is New Way Forward Designed For? 36:39 Which Tools Help People Reinvent Their Lives? 38:48 Can Small Steps Really Change Your Life? 40:56 What If You Are Just Trying to Survive? 44:29 Can Society Adapt to Longer Lives? 47:52 How Do Identity, Meaning and Regret Change With Age? 52:33 How Can People Use New Way Forward? 54:44 How Do You Move Past Fear and Start? 57:10 Rapid-Fire Longevity Questions 01:01:09 What Makes a Good Second Half of Life?

Why do we lose muscle as we age, and how much can we rebuild, even in our seventies? For Dr Oskar Wenbar, the interest began after a stroke left his father bedridden. Watching his father’s physical condition deteriorate and his confidence disappear drew him into research on ageing muscle. In this episode, we look at what changes inside our muscles as we age, why it matters far beyond strength, and how much can be regained. We then move into more contested territory: testosterone replacement therapy and hormone optimisation, the muscle people may lose on GLP-1 weight-loss drugs, peptides, NMN, and whether biological-age tests tell us anything useful. Where is there good evidence to act, and where are we getting ahead of it? About the guest Dr Oskar Wenbar is a UK-based pharmacist and researcher whose PhD work at the University of East Anglia focused on skeletal muscle ageing. Born in Poland and raised in Chicago, he studied pharmacy in England and worked as a hospital pharmacist before moving into research. He is a co-founder of Evaro, a digital healthcare company that has served more than two million patients across the UK through online consultations and prescription treatments. Links and resources Evaro Evaro bios Dr Oskar Wenbar on LinkedIn Tasso 00:00 Welcome and Guest Intro 01:45 Oscar’s Journey to Longevity 05:42 Inside Ageing Muscle 08:49 Satellite Cells Explained 11:39 Why Muscle Loss Matters 15:33 Can You Rebuild Muscle 16:30 Training and Protein Uptake 19:47 Fast Twitch Fibres and Falls 20:54 DHT Testosterone and Muscle 23:08 From Mice to Human Evidence 24:43 Testosterone Decline Basics 27:06 Deficiency vs Optimization Debate 29:41 Stigma and Safety Evidence 31:02 UK vs US Testosterone Culture 33:54 Muscle Response and GLP-1 Risks 36:05 Peptides Hype Explained 38:12 NMN and NAD Boosters 39:36 Biological Age and Blood Testing 40:48 Needle-Free Blood Draw Devices 43:34 Longevity Basics and Essential Labs 45:51 Rapid Fire and Final Takeaways

65 billion dollars. That is roughly what Nebius was worth on the stock market when we recorded this episode. Yet most people have never heard of it. So what does the company actually do, and why are scientists using its computing power to search for new treatments? Dr Ilya Burkov, Global Head of Scientific AI and Healthcare at Nebius, joins Beyond Longevity to explain how AI is being used in research and what happens behind the scenes when a biotech company needs far more computing power than it has in its own lab. Ilya has a PhD in medicine and worked in medical research before moving into technology at Amazon Web Services. He joined Nebius in 2024. We talk about the difference between asking ChatGPT a question and using AI to investigate a potential drug. Ilya explains why access to computing power matters, what Nebius provides to research teams and large companies, and why a calculation that takes two days on a lab’s own equipment could take just 23 minutes with more powerful computing. We also discuss AlphaFold, the protection of research data and intellectual property, and the limits of AI in drug discovery. If AI points scientists towards a promising molecule but cannot explain why it chose it, has it made a discovery? And could the same tools help us understand something as complicated as ageing? Nebius Cloud for Scientific AI and Healthcare: https://nebius.com/solutions/life-sciences-and-healthcare Dr Ilya Burkov on LinkedIn: https://www.linkedin.com/in/ilyaburkov/ 00:00 Can AI Discover Without Understanding? 00:55 Meet Dr Ilya Burkov 02:08 Can AI Speed Up Scientific Research? 03:47 Why Did Dr Ilya Move from the Lab into Technology? 06:06 How Is Scientific AI Different from ChatGPT? 08:55 What Does AI Drug Discovery Actually Mean? 11:36 Why Do Biotech Investors Ask About Computing Power? 13:04 What Does Nebius Actually Do? 16:36 Does Nebius Provide the Kitchen or Help with the Cooking? 18:02 Why Does Biotech Need a Specialist AI Cloud? 20:48 How Are Researchers Using Nebius in Practice? 32:25 How Are Data and IP Protected in the Cloud? 33:47 What Did AlphaFold Change About Protein Folding? 37:43 Does AI Understand What It Discovers? 39:30 Is Ageing Perfect for AI or a Complete Nightmare? 44:35 How Do Europe, the US and Asia Regulate AI? 47:57 Why Are Companies Reserving Computing Power Early? 49:59 Rapid-Fire Questions 52:52 Closing Takeaways