AMPK, Sirtuins, NAD and Metformin

Most conversations about longevity focus on tactics. This episode breaks down the biology underneath them. You’ll hear a systems level analysis of how insulin signaling, mTOR, mitochondrial function, inflammation, and nutrient sensing interact to determine biological age, disease risk, and long term human performance. This is not surface level biohacking. It is a deep dive into the mechanisms that actually control aging, metabolism, muscle preservation, and brain optimization, and why most anti aging strategies fail when they ignore these foundations. 

This all-time classic episode from 2024, has host Dave Asprey joined by Mark Hyman, a practicing physician and one of the most respected leaders in functional medicine. Dr. Hyman is the founder and senior advisor of The UltraWellnessCenter, the founder and former head of strategy and innovation at the Cleveland Clinic Center for Functional Medicine, and a long time advocate for treating root causes instead of managing disease. With over 30 years of clinical experience, his work focuses on restoring mitochondrial health, optimizing metabolism, reversing chronic disease, and slowing biological aging using science backed interventions.  

Together, Dave and Mark dismantle common myths around protein, carnivore diets, ketosis, fasting, supplements, and longevity drugs. They explain why sugar accelerates aging faster than protein, how mTOR must cycle instead of staying suppressed, and why muscle, mitochondria, and metabolic flexibility matter more than calorie restriction. The conversation also covers nootropics, sleep optimization, neuroplasticity, AI driven diagnostics, and how functional medicine reframes aging as a reversible biological process rather than an inevitable decline.  

You’ll learn: 

• How insulin and nutrient sensing control aging speed 

• Why mitochondria sit at the center of longevity and disease 

• The truth about mTOR, fasting, and protein intake 

• How ketosis and metabolic flexibility protect long term health 

• Where supplements and nootropics actually fit in brain optimization 

• Why functional medicine outperforms symptom based care 

• How AI and advanced testing are reshaping modern medicine 

Thank you to our sponsors! 

- MASA Chips | Go to https://www.masachips.com/DAVEASPREY and use code DAVEASPREY for 25% off your first order.  

-ARMRA | Go to https://tryarmra.com/ and use the code DAVE to get 15% off your first order. 

-OneSkin | Try OneSkin for 15% off with code DAVE at https://www.oneskin.co/DAVE. 

Dave Asprey is a four-time New York Times bestselling author, founder of Bulletproof Coffee, and the father of biohacking. With over 1,000 interviews and 1 million monthly listeners, The Human Upgrade brings you the knowledge to take control of your biology, extend your longevity, and optimize every system in your body and mind. Each episode delivers cutting-edge insights in health, performance, neuroscience, supplements, nutrition, biohacking, emotional intelligence, and conscious living. 

New episodes are released every Tuesday, Thursday, Friday, and Sunday (BONUS). Dave asks the questions no one else will and gives you real tools to become stronger, smarter, and more resilient. 

Keywords: longevity biohacking, functional medicine longevity, biological age reversal, mitochondria and aging, mTOR pathway aging, insulin resistance and aging, metabolic flexibility, fasting and longevity, ketosis and metabolism, protein intake and mTOR, muscle and longevity, inflammaging, chronic inflammation aging, mitochondrial dysfunction, nutrient sensing pathways, rapamycin longevity, metformin longevity debate, carnivore diet longevity, sugar and aging, brain optimization longevity, neuroplasticity and aging, sleep optimization biohacking, supplements for longevity, anti aging metabolism, human performance optimization, Dave Asprey longevity, Mark Hyman longevity 

Resources:   

• Mark’s Website: https://drhyman.com/ 

• Dave Asprey's Latest News | Go to https://daveasprey.com/ to join Inside Track today.  

• Danger Coffee: https://dangercoffee.com/discount/dave15   

• My Daily Supplements: SuppGrade Labs (15% Off)   

• Favorite Blue Light Blocking Glasses: TrueDark (15% Off)   

• Dave Asprey’s BEYOND Conference: https://beyondconference.com   

• Dave Asprey’s New Book – Heavily Meditated: https://daveasprey.com/heavily-meditated  

• Upgrade Collective: https://www.ourupgradecollective.com   

• Upgrade Labs: https://upgradelabs.com   

• 40 Years of Zen: https://40yearsofzen.com  

Timestamps: 

0:00 - Trailer 

0:45 - Introduction 

4:49 - Aging as a Treatable Disease 

7:50 - The Hallmarks of Aging 

14:23 - Nutrient Sensing and Longevity Switches 

17:37 - Time Restricted Eating and Autophagy 

20:44 - The Four Longevity Pathways 

21:49 - Metformin Debate 

25:30 - Ozempic and Weight Loss 

28:42 - Rapamycin and mTOR 

36:23 - Meat, Protein, and Aging 

39:46 - Protein Quality and Muscle Synthesis 

45:50 - Protein Timing for Muscle Building 

48:08 - Metabolic Flexibility 

51:32 - Inflammaging 

55:26 - Zombie Cells and Senescence 

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