In this episode of The Human Upgrade, Host Dave Asprey sits down with MIT PhD and pioneering longevity scientist Dr. Leonard Guarente to uncover the molecule that controls how fast you age. With over 40 years of research and 250 published studies, Dr. Guarente explains how NAD+, sirtuins, and DNA methylation clocks can accurately measure and slow biological aging. You’ll learn how to boost mitochondrial function, improve neuroplasticity, and extend healthspan using targeted supplements, nutrition strategies, and biohacking tools. The conversation covers the science of epigenetic reprogramming, homocysteine reduction, and oxidative stress repair, plus actionable takeaways on fasting, ketosis, cold therapy, and sleep optimization. Whether you want to increase resilience, upgrade brain performance, or tap into functional medicine breakthroughs, this episode gives you a masterclass in smarter not harder longevity hacking.
Learn how to slow, and even reverse, your biological age with cutting-edge science on the molecule that controls your longevity. Host Dave Asprey sits down with Dr. Leonard Guarente, an MIT PhD and one of the most respected longevity researchers in the world, to reveal how NAD+, sirtuins, and DNA methylation clocks can help you hack aging, upgrade your mitochondria, and extend your healthspan. This episode gives you the real science, proven by over 250 studies, behind supplements, nutrition, and biohacking tools that actually work for brain optimization, metabolism, and human performance.
You’ll learn why NAD+ is a master regulator of mitochondrial health, how DNA methylation clocks accurately measure biological age, and why boosting sirtuin activity improves resilience, neuroplasticity, and recovery. Dr. Guarente shares insider strategies from decades of functional medicine research, including nootropics, targeted supplements, fasting protocols, and diet adjustments from carnivore to Mediterranean that can shift your metabolism toward longevity. Dave and Dr. Guarente explore advanced biohacks like cold therapy, sleep optimization, and ketosis, plus how to balance these interventions with your genetics, lifestyle, and health goals. You’ll also hear about the surprising role of homocysteine in brain aging, how to use lab testing to guide your longevity plan, and why resilience is the ultimate measure of health.
You’ll learn:
Whether you want to sharpen your brain, protect your heart, or upgrade your energy systems, this is a masterclass in smarter not harder biohacking for a longer, higher-performing life.
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?is the top podcast for people who want to take control of their biology, extend their longevity, and optimize every system in the body and mind. Each episode features cutting-edge insights in health, performance, neuroscience, supplements, nutrition, hacking, emotional intelligence, and conscious living.
Episodes are released every Tuesday, Thursday, and Friday (audio-only) where Dave asks the questions no one else dares, and brings you real tools to become more resilient, aware, and high performing.
Keywords: NAD+ supplementation, Sirtuin activation, DNA methylation clocks, Biological age testing, Mitochondrial biogenesis, Epigenetic reprogramming, Pterostilbene benefits, Nicotinamide riboside (NR), Nicotinamide mononucleotide (NMN), Homocysteine reduction, Oxidative stress repair, Superoxide dismutase (SOD) activation, Functional medicine longevity, Healthspan optimization, Resveratrol bioavailability, Menopause mitochondrial support, Phenylbutyrate and protein folding, High-fat diet longevity studies, Neurodegenerative disease biohacking, INCHIANTI aging study
Thank you to our sponsors!
0:00 — Trailer
Dave sets the stage with the science of longevity molecules and why they matter.
0:59 — Intro
Dr. Leonard Guarente shares how his research at MIT shaped the field of aging biology.
7:04 — Animal vs Human Aging Studies
The surprising differences between lab animals and humans when studying lifespan.
10:07 — Discovery of Sirtuins
How the SIR2 gene was uncovered and why sirtuins became a breakthrough in aging science.
14:43 — NAD’s Role in Aging
Exploring how NAD fuels mitochondria, supports DNA repair, and influences aging speed.
15:34 — Resveratrol vs Pterostilbene
A comparison of two popular supplements and what the science really shows.
23:13 — Timing NAD Supplementation
When and how to take NAD for the best cellular and metabolic benefits.
36:34 — Diet & Lifestyle Factors
Why fasting, ketosis, and diet customization change how your body ages.
50:05 — Elysium’s Basis & Signal
Breaking down the flagship NAD products designed to support longevity.
1:00:03 — Future Clinical Trials
What’s next in human trials for NAD, sirtuins, and advanced longevity research.
1:05:14 — Psychology of Aging & Wrap-Up
The mental and emotional factors that influence healthspan and resilience.
Resources:
“Follow” or “subscribe” to The Human Upgrade™ with Dave Asprey on your favorite podcast platform.
Go to Apple Podcasts at daveasprey.com/apple and leave a (hopefully) 5-star rating and a creative review.
Got a comment, idea or question for the podcast? Submit via this form!
Follow @thehumanupgradepodcast on Instagram and Facebook.
Learn directly from Dave Asprey alongside others in a membership group: ourupgradecollective.com.

Smarter Not Harder: The Biohacker’s Guide to Getting the Body and Mind You Want is about helping you to become the best version of yourself by embracing laziness while increasing your energy and optimizing your biology.
Subscribe to become an “Insider”, and receive weekly biohacking tips and tech directly from Dave to start hacking your way to stronger mental performance and physical results.
Receive weekly biohacking tips and tech by becoming a Dave Asprey insider.