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Peter Attia MDPeter Attia MD

#112 – Ned David, Ph.D.: How cellular senescence influences aging, and what we can do about it

Sign up to receive Peter's email newsletter: https://bit.ly/4c602k2 Original release date: 6/1/20 Ned David is the co-founder of Unity Biotechnology, a company developing senolytic medicines—molecules that target and destroy senescent cells in the human body. In this episode, Ned explains the science of cellular senescence and how it impacts the aging process. Ned discusses how senolytics may delay, prevent, treat, or even reverse age-related diseases, including cancer, cardiovascular disease, and neurodegenerative disease. As a serial entrepreneur, Ned also provides advice on how to transform a simple idea into the creation of a company. We discuss: -Defining longevity and the principles of aging [2:50]; -The control knobs of aging and how we can turn them [15:10]; -Role of cellular senescence in aging and cancer [27:00]; -History of senescence in scientific study [40:30]; -The cellular senescence paradox [46:00]; -Developing medicines that target cellular senescence [52:15]; -Ned’s lessons on risk analysis in business [1:05:15]; -The search for a molecule that could eliminate senescent cells [1:15:15]; -Senescent cell elimination example in osteoarthritic knees [1:30:30]; -Extending lifespan by removing senescent cells [1:45:00]; -Senolytic molecule example in macular degeneration reversal [1:52:30]; -The future of senescent cell targeting [1:58:30]; -The role of cellular senescence and metabolic syndrome [2:01:30]; -The role of cellular senescence and brain health [2:03:30] -How building the company Kythera prepared Ned for his grander project of creating Unity Biotechnology [2:05:45]; -Advice for someone considering an entrepreneurial career path versus an academic career path [2:08:50]; and -More. Show notes page: https://peterattiamd.com/neddavid/ -------- About: The Peter Attia Drive is a weekly, ultra-deep-dive podcast focusing on maximizing health, longevity, critical thinking…and a few other things. With over 30 million episodes downloaded, it features topics including fasting, ketosis, Alzheimer’s disease, cancer, mental health, and much more. Peter is a physician focusing on the applied science of longevity. His practice deals extensively with nutritional interventions, exercise physiology, sleep physiology, emotional and mental health, and pharmacology to increase lifespan (delay the onset of chronic disease), while simultaneously improving healthspan (quality of life). Learn more: https://peterattiamd.com Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter Connect with Peter on: Facebook: http://bit.ly/PeterAttiaMDFB Twitter: http://bit.ly/PeterAttiaMDTW Instagram: http://bit.ly/PeterAttiaMDIG Subscribe to The Drive: Apple Podcast: http://bit.ly/TheDriveApplePodcasts Overcast: http://bit.ly/TheDriveOvercast Spotify: http://bit.ly/TheDriveSpotify Google Podcasts: http://bit.ly/TheDriveGoogle

Peter AttiahostNed Davidguest
Jul 8, 20202h 15mWatch on YouTube ↗

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At a glance

WHAT IT’S REALLY ABOUT

Cellular senescence as a druggable aging mechanism: science, strategy, early results

  1. Ned David frames longevity as reducing the “indignities” of aging—mobility loss, degenerative disease, and cognitive decline—by using biology to change how aging manifests in people.
  2. He lays out multiple aging “control knobs,” including mTOR/caloric restriction, circulating “young blood” effects, mitochondrial dysfunction, and epigenetic methylation changes, while stressing uncertainty about which are causes versus consequences.
  3. He explains cellular senescence as a stress response where cells permanently stop dividing and later harm tissues through a senescence-associated secretory phenotype (SASP), even when senescent cells are a small fraction of total cells.
  4. He describes mouse studies (including genetically engineered clearance of senescent cells) that show delayed or reduced features of aging and longer average lifespan when senescent cells are eliminated from midlife onward.
  5. He details Unity’s translational approach: identify drug-like senolytics, pick diseases with clear regulatory paths (not “aging” broadly), and test local delivery first, highlighting early osteoarthritis clinical findings and upcoming work in eye diseases.

IDEAS WORTH REMEMBERING

5 ideas

Aging is biologically malleable, not rigid.

He argues lifespan varies dramatically across similar organisms, implying aging can be altered rather than being a fixed, inevitable “decay-only” process. He frames this as evidence that biology contains tunable systems that set aging pace.

Single-gene changes proved “control knobs” exist—even if translation is imperfect.

He highlights early gene-perturbation work in worms (e.g., the DAF-2/DAF-16 pathway) as a proof that single genetic changes can strongly affect lifespan, while acknowledging the magnitude doesn’t translate as cleanly to mammals.

mTOR/caloric restriction is presented as the best cross-lab, cross-species validated longevity knob.

He describes caloric restriction and rapamycin as converging on the same “master decision-maker” biology (mTOR), calling it the most consistently validated longevity mechanism across species and labs.

A small number of senescent cells can drive large dysfunction via the SASP.

He defines senescent cells as stressed cells that permanently stop dividing and accumulate with age, usually at low abundance, but can have outsized tissue effects through the SASP—an inflammatory/pro-fibrotic secretome.

The goal isn’t to block senescence—it’s to clear senescent cells after they’ve formed.

He emphasizes that senescence itself is a critical anticancer “emergency brake,” citing data that animals unable to make senescent cells develop tumors early. Unity’s strategy is to leave the brake intact and remove already-senescent cells after they form.

WORDS WORTH SAVING

5 quotes

So my father, for example, he has profound degenerative disc disease, which makes him functionally immobile. It defines his life. My stepfather died of Alzheimer's at eighty-seven. That defined the final chapter of his life.

— Ned David

And the first principle is that aging's not a rigid thing, so it's this flexible, malleable thing.

— Ned David

The notion that you could essentially break the function of something or at least make it function a lot less well and double the lifespan of a creature was just a total mind warp for me and other people.

— Ned David

So we all begin life as a single cell at conception, and then over the arc of our lives, we, the single cell, will divide as many as 50 times. And on the road to 50 divisions, the cells that make us up will encounter some form of stress they cannot resolve. They will pull an emergency brake, and they will stop dividing forever.

— Ned David

If you can summon the discipline and the simplicity to distill the next, say, four to five years of your life down to, call it, two to four risks, 'cause any more than that and your life gets too complicated, and then you can build work plans that systematically remove each of those risks or do not remove them.

— Ned David

Defining longevity as freedom from age-related disabilityAging “control knobs” and cross-species lifespan variationmTOR, caloric restriction, and rapamycinYoung-blood parabiosis effectsMitochondrial dysfunction with ageEpigenetic methylation clocks and reprogramming (Yamanaka factors)Cellular senescence, SASP, and disease-specific targeting strategies

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