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#610: The Life-Extension Episode – Dr. Matt Kaeberlein On The Dog Aging Project, Rapamycin, Metformin, Spermidine, NAD+ Precursors, Urolithin A, Acarbose, And Much More | Tim Ferriss Show

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Key Takeaways

  • “Most of the major causes of death and disability and functional decline we experience are due to the biology of aging… that’s because of the underlying biology that creates a change in our physiology.” –Dr. Matt Kaeberlein
  • Rapamycin and caloric restriction is the most potent healthspan interventions we have now to push declines and disease functions
  • There is a question as to whether injected NAD translates into an actual boost in bioavailable NAD in cells and tissues – the body of evidence on NAD and NMN is weak
  • Resveratrol is very controversial but seems like the consensus is now that it has no effect as a therapeutic target
  • “[Resistance exercise] is the one thing I think everyone should do to give themselves a chance to be healthy as long as possible.” – Dr. Matt Kaeberlein
  • There is a risk of doing nothing to maintain our health as we get older
  • We need to separate the signal from the noise in science – there’s a lot of science out now that ignores the data that doesn’t fit the model (for sound researchers, follow people like Brian Kennedy, Anne Brunet at Standford, Yousin Shuh)


Dr. Matt Kaeberlein (@mkaeberlein) is a professor of Laboratory Medicine and Pathology at the University of Washington School of Medicine, with adjunct appointments in Genome Sciences and Oral Health Sciences. Dr. Kaeberlein’s research interests are focused on understanding biological mechanisms of aging in order to facilitate translational interventions that promote healthspan and improve the quality of life for people and companion animals. Among his many accomplishments, Dr. Kaeberlein is the founding director of the University of Washington Healthy Aging and Longevity Research Institute and the founder of Dog Aging Project.

In this episode, Tim Ferriss and Dr. Matt Kaeberlein discuss the science and progress of longevity research, covering wide-ranging topics from rapamycin, metformin, spermidine, and much more.

Host: Tim Ferriss (@tferriss)

Dog Aging Project

  • Ongoing longevity study on dogs exploring the most important environmental and genetic factors that influence biological aging in dogs (assuming the same happens in people)
  • The largest longitudinal study of any animal study on aging
  • Two study arms: control + intervention using rapamycin
  • Hypothesis: if rapamycin restores and preserves organ function in mice, will it do the same in dogs which live much longer
  • Dream testing if money wasn’t an issue: nutritional interventions, testing anything that was beneficial in mice (such as acarbose, metformin, spermidine, NAD precursors, alpha-ketoglutarate)
  • In pets: differences in disease diagnoses in pets on time-restricted eating versus dogs fed more than once per day – but it was a cross-sectional, observational study so we can’t infer causality

Aging Biology, Healthspan, Lifespan

  • Aging biology: physiological changes that occur as animals and organisms age
  • Components of aging: molecular, functional, behavioral – all driven by the biology of aging
  • Healthspan: a period of life spent in good health
  • Healthspan is usually different than lifespan, taking into consideration functional health versus the number of years alive
  • Interestingly, more drugs tend to favor extending lifespan in males versus females in mice studies
  • Geroscience: the area of research that ties together the biology of aging with age-related diseases

Rapamycin, Inflammation, Immune System

  • Apoptosis is cell death in response to damage (this is good) versus senescent cells are damaged cells that won’t die but stop dividing and give off signals that trigger cytokines and inflammatory processes
  • We accumulate more and more senescent cells as we age which is likely the reason we have chronic inflammation with aging
  • Sterile inflammation: as we age, our immune system is responding inappropriately to things it shouldn’t be responding to
  • A chronic inflammatory state in tissues repairs the ability of the immune system to do what it needs to do
  • Rapamycin is particularly good at reducing age-related sterile inflammation (inflammation not caused by infection)
  • Studies have shown an enhanced immune system response after taking 6 weeks of rapamycin
  • Rapamycin doesn’t kill senescent cells but does stop the inflammatory response & seems to reboot the immune system, maybe by killing off senescent cells
  • Rapamycin was first approved by FDA in the 90s to prevent organ transplant rejection
  • Rapamycin inhibits mTor (a protein that promotes muscle growth via protein synthesis)
  • Pros of 4-12 weeks of rapamycin cycle based on animal studies: (1) has been shown to make organ function better; (2) reversal of functional declines in the immune system; (3) aged heart functions better; (4) reversal of periodontal disease; (5) rejuvenating ovarian function; (6) enhancing immune response to vaccinations
  • In mice, rapamycin expresses most of its benefit when started in middle age through the end of life (about 12 weeks)
  • Cons: (1) risk of side effects may go up the longer you take it; (2) we don’t know quantitative estimates of risk-reward; (3) we don’t have precise dosing; (4) human studies still need to be done; (5) potential muscle loss concerns since mTor is inhibited (unlikely based on studies which show muscles actually function better)

Life-Extension Exploratory Drugs

  • Acarbose: close to rapamycin in terms of the magnitude of effect, but outcomes are better in males than females
  • Spermidine: found in food; seems to enhance autophagy (clears damaged cells)
  • Urolithin A: autophagy booster; seems to boost mitochondrial autophagy specifically which restores mitochondrial function by breaking down damaged mitochondria and making new mitochondria
  • Studies have shown muscle improvement function in older adults taking Urolithin A but much more research needs to be done
  • 17-alpha estradiol: mechanism unknown at this point but seems to work in males and may have cardioprotective effects
  • Depranil: shown to extend life span in dogs but hasn’t been studied for some reason and research appears stalled
  • NAD stands for nicotinamide (vitamin B3) adenine (sugar) dinucleotide (phosphate)
  • NAD is critical to our body – without it, we can’t make energy and would be dead in less than a minute
  • NAD levels naturally decline with age – there’s a potentially metabolic upside to being able to take and replace NAD
  • Metformin: in mice, it doesn’t actually increase lifespan – in people, the data is supportive if you’re diabetic or metabolically compromised but most relatively healthy and active people don’t need it

The Complexity Of NAD & NAD Boosters

  • NAD is administered via infusion or injected into the butt
  • There is a question as to whether NAD injected translates into an actual boost in bioavailable NAD in cells and tissues
  • It’s unclear how stable NAD precursors are – the most common two: (1) nicatinamide riboside (NR) and (2) Nicotinamide Mononucleotide (NMN)
  • NR is the most well-known and well-studied NAD booster and is a compound of the nicotinamide +sugar without the phosphate
  • It’s possible some of the irreplicable findings in NAD booster studies can be attributed to missing study details such as temperature control, method of addition to feeding
  • The body of evidence is weak on both NAD and NMN


  • Sirtuins are a family of proteins named after a yeast protein
  • Sirtuins are NAD-dependent acetylases
  • Sirtuins consume NAD so you lose NAD when sirtuins are active – and they require NAD so as NAD goes down with aging, sirtuins do as well
  • Sirtuins play an important role in biology, but they’re unlikely to have the effects on longevity that we want – there’s really no evidence to support it as a therapeutic target at this point
  • Resveratrol is a natural product (polyphenol) found in the skin of grapes used for wine
  • Resveratrol binds to many things and has a whole host of effects and may have some benefits but it doesn’t robustly affect the biology of aging
  • David Sinclair was successful at marketing the story which really put resveratrol on the map – in part by suggesting that resveratrol activates sirtuins in combination with caloric restriction
  • Resveratrol is very controversial but it seems like the consensus is now no effect – once you believe something is true, it’s hard to rewind

What’s Holding Back Longevity Research?

  • A Saudi organization called Hevolution is dedicating $1 billion per year into longevity and lifespan research – roughly 2/3 will go to grants, and approximately 1/3 will go into private sector investment
  • Low funding: cancer research gets $6 billion per year from NIH alone – longevity research & biology of aging gets $350 million per year
    • Worth noting: when cancer research funding started, cancer was the 2nd leading cause of death – it still is today
    • Without cancer, the average life expectancy would only increase 3 years because we’re not really moving the needle on other declines in organ function that go with aging
  • The research has only matured in the last 20 years and warranted more research
  • The promise of improving healthspan is much greater than approaching each disease on its own
  • There’s a small pool of people in the aging research field so recruitment in the field also needs to be part of the expansion effort
  • Improvements that could be made: (1) marketing (of biology, not just hype) to public and policy-makers; (2) clinical trials are currently lacking because there is no clear path to profit and FDA approval – we also need a modified disease approach where there is a cluster instead of single outcome; (3) need to explore age-related indications with a shorter timeframe; (4) study periodontal disease as disease-endpoint for clinical use of rapamycin; (5)

“Falling For The Hype”

  • You need to separate signal from noise and clean from sloppy science
  • Check out Peter Attia’s series Studying Studies to learn how to read and assess scientific papers
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Notes By Maryann

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