The guest
Dr. Matt Kaeberlein: Professor of laboratory medicine and pathology at the University of Washington School of Medicine, founding director of the UW Healthy Aging and Longevity Research Institute, and founder/co-director of the Dog Aging Project; a leading researcher on the biology of aging and rapamycin.
What this episode covers
Tim Ferriss interviews aging biologist Dr. Matt Kaeberlein about what is real versus hype in longevity science. Kaeberlein explains the biology of aging, why he focuses on rapamycin (and how he used it to self-treat his own frozen shoulder), and the Dog Aging Project's clinical trial testing rapamycin in companion dogs. He walks through candidate interventions like alpha-ketoglutarate, spermidine, urolithin A, metformin and NAD precursors, while debunking the resveratrol and sirtuin stories. The conversation stresses healthspan over raw lifespan, the dangers of short-lived controls in studies, and the field's underfunding and poor science communication.
Recommended on this episode
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Rapamycin (sirolimus / Rapamune)
“the one that i have focused on the most throughout my career; i started taking rapamycin; i take rapamycin off and on”
“that's the drug that i if i had to pick one intervention that's the one that i have focused on the most throughout my career”— Matt Kaeberlein
The guest's own work
BookBy the guestISBN verified
The 4-Hour Body
Tim Ferriss
“i wrote about the health benefits of using continuous glucose monitors cgm's more than 10 years ago in the four hour body”— Tim Ferriss
Also referenced (named, not recommended)
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The Paleo Solution
Robb Wolf
“rob wolf who is a former research biochemist and two-time new york times best-selling author of the paleo solution and wired to eat”— Tim Ferriss
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Wired to Eat
Robb Wolf
“two-time new york times best-selling author of the paleo solution and wired to eat rob created element by scratching his own itch”— Tim Ferriss
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Acarbose
“there are other drugs like acarbose which is an anti-diabetic drug that is in males at least close to rapamycin in terms of the magnitude of effect”— Matt Kaeberlein
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17-alpha estradiol
“17 alpha estradiol which is a sex hormone extends lifespan in males ndga is another one”— Matt Kaeberlein
ProductReferenced
NDGA (nordihydroguaiaretic acid)
“17 alpha estradiol which is a sex hormone extends lifespan in males ndga is another one”— Matt Kaeberlein
ProductReferenced
Metformin
“metformin which is the most commonly prescribed anti-diabetic drug in the world it's gotten a lot of attention for its potential effects on longevity”— Matt Kaeberlein
ProductReferenced
Nicotinamide riboside (NR)
“a nicotinamide riboside which is an nad precursor did not extend lifespan by the itp but there's a lot of evidence that you can have beneficial effects”— Matt Kaeberlein
ProductReferenced
Alpha-ketoglutarate
“one is alpha ketoglutarate which is a natural product metabolite that a lot of people are thinking about now there's one study that showed a small life span extension in mice”— Matt Kaeberlein
ProductReferenced
Spermidine
“two that actually are thought to target autophagy or mitophagy mitochondrial autophagy one is called spermadine and the other is called urolithin a”— Matt Kaeberlein
ProductReferenced
Urolithin A
“the other is called urolithin a and so i would take a close look at those”— Matt Kaeberlein
ProductReferenced
Deprenyl
“there's one that i have here in my notes that i'd love to know if you have any opinion on which is depranil”— Tim Ferriss
BookReferencedISBN verified
Smart Drugs
“freshman year reading volume one of a series well later became a series called smart drugs and it talked about off-label use of all sorts of things”— Tim Ferriss
ProductReferenced
Nicotinamide mononucleotide (NMN)
“there are two that are commonly talked about and studied nicotinamide riboside and nicotinamide mononucleotide”— Matt Kaeberlein
ProductReferenced
Modafinil
“almost all of the top sprinters in the world were diagnosed with narcolepsy because they wanted to use modafinil because it's a performance enhancer”— Tim Ferriss
Big reveals from this episode
- Kaeberlein treated his own frozen shoulder with a 10-week course of rapamycin, regaining about 90 percent range of motion with the pain gone and not returning, after physical therapy had failed.
- In mice, rapamycin doesn't just slow aging but functionally reverses declines: the aged immune system responds to vaccines again, the aged heart works better, and eight weeks of treatment reversed periodontal disease and regrew bone around teeth.
- Analyzing roughly 25,000 dogs in the Dog Aging Project, dogs fed once a day had lower risk in six of ten age-related disease categories than dogs fed more often, with all ten trending the right direction (though observational, not proven causal).
- Kaeberlein's lab showed resveratrol does NOT activate sirtuins in living cells; the famous 2003 result only worked because the test peptide had an artificial chemical group, and a large meta-analysis now finds resveratrol has essentially zero effect on aging.
- Hundreds of millions of dollars chasing mammalian sirtuins as aging regulators have 'completely fallen flat'; the field was led down this path with never any solid evidence to support it.
- A halted trial (resTORbio) of a six-week rapamycin-derivative course was later found to reduce significant infections from several viruses, including a coronavirus, by around 50 percent over the following year, a decision made in November 2019, months before COVID.
- Curing all cancer would add only about three years to a 50-year-old's life expectancy, and heart disease about the same; targeting the underlying biology of aging offers far greater potential gains.
Worth remembering
- Kaeberlein earned undergraduate degrees in both mathematics and biochemistry and nearly pursued math before choosing biology.
- The Dog Aging Project is the largest longitudinal study of aging in any animal, following more than 40,000 companion dogs across the US.
- Rapamycin (clinically called sirolimus, brand Rapamune) was FDA-approved around 1999, mainly to prevent organ transplant rejection.
- Many anti-aging drugs from the NIA Interventions Testing Program extend lifespan in only one sex, tending to favor males.
- The largest lifespan extension shown with rapamycin in mice is about a 25 percent increase.
- In mice, an estimated 60 to 90 percent of deaths are due to cancer; in dogs, cancer is also a leading killer (euthanasia being the technical leading cause of death).
- Aging biology research gets about 350 million dollars a year from the NIH versus roughly 6 billion for cancer; a Saudi-funded foundation has pledged about 1 billion a year going forward.
- Black-6 mice normally live around 900 days, yet many published 'lifespan-extending' studies use sick controls living only 650 days, inflating percentage effects.
- Resveratrol is one of the 'dirtiest' drugs known, binding many targets, and has repeatedly fallen out of pharmaceutical screens.
- Acarbose and 17-alpha-estradiol extend male mouse lifespan; the latter works only in males via an unknown mechanism.
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