#10 - Matt Kaeberlein, Ph.D.: rapamycin and dogs — man's best friends? — living longer, healthier lives and turning back the clock on aging, and age-related diseases
Peter Attia interviews Matt Kaberlin, a University of Washington researcher specializing in the biology of aging. They discuss the Dog Aging Project, rapamycin's effects on healthspan and lifespan in dogs and mice, and its potential for treating age-related diseases like cancer, heart disease, and Alzheimer's.
Deep Dive Analysis
16 Topic Outline
Introduction to Matt Kaberlin and his aging research
Matt's academic journey and 'aha moment' in aging biology
Early work on sirtuins and lifespan extension
Rationale for the Dog Aging Project
Common causes of death and age-related diseases in dogs
Rapamycin's safety, side effects, and dosing considerations
Rapamycin's counterintuitive effect on immune function
Designing the initial rapamycin trial in healthy dogs
Results of the initial dog rapamycin study
Rapamycin's role in cancer treatment and prevention
Rapamycin's rejuvenating effects on various organs
Potential for rapamycin in Alzheimer's disease
Comparing rapamycin to caloric restriction and metabolic signatures
Rapamycin's impact on the gut microbiome and intestinal health
Designing a definitive five-year dog aging study
Public perception and the future of human anti-aging trials
10 Key Concepts
Biology of Aging
A field that studies the fundamental factors influencing the rate of aging, using genetics, molecular biology, and biochemistry to understand a complex and fundamental biological process.
Sirtuins
A class of proteins, with Sirtu being the founding member in yeast, that when activated or overexpressed, have been shown to extend lifespan and slow aging in organisms like yeast and C. elegans.
Dog Aging Project
A research initiative that uses companion dogs as a model to understand how genetic and environmental factors influence aging. Dogs are unique because they share the human environment, offering a relevant model for testing anti-aging interventions.
Trough Levels
The lowest concentration of a drug in the blood, typically measured just before the next dose is administered. For some drugs like rapamycin, trough levels are thought to correlate most strongly with side effects.
Peak Levels
The highest concentration of a drug in the blood, typically occurring shortly after a dose is administered. This represents the maximum exposure to the drug during a dosing interval.
Immunosuppression vs. Immune Enhancement
While rapamycin is known as an immunosuppressant at high doses in transplant patients, studies show that short-term, lower-dose treatment in aged mice and elderly people can actually improve immune function, such as vaccine response, potentially by restoring stem cell function.
Rejuvenating Function
Beyond merely delaying decline, rapamycin appears to actively improve or restore function in some aged organs and tissues, making them work more like a youthful state. This effect is suspected to be mediated by stem cells.
Intestinal Barrier Function
The integrity of the gut lining that prevents microbes and their products from entering the circulatory system. This function declines with age, potentially contributing to systemic inflammation, and rapamycin may help improve it.
Segmented Filamentous Bacteria (SFB)
A specific type of bacterium whose presence in the gut microbiome has been observed to increase with rapamycin treatment in mice. SFB has been linked to conditions like diabetes and obesity, and also to T helper cell maturation.
TAME Trial
The 'Targeting Aging with Metformin' trial is a proposed clinical study for metformin in people who have at least one age-related disease (but not diabetes). Its goal is to investigate if metformin can delay or prevent the onset of multiple age-related conditions, serving as an initial human anti-aging trial.
3 Questions Answered
Dogs generally die from similar age-related diseases as humans, such as cancer (most common), kidney disease, and heart disease (often cardiomyopathy or valvular, less atherosclerosis). However, a significant number of pet dogs die from euthanasia due to severe illness, which serves as a proxy for healthspan.
For most cancers, once diagnosed, rapamycin has been disappointing in its effectiveness. This may be because tumors evolve to ignore mTOR inhibition, or because the effects of rapamycin on the immune system can be complex, potentially promoting some cancers at very high doses while boosting immune surveillance at lower doses.
Despite promising evidence in mouse models showing improvements in cognitive function and reductions in amyloid pathology, there hasn't been a definitive rapamycin trial for Alzheimer's disease. This is due to the practical challenges of long, expensive trials, the risk of failure impacting drug reputation, and the scientific community's historical approach to AD not fully recognizing it as a disease of aging.
13 Actionable Insights
1. Rapamycin for Immune Rejuvenation
Consider short-term rapamycin treatment (e.g., 6-10 weeks) followed by a 2-week washout period to potentially restore immune function, as evidenced by improved vaccine response in aged mice and people.
2. Rapamycin for Cardiac Rejuvenation
Rapamycin treatment for 6 to 10 weeks has been shown to improve heart function in aged mice, restoring it halfway to youthful levels, with benefits observed while the treatment is ongoing.
3. Rapamycin for Early Cognitive Decline
For individuals experiencing mild cognitive impairment, rapamycin may offer a promising intervention to improve cognitive function and potentially reduce amyloid accumulation, based on studies in aged animals and Alzheimer’s disease mouse models.
4. Rapamycin Rejuvenates Multiple Tissues
Rapamycin has demonstrated a rejuvenating effect, not just delaying decline, but improving function back towards a more youthful state in areas like immune function, cardiac function, intestinal stem cells, and alveolar bone levels, likely through stem cell mediation.
5. Rapamycin Dosing for Healthy Dogs
For healthy, middle-aged dogs (at least 40 pounds and 6 years old), a rapamycin dosing strategy of 0.1 mg/kg or 0.05 mg/kg given three times a week (e.g., Monday, Wednesday, Friday) showed no significant side effects over 10 weeks and improved heart function.
6. Monitor Long-Term Rapamycin Use
If considering long-term rapamycin treatment, especially for conditions like declining cardiac function, continuous monitoring (e.g., echocardiograms every three months) is recommended to assess efficacy and detect any potential side effects.
7. Rapamycin Enhances Cancer Surveillance
Boosting age-related immune function with rapamycin can enhance immune surveillance, which is a potent anti-cancer mechanism, suggesting a role for rapamycin in cancer prevention.
8. Avoid High-Dose Rapamycin
Extremely high doses of rapamycin may have detrimental effects on the immune system, potentially promoting certain aggressive cancers, as observed in female mice, highlighting the importance of dose optimization.
9. Improve Intestinal Barrier Function
Improving age-related decline in intestinal barrier function can reduce systemic inflammation, which is a significant contributor to aging, and rapamycin may play a role in this improvement.
10. Rapamycin Benefits are Dose-Dependent
Both the beneficial effects and potential side effects of rapamycin are strongly linked to its dose, with trough levels potentially correlating most strongly with side effects, emphasizing the need for careful dose titration.
11. Explore Metabolome for Biomarkers
To identify predictive signatures for anti-aging interventions like rapamycin, focus research efforts on the serum metabolome, as it is a promising area for correlating with functional effects and lifespan.
12. Conduct Short-Term Human Trials
To build evidence for rapamycin’s effects in humans, conduct short clinical trials (e.g., 6-10 weeks) in healthy elderly individuals, focusing on impactful functional outcomes like immune function, cardiac function, or alveolar bone levels.
13. Listen to Sabatini Podcast
For listeners seeking foundational knowledge on mTOR and rapamycin, it is recommended to listen to the podcast with David Sabatini, as it provides essential background information.
8 Key Quotes
It was really almost like an aha moment where it just clicked with me that it was really fascinating that you could use genetics and molecular biology and biochemistry to study something as complicated and fundamental as the biology of aging.
Matt Kaberlin
If we can actually slow aging in people's pets, that's going to have a huge impact both on the quality of life for the pets and the owners, but also the way that people think about the biology of aging.
Matt Kaberlin
There is a very low tolerance for side effects when you're talking about treating a healthy person or dog.
Matt Kaberlin
My personal view is that there should be a tolerance for some level of risk if the outcome is going to be 10 percent, 20 percent, 30 percent more time spent in good health.
Matt Kaberlin
You take this oath at the end of medical school, the Hippocratic Oath, the first thing you learn to say is, first, do no harm. And I think the spirit of that is excellent, but I also think it's highly impractical in a world where it forces you into binary thinking.
Peter Attia
I think that autophagy, some markers of autophagy going up can be a response to a pathological condition. Also, what often happens is that response of turning up autophagy does not lead to productive autophagy.
Matt Kaberlin
I really think that one of the reasons why the preclinical research has been disappointing at developing therapies for Alzheimer's disease is because very rarely have people approach that from the perspective that this is a disease of aging.
Matt Kaberlin
I think that dog owners are more likely to give their dog a prescription medication than they are to take their own prescription medication.
Matt Kaberlin
1 Protocols
Definitive Dog Aging Study (Proposed)
Matt Kaberlin- Enroll 450-500 middle-aged healthy companion dogs, each at least 6-8 years old and weighing over 40 pounds.
- Randomize dogs into three groups: a placebo group, a short-term rapamycin treatment group (e.g., one year on, four years off), and a continuous rapamycin treatment group (five years on).
- Administer rapamycin according to the assigned schedule and dose (specifics to be optimized, but likely building on prior findings).
- Monitor lifespan as a primary outcome measure.
- Track a broad range of functional measures of aging, including heart function (via echocardiograms), activity levels (using GPS trackers on collars), cancer incidence, and kidney function.
- Conduct routine blood chemistry tests on the dogs approximately every six months.
- Collect serum for metabolomics and fecal samples for microbiome analysis.
- Execute the study over a five-year period, collaborating with 5-7 veterinary schools across the United States to ensure diverse participation and specialized care.