#175 - Matt Kaeberlein, Ph.D.: The biology of aging, rapamycin, and other interventions that target the aging process
Dr. Matt Kaeberlein, a globally recognized researcher on aging, discusses defining aging, the relationship between aging and disease, and the potential of molecules like rapamycin for lifespan extension. He shares insights from the Dog Aging Project and explores mTOR, sirtuins, and NAD precursors.
Deep Dive Analysis
12 Topic Outline
Defining Aging: Molecular vs. Functional Perspectives
Relationship Between Aging, Functional Decline, and Disease
Impact of Curing Diseases vs. Targeting Biological Aging
Rapamycin as a Geroprotective Agent: Human Studies
The Role of Inflammation in Aging and Immune Function
Challenges of Clinical Trials for Aging Interventions
Periodontal Disease as a Potential Clinical Trial Endpoint
Biomarkers of Aging and Epigenetic Clocks
The Dog Aging Project: Studying Rapamycin in Pet Dogs
mTOR Complex 1 (mTORC1) vs. mTOR Complex 2 (mTORC2)
TORIN2: A Catalytic mTOR Inhibitor and its Potential
Sirtuins, NAD, and NAD Precursors (NR/NMN)
7 Key Concepts
Hallmarks of Aging
A framework describing the molecular and cellular damage that occurs during aging, including mitochondrial dysfunction, telomere shortening, cellular senescence, DNA damage, stem cell fatigue, protein misfolding, deregulated nutrient sensing, intracellular communication, and epigenetic modulation. These contribute to functional declines and age-related diseases.
Functional Definition of Aging
An appreciation for the observable declines across every organ system in the body that accompany aging, such as frailty. These functional declines often precede the clinical diagnosis of age-related diseases and significantly impact quality of life.
mTOR Complex 1 (mTORC1)
One of two protein complexes involving mTOR, largely responsive to nutrient levels. It regulates processes like autophagy, mRNA translation, and metabolism. Rapamycin specifically inhibits mTORC1 by binding to FKBP12 and disrupting the complex.
mTOR Complex 2 (mTORC2)
The second protein complex involving mTOR, with different partner proteins and distinct functional roles compared to mTORC1. While rapamycin primarily inhibits mTORC1, chronic high-dose rapamycin can have feedback effects leading to mTORC2 inhibition.
TORIN2
A catalytic (ATP competitive) inhibitor of mTOR, meaning it directly inhibits the kinase activity of mTOR. Unlike rapamycin, TORIN2 is designed to inhibit both mTORC1 and mTORC2, and its effects on aging are currently under investigation.
Sirtuins
A class of NAD-dependent enzymes, primarily deacetylases, that remove acetyl groups from other proteins. Their activity requires and consumes NAD, and is inhibited by NADH, making the NAD:NADH ratio a proxy for sirtuin activity. They are implicated in aging, but their role in lifespan extension in mammals is mixed.
NAD Precursors (NR/NMN)
Molecules like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) that can be converted into NAD within cells. The idea is that boosting NAD levels, which decline with age, could enhance sirtuin activity and positively impact aging, though reproducibility and efficacy in humans are still debated.
7 Questions Answered
Aging can be defined from a molecular perspective, focusing on cellular damage like mitochondrial dysfunction and telomere shortening, or from a functional perspective, observing declines across organ systems like frailty. Matt primarily focuses on the biological aspects, acknowledging social aspects are also important for quality of life.
No, curing individual age-related diseases like all cancers or heart disease has a relatively small impact on overall life expectancy (e.g., ~3 years for all cancers). In contrast, interventions targeting the fundamental biology of aging could hypothetically extend healthy lifespan by much greater amounts.
Clinical trials with rapamycin and its analogs (like Everolimus) at lower, intermittent doses (e.g., 5mg once a week) in older adults have shown very low incidence of adverse events, comparable to placebo. This challenges the common misconception that rapamycin is too unsafe for aging applications.
Pet dogs share the human environment, exhibit significant genetic and phenotypic diversity (including lifespan differences across breeds), age about 7 times faster than humans, and develop nearly all the same age-related diseases and functional declines as people, making them a powerful translational model.
mTORC1 is primarily responsive to nutrient levels and regulates processes like autophagy and protein synthesis. Rapamycin specifically inhibits mTORC1. mTORC2 has different partner proteins and functions, and is typically only inhibited by rapamycin at higher, chronic doses or by catalytic inhibitors like TORIN2.
While there is some preclinical literature suggesting benefits from NAD precursors, the results are inconsistent and difficult to reproduce across different studies and labs, including the NIA's Interventions Testing Program. Their efficacy in humans is not yet robustly established, though they are generally considered safe.
It's challenging because regulators are hesitant to approve trials in healthy individuals for a non-disease endpoint like 'aging,' and true lifespan studies in humans are impractical. There's also a lack of validated biomarkers of aging to measure intervention efficacy over shorter timeframes.
20 Actionable Insights
1. Prioritize Biological Aging Interventions
Focus on interventions that target the fundamental biology of aging for a more significant and broad impact on healthy lifespan, rather than treating individual diseases in isolation. This approach is estimated to add decades of healthy life, unlike single-disease cures.
2. Start Prevention Early
Begin prevention efforts as early as possible to mimic the healthy aging trajectory observed in centenarians, who experience a significant phase shift in disease onset.
3. Consider Once-Weekly Rapamycin Dosing
For individuals considering rapamycin, once-weekly dosing (e.g., 5-8mg, potentially with cycling periods like 8 weeks on, 6 weeks off) is a common self-experimentation protocol, though it lacks robust long-term clinical trial data.
4. Rapamycin Safety at Low Doses
Be reassured that rapamycin (and similar mTOR inhibitors like Everolimus or RTB101) at doses considered for anti-aging purposes do not show significant side effects, especially compared to widely used drugs like statins.
5. Lower ApoB & Improve Metabolic Health
Implement strategies (lifestyle, nutrition, or pharmacological) to lower ApoB and improve metabolic health (e.g., regulating glucose and insulin) to dramatically reduce the risk of atherosclerosis.
6. Fasting for Inflammation Reduction
Consider incorporating fasting into your routine, as it appears to reduce chronic inflammatory signaling, which is a critical factor in many age-related declines and diseases.
7. Evaluate Benefits & Risks
When considering any intervention, carefully weigh its potential beneficial effects against the associated risks and potential side effects, as every drug has a dose-dependent response.
8. Understand Aging as Progressive Decline
Recognize that normal aging is a progressive, chronic decline in function, not a healthy state, especially for typical older adults (e.g., 65-70 years old). This perspective should inform the acceptable level of risk for interventions aiming to slow or reverse this decline.
9. Maintain Good Oral Health
Prioritize good oral hygiene and address periodontal disease, as it is highly prevalent in older adults and linked to an increased risk of dementia, cardiovascular disease, and diabetes, likely through inflammatory pathways.
10. Caution with Epigenetic Clocks
Do not rely on current epigenetic clocks or telomere length measurements as definitive or helpful biomarkers for true biological age, as they can be easily manipulated by short-term interventions and lack robust biological explanations.
11. Sirtuins & NAD Precursors: Limited Evidence
Be aware that while sirtuins and NAD precursors (NR, NMN) show ‘a ton of smoke’ for anti-aging benefits in some studies, the evidence for their robust and reproducible efficacy, especially for lifespan extension, is mixed and not as strong as for mTOR inhibitors like rapamycin.
12. NAD Precursors: Safe but Unproven
NAD precursors like NR and NMN are considered very safe with minimal downside (primarily cost); however, their upside for anti-aging effects in humans is currently unclear and lacks definitive clinical trial evidence.
13. Do Not Use Rapamycin Before 25
Avoid using rapamycin in developing individuals, specifically before the age of 25, as its effects on development are not fully understood and could be detrimental.
14. Recognize Functional Declines as Early Aging
Pay attention to functional declines in various organ systems as early indicators of aging, often preceding the diagnosis of overt age-related diseases.
15. Prioritize Minimizing Side Effects
In any treatment, especially for long-term use or in vulnerable populations (like pets or healthy individuals), prioritize strategies that minimize the likelihood of side effects, such as optimizing dosing frequency.
16. Value Social Aspects of Aging
Recognize that social aspects are extremely important for quality of life as people get older, intersecting significantly with biological aging.
17. Peter Atiyah’s Rapamycin Protocol
Peter Atiyah takes 5-8mg of rapamycin once weekly, having previously cycled it (8 weeks on, 6 weeks off), but notes he is ‘flying blind’ without biomarkers to guide this decision.
18. Matt Caberlin’s Frozen Shoulder Protocol
Matt Caberlin used 8mg of rapamycin once weekly for eight weeks to resolve severe frozen shoulder, attributing the improvement to rapamycin’s anti-inflammatory effects (he explicitly states this is not an encouragement for others to do the same).
19. Advocate for Regulatory Changes
Support efforts to change regulatory environments (e.g., FDA) to allow clinical trials of geroprotective drugs in healthy individuals, using quantitative functional endpoints, and to address the challenges of off-patent drugs.
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6 Key Quotes
You can't argue that biological age is the single greatest risk factor for every major cause of death and disability in developed countries. That is just a fact.
Matt Kaeberlein
The impact on life expectancy is actually from curing disease is actually quite small.
Matt Kaeberlein
There's no evidence actually for significant side effects from rapamycin monotherapy, everolimus monotherapy, or RTB 101 at the doses that people are talking about using in this context. That's just blatantly false.
Matt Kaeberlein
I would not call a 65 year old, a typical 65 or 70 year old healthy. They're not, they're functionally impaired.
Matt Kaeberlein
I don't think I will ever understand aging fully. And I don't think the field will, at least in any timeframe that I can expect to experience, right? But I also believe that we don't have to understand it fully to be able to have an impact on the biology of aging through interventions.
Matt Kaeberlein
I think that the underlying theme that seems to be similar about all of these things that work in mice is if you look in tissues of aged mice at inflammatory cytokines, P16, P21, markers of senescence, they seem to be tamped down by all of these, these interventions, which might explain the functional improvements that we see from using these interventions in aged mice.
Matt Kaeberlein
1 Protocols
Rapamycin Treatment for Frozen Shoulder
Matt Kaeberlein- Take 8 mg of rapamycin once a week.
- Continue treatment for 8 weeks.