How does rapamycin affect immune function, given its use as an immunosuppressant?

While rapamycin is known as an immunosuppressant in transplant patients at high doses with other drugs, studies in healthy elderly individuals and mice show a different effect. Short-term, lower-dose rapamycin treatment, often with a washout period, has been observed to improve immune function, particularly vaccine response, suggesting it can restore an aged immune system.

What were the key findings of the initial 10-week rapamycin trial in dogs?

The initial 10-week study in healthy middle-aged companion dogs showed no significant side effects and promising improvements in cardiac function, specifically ejection fraction and fractional shortening. While the cohort was small and results were borderline statistically significant, the positive trend and a dramatic case study in a Doberman Pinscher with cardiomyopathy were encouraging.

Can rapamycin actually reverse or rejuvenate age-related decline, or does it only slow it?

Matt Kaeberlein believes rapamycin can do more than just delay age-related decline; it appears to have rejuvenating effects in certain organs and tissues, at least in mice. This includes restoring immune function, improving cardiac function, regenerating intestinal stem cells, and boosting alveolar bone levels back to a more youthful state. The mechanisms are thought to be largely stem cell-mediated.

What is the evidence for rapamycin's potential in treating Alzheimer's disease?

Studies in mouse models of Alzheimer's disease show that rapamycin can improve cognitive function and reduce amyloid-beta aggregation, even when treatment starts late after pathology has set in. While human trials are lacking, the ability of rapamycin to target the fundamental molecular pathways of aging makes it a promising candidate, especially for early-stage cognitive impairment.

How does rapamycin's mechanism compare to caloric restriction for longevity?

Both rapamycin and caloric restriction extend lifespan, but their metabolic effects differ. Rapamycin inhibits mTOR, which is also a key effect of caloric restriction, suggesting overlap. However, they are not identical, and their gene expression and metabolic profiles are not entirely similar, especially at lower rapamycin doses. More research is needed to understand their precise interaction and whether caloric restriction can serve as a metabolic signature for optimal rapamycin dosing.

What are the plans for a large-scale, long-term rapamycin study in dogs?

The proposed study is a five-year, randomized, double-blind, placebo-controlled trial involving 450-500 healthy middle-aged dogs across five to seven veterinary school sites. It will evaluate lifespan, heart function, activity levels, cancer incidence, kidney function, blood chemistry, metabolomics, and the microbiome. The study will include continuous treatment and a short-term 'on-then-off' treatment group to assess the durability of effects.

What impact could successful aging studies in dogs have on human aging research and public perception?

A successful, large-scale study demonstrating anti-aging effects in companion dogs could significantly shift public and scientific perception about the possibility of modifying aging. It would provide compelling real-world evidence that could foster acceptance of human clinical trials for healthy aging, a challenging area for funding and regulatory approval.

Key Moments

#10 – Matt Kaeberlein, Ph.D.: rapamycin and dogs — living longer, healthier & turning back the clock

Peter Attia MD

People & Blogs4 min read93 min video

Dec 23, 2019|4,688 views|106|5

rapamycin mTOR dogs longevity lifespan lifespan of dogs

Save to Pod

Key Moments

On this page

TL;DR

Exploring aging with Matt Kaeberlein: Dogs, rapamycin, healthspan, and the Dog Aging Project.

Key Insights

Dogs are valuable models for aging research due to shared environments with humans, offering unique insights beyond traditional lab animals.

Rapamycin shows promise in improving healthspan by targeting aging pathways, with dose and timing being critical factors for both efficacy and side effects.

The Dog Aging Project aims to test interventions like rapamycin in a real-world setting, focusing on safety, efficacy, and improving quality of life for companion animals.

While dogs share many age-related diseases with humans, their disease prevalence differs, particularly in vascular disease, but cancer and kidney disease are common.

Research suggests rapamycin may not only delay aging but potentially rejuvenate certain tissues and organs, possibly through stem cell mechanisms.

Understanding and treating age-related cognitive decline, like Alzheimer's in humans, is a key area where rapamycin's potential is being explored.

THE JOY OF AGING RESEARCH WITH FOUR-LEGGED FRIENDS

Matt Kaeberlein, a leading researcher in aging biology, discusses his transition to studying aging in dogs. He highlights dogs as exceptional models because they share our environment, unlike mice or yeast. This shared environment provides unique insights into how genetic and environmental factors influence aging and age-related diseases, making them highly relevant for understanding human aging.

RAPAMYCIN: THE GOD MOLECULE FOR HEALTHSPAN

The conversation delves into rapamycin, a drug known for its potential to extend lifespan and healthspan. Kaeberlein explains that the benefits and side effects of rapamycin are strongly dose-dependent. Research suggests that a careful dosing strategy, aiming for lower trough levels, might offer therapeutic benefits without significant adverse effects, especially when used as a monotherapy in healthy individuals or animals.

THE DOG AGING PROJECT: A REAL-WORLD LONGEVITY STUDY

Kaeberlein elaborates on the Dog Aging Project, a significant initiative to test aging interventions directly in companion dogs. This project aims to bridge the gap between laboratory findings in rodents and their applicability to humans. By studying interventions like rapamycin in dogs, researchers hope to gather crucial data on safety, efficacy, and healthspan extension in a mammal that closely mirrors human physiology and lifestyle.

UNDERSTANDING CANINE AGING AND DISEASE

The discussion touches upon how dogs age and the diseases they commonly face. While dogs develop many of the same age-related diseases as humans, their prevalence varies. Cancer is a leading cause of death, particularly in larger breeds, and kidney disease is also significant. Notably, vascular diseases like atherosclerosis are less common in dogs compared to humans.

RAPAMYCIN'S EFFECT ON HEALTHY AGING AND ORGAN FUNCTION

Kaeberlein shares findings from initial studies, including a 10-week trial in healthy dogs using rapamycin. The results, though preliminary, showed improvements in cardiac function, with dogs that had lower initial function experiencing the greatest benefits. This suggests rapamycin might not only delay decline but also rejuvenate certain organ systems, a phenomenon observed in mice across various tissues like the immune system and heart.

EXPLORING COGNITIVE DECLINE AND AUTOPHAGY

Cognitive decline and dementia are discussed as age-related issues in dogs, akin to Alzheimer's in humans. The role of autophagy, a cellular clearing process, is explored in relation to rapamycin. While rapamycin can increase autophagy markers, its precise impact, especially in conditions like cancer, is complex and requires careful interpretation, potentially distinguishing between a cellular response and a productive mechanism.

THE POTENTIAL FOR REJUVENATION AND THERAPEUTIC WINDOWS

Research indicates that rapamycin might not just slow aging but also reverse some aspects of aging, rejuvenating tissues like immune cells, cardiac muscle, and even alveolar bone. This 'rejuvenation' effect is particularly potent in tissues where stem cell senescence plays a significant role, hinting at a broader impact beyond simply delaying the aging process and opening doors for treatments targeting age-related functional decline.

CHALLENGES AND FUTURE DIRECTIONS IN AGING RESEARCH

The conversation highlights the difficulties in translating findings from mice to humans and the practical challenges in conducting large-scale aging trials. Questions about optimal dosing, long-term safety, and the cost of interventions like rapamycin are paramount. The potential for rapamycin to modulate the gut microbiome and its implications for systemic health are also areas of ongoing investigation.

THE PROSPECT OF LARGE-SCALE TRIALS AND PUBLIC PERCEPTION

Kaeberlein outlines the design for a five-year study in dogs, aiming to provide definitive evidence on rapamycin's effects on lifespan and healthspan. He acknowledges the significant impact such research could have on public perception of aging science, potentially normalizing interventions that promote healthspan and delay age-related diseases. The involvement of owners and veterinary schools is crucial for the success of these large-scale studies.

MOVING TOWARDS INTERVENTIONS FOR HEALTHY AGING

The discussion emphasizes the shift from treating diseases to preventing them and promoting healthspan. While definitive human trials for anti-aging interventions are challenging to fund and design, the Dog Aging Project offers a viable path to gather robust data. The ultimate goal is to inform strategies for keeping both dogs and humans healthier for longer, moving aging from an inevitable decline to a manageable process.

Mentioned in This Episode

●Supplements

●Companies

●Organizations

●Drugs & Medications

●Studies Cited

●Concepts

●People Referenced

Common Questions

The Dog Aging Project, directed by Matt Kaeberlein, uses companion dogs as a model for aging research. Dogs are unique because they share our environment, making them highly relevant to human aging. Their genetic diversity across breeds and mixed populations also makes them excellent subjects for understanding how genetic and environmental factors influence aging.

Topics

Health & Longevity MTOR Pathway Neuroscience & the Brain Medicine & Clinical Mindset & Self-Improvement Dog Aging Longevity Research Immune Modulation Cardiovascular Health Alzheimer'S Disease

Mentioned in this video

People

Peter Attia

Host of the Peter Attia Drive podcast, focused on optimizing performance, health, longevity, and critical thinking.

Felipe Sierra

Head of the Division of Aging Biology at NIH, who agreed to allocate surplus funds for Matt Kaeberlein's dog aging project.

David Sabatini

Renowned researcher known for his work on mTOR and rapamycin, who introduced Peter Attia to Matt Kaeberlein.

Daniel Promislow

Moved to the University of Washington and started thinking about dogs as a model for aging, prompting Matt Kaeberlein's involvement.

Matt Kaeberlein

Guest on the podcast, recognized globally for his research in the biology of aging and director of the Dog Aging Project.

Heidi Tissenbaum

A postdoc in Leonard Guarente's lab who showed that overexpressing the worm version of Sir2 (a sirtuin) extended lifespan in C. elegans.

Leonard Guarente

Matt Kaeberlein's PhD advisor at MIT, whose seminar on the genetics of aging inspired Matt's career path.

Terry Gross

Host of NPR's Fresh Air, mentioned in the context of media attention the Dog Aging Project has received.

Organizations

MIT

Where Matt Kaeberlein earned his PhD, working in the lab of Lenny Guarente.

Western Washington University

Where Matt Kaeberlein received his undergraduate degrees in biochemistry and mathematics.

Texas A&M Veterinary College

The institution where the lead veterinarian for the proposed large-scale dog aging study is located, serving as a coordinating site.

University of Washington

Matt Kaeberlein's current institution where he runs a lab and conducts research on aging.

SFB

A bacterium whose increase was observed dramatically in rapamycin-treated mice, linked to diabetes, obesity, and T-helper cell maturation.

Dog Aging Project

A research initiative directed by Matt Kaeberlein, focusing on dogs as an animal model to study aging and test interventions like rapamycin.

University of Tennessee

A veterinary group that Matt Kaeberlein consulted for their expertise on rapamycin dosing and pharmacokinetics in dogs with hemangiosarcoma of the spleen.

University of Texas at San Antonio

Conducting research studies on aging in marmosets, including studies involving rapamycin.

University of Georgia

Daniel Promislow's previous institution before moving to the University of Washington.

National Institute on Aging

The potential funding body for the proposed large-scale dog aging study, if political and scientific hurdles can be overcome.

National Institutes of Health

Provided partial funding for the initial dog rapamycin study through unspent funds from a Nathan Shock Center of Excellence.

Drugs & Medications

Everolimus

A derivative of rapamycin used in a study on healthy elderly people to test effects on immune function.

Rapamycin

A drug known to extend lifespan and slow aging, primarily by inhibiting the mTOR pathway, extensively discussed in the podcast.

Metformin

A drug considered very safe with good human data suggesting it reduces age-related diseases, proposed for the TAME trial as an intervention for healthy aging.

Concepts

mTOR

A protein kinase that regulates cell growth, proliferation, and survival, central to aging research and rapamycin's mechanism.

Daf-2

A gene in C. elegans known to extend lifespan when mutated, part of the insulin/IGF-1 signaling pathway.

Sirtuins

A class of proteins involved in cellular regulation, first shown by Matt Kaeberlein to extend lifespan in yeast and C. elegans.

Supplements

NAD

A coenzyme discussed as another topic of interest in longevity, alongside sirtuins and rapamycin.

Companies

Novartis

Pharmaceutical company that conducted a study on everolimus, a rapamycin derivative, in healthy elderly people and developed rapamycin derivatives under patent.

RestorBio

A company further developing rapamycin derivatives that are under patent, potentially for future clinical trials.

Studies & Research

TAME trial

A proposed clinical trial investigating metformin for healthy aging in humans, discussed for its potential to build scientific and public credibility for aging research.