How does the relationship between aging and disease evolve over time?

Functional declines often precede overt age-related diseases. While aging biology contributes to disease risk, the pathology of a disease can eventually become mechanistically distinct from normative aging processes, making interventions effective for the disease without impacting aging itself.

Why is age considered the greatest risk factor for diseases like atherosclerosis?

Age is hands-down the number one risk factor for atherosclerosis, even more so than classic factors like smoking or high blood pressure. A 70-year-old in perfect health has a significantly worse 10-year mortality prediction than a 20-year-old with multiple risk factors.

What is the anticipated impact on life expectancy of curing individual diseases versus targeting biological aging directly?

Curing all cancers might add about three years to life expectancy, and curing heart disease a similar amount, totaling about seven years if both were cured. In contrast, targeting biological aging, based on animal studies, hypothetically could add about 20 years of healthy life.

What common characteristics are observed in centenarians regarding disease?

Centenarians generally get chronic diseases later in life, experiencing a 20-30 year phase shift in disease onset. They don't typically live longer with multiple age-related diseases, and don't necessarily have magical protection once a disease manifests.

Why don't we see strong 'longevity gene' variants in humans that significantly extend lifespan, as seen in lab animals?

Strong genetic variants that dramatically extend lifespan in lab animals, such as those impacting mTOR, are often incompatible with normal development or reproduction. Such mutations would likely be selected against in human evolution (e.g., they might not make it through gestation or would be sterile).

What are the regulatory challenges in conducting clinical trials for aging interventions in healthy people?

Regulators are hesitant to approve trials in healthy individuals due to risk concerns, and current clinical trial apparatus is designed for disease endpoints, not 'aging' itself. The immense duration needed to observe a true longevity benefit also poses a major logistical hurdle.

How has the understanding of Rapamycin's immune effects evolved?

While rapamycin is known as an immune suppressant in high doses for organ transplant, studies show that lower, intermittent doses can actually boost vaccine response and broadly improve immune function in older adults by tamping down chronic sterile inflammation.

What is Matt Kaeberlein's personal experience with Rapamycin for a frozen shoulder?

After being diagnosed with a painful, debilitating frozen shoulder, Matt Kaeberlein self-experimented with 8mg of rapamycin once a week for eight weeks. He experienced a significant reduction in pain and restored range of motion, suggesting its anti-inflammatory effects were key.

What are epigenetic clocks, and what are their limitations as biomarkers of aging?

Epigenetic clocks measure chemical marks on DNA that change with age, correlating strongly with chronological age and disease risk. However, concerns exist about the high dimensionality of omics data leading to spurious correlations, and their manipulability by short-term, sometimes irrelevant, interventions.

Why are companion dogs valuable models for studying aging and longevity interventions?

Dogs share much of the human environment, have diverse genetics, and experience age-related diseases and functional declines similar to humans, but at an accelerated rate (7-10 times faster), allowing for lifespan studies within practical timeframes (e.g., a three-year clinical trial).

What is the rationale behind using once-weekly dosing of Rapamycin in the Dog Aging Project's TRIAD study?

The once-weekly dosing strategy for dogs is based on human data suggesting it's as effective as daily dosing for immune function with fewer side effects. It also improves compliance and reduces potential for errors in a field trial with pet owners, minimizing risks to animal welfare.

How do mTOR Complex 1 and mTOR Complex 2 differ, and how does Rapamycin affect them?

mTORC1 is primarily responsive to nutrient levels, regulating autophagy and translation. mTORC2 has different functions, less understood in aging. Rapamycin specifically inhibits mTORC1, but chronic high-dose inhibition of mTORC1 can have feedback effects that also inhibit mTORC2.

What roles do NAD+ and sirtuins play in the context of aging?

Sirtuins are NAD+-dependent enzymes that remove acetyl groups from proteins, and their activity declines with age as NAD+ levels are impaired. Boosting NAD+ levels via precursors like NR or NMN is hypothesized to restore sirtuin activity and positively impact aging.

What are the current challenges and controversies surrounding NAD+ precursors like NR and NMN?

Despite much popular interest, the preclinical literature for NR and NMN shows inconsistent reproducibility, with conflicting evidence regarding their biological availability and efficacy. There's also controversy between different research camps, and difficulty for labs to reproduce results.

Key Moments

175 - The biology of aging, rapamycin, and other interventions that target the aging process

Peter Attia MD

People & Blogs4 min read170 min video

Sep 13, 2021|44,281 views|1,064|108

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Key Moments

TL;DR

Exploring aging definitions, the potential of Rapamycin and other interventions to extend healthy lifespan beyond current disease-focused medicine.

Key Insights

Aging is a complex, multifactorial biological process, not merely a collection of diseases, necessitating a shift from 20th-century disease-centric medicine to 21st-century aging biology.

Rapamycin, an mTOR inhibitor, shows robust and reproducible effects in extending lifespan and reversing functional declines in various animal models, including mice and dogs, without significant side effects at lower, intermittent doses.

The centenarian paradox highlights that exceptional longevity stems from delaying the onset of age-related diseases, not living longer with them, suggesting early intervention as a critical strategy.

Biomarkers for aging are severely lacking; current epigenetic clocks, while correlating with chronological age, need further validation for biological relevance and predictive power for individual interventions.

The Dog Aging Project is a unique and powerful model for studying aging and intervention efficacy, offering a bridge between laboratory animal studies and human clinical trials due to shared environments and accelerated aging.

Inflammation plays a crucial role in aging and age-related diseases, and many successful anti-aging interventions, including Rapamycin and potentially senolytics, appear to work by dampening chronic sterile inflammation.

DEFINING AGING: BEYOND CHRONOLOGY AND DISEASE

Aging encompasses more than just the passage of time; it's a profound biological process characterized by molecular damage, functional declines across all organ systems, and an increased susceptibility to disease. While hallmarks of aging like mitochondrial dysfunction and cellular senescence provide a molecular framework, a comprehensive understanding requires integrating functional metrics like frailty. Critically, chronic diseases commonly associated with aging, such as cancer and cardiovascular disease, are not merely extensions of normal aging but often represent distinct pathologies. This distinction is crucial for developing effective interventions, as targeting fundamental aging mechanisms may offer broader, more impactful benefits than solely treating individual diseases.

THE INTERPLAY OF AGING, DISEASE, AND CLINICAL STRATEGIES

Age is the single greatest risk factor for nearly all major causes of death and disability. However, current medical practice primarily focuses on a 'disease-first' approach, often intervening only after overt disease manifests. This strategy, while saving lives, has a limited impact on overall healthy lifespan. For instance, curing all cancers or heart disease might only add a few years to average life expectancy. A more potent approach, termed '21st-century medicine,' targets the biology of aging itself. This promises to delay the onset of multiple age-related diseases simultaneously, extending not only total lifespan but, more importantly, a longer period of healthy, functional life, as observed in studies of centenarians who delay disease onset rather than living longer with illness.

RAPAMYCIN: A FRONTRUNNER IN AGING INTERVENTION

Rapamycin is an allosteric inhibitor of mTOR complex 1 (mTORC1), a key nutrient-sensing pathway. Preclinical studies in mice consistently demonstrate its ability to extend healthy lifespan by 15-30%, even when initiated in middle or late age. Functionally, Rapamycin can reverse age-related declines in various tissues and organs, including the heart and immune system. Its mechanism of action is believed to involve dampening chronic sterile inflammation, a hallmark of aging, and potentially shifting metabolism away from glucose dependence towards fat utilization. While Rapamycin is used clinically as an immunosuppressant at high doses, research suggests that lower, intermittent dosing for anti-aging purposes carries significantly fewer and milder side effects.

CHALLENGES IN TRANSLATING ANTI-AGING INTERVENTIONS TO HUMANS

Translating promising anti-aging interventions like Rapamycin from animal models to human clinical practice faces substantial hurdles. The regulatory environment is ill-equipped for 'healthy aging' trials, which would require studying non-diseased individuals over decades. This necessitates developing clear, quantifiable, and ethically acceptable endpoints that reflect functional declines rather than just disease. Furthermore, the absence of validated biomarkers of biological aging makes it difficult to assess the efficacy of interventions in humans within a reasonable timeframe. Misconceptions about drug safety, particularly for Rapamycin, further complicate regulatory and public acceptance, despite evidence of its safety at doses relevant for anti-aging.

THE DOG AGING PROJECT: A CRITICAL BRIDGE FOR TRANSLATION

The Dog Aging Project offers a unique and powerful model for accelerating research into aging and longevity. Companion dogs share our environment, manifest similar age-related diseases and functional declines, and age approximately seven times faster than humans, making them an ideal translational model. The project aims to conduct large-scale observational studies to understand genetic and environmental factors influencing healthy aging in dogs, and, critically, to run veterinary clinical trials. The first such trial, 'TRIAD,' is testing Rapamycin in hundreds of middle-aged pet dogs, with lifespan as a primary endpoint, alongside a host of secondary functional and biological measures. This offers a feasible route to gather robust data on anti-aging interventions, bridging the gap between laboratory mice and human trials.

EXPLORING OTHER PATHWAYS: TORIN2, NAD+, AND SIRTINS

Beyond Rapamycin, other molecular pathways are being explored for their anti-aging potential. Torin2, a catalytic inhibitor of mTOR, targets both mTORC1 and mTORC2. Its effects on lifespan and aging in mice remain largely unexplored, representing a significant knowledge gap. The NAD+/sirtuin pathway has also gained considerable attention, with NAD+ precursors like Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN) touted as potential 'longevity boosters.' While sirtuins are NAD+-dependent enzymes linked to aging in model organisms, the evidence for their robust lifespan-extending effects in mice, and the clinical efficacy of NAD+ precursors, is inconsistent and less reproducible compared to mTOR inhibitors, highlighting the need for more rigorous and transparent research in this area.

Mentioned in This Episode

●Supplements

●Companies

●Organizations

●Books

●Studies Cited

●Concepts

●People Referenced

Common Questions

Biological aging is often seen through molecular definitions, such as mitochondrial dysfunction, telomere shortening, cellular senescence, protein misfolding, DNA damage, and deregulated nutrient sensing. It's also increasingly viewed functionally through declines like frailty.

Topics

Health & Longevity Neuroscience & the Brain Mindset & Self-Improvement Mitochondrial Dysfunction Epigenetic Clocks Clinical Trials Immune Function Biomarkers Of Aging Aging Biology Medicine & Clinical NAD+ Metabolism MTOR Inhibition Longevity Interventions Pet Health

Mentioned in this video

Drugs & Medications

Rapamycin

A drug that inhibits the mTOR pathway, extensively discussed for its role in aging, immune function, and lifespan extension in laboratory animals. Its potential in humans is explored regarding dosing strategies and side effects.

Everolimus

A derivative of rapamycin with the same biochemical mechanism, used in clinical trials to improve vaccine response and immune function in older adults.

Metformin

A drug considered for the TAME trial due to existing human data supporting its use in targeting aging, despite concerns about regulatory appetite for rapamycin.

Torin 2

A catalytic (ATP competitive) inhibitor of mTOR that theoretically inhibits both mTORC1 and mTORC2, showing potential in mitochondrial disease models, but not yet tested for aging effects in mice lifespan studies.

RTB 101

A dual kinase inhibitor, also an mTOR inhibitor, studied in combination with everolimus and alone for improving immune function in older adults. Its phase 3 trial failed to hit its endpoint.

Concepts

Alzheimer's disease

An age-related neurodegenerative disease, mentioned as one of the major causes of death and disability where biological age is a significant risk factor, and its relationship to aging biology is explored.

cardiovascular disease

An age-related condition, discussed as a major cause of death and disability for which biological age is the single greatest risk factor. Its prevention often involves targeting specific metrics like APOB.

mTOR pathway

A fundamental cellular pathway, a target of Rapamycin, which plays a crucial role in regulating cell division and cell cycle, and is central to discussions on aging biology and interventions.

Hematopoietic Stem Cells

Stem cells primarily responsible for the production of red blood cells, white blood cells, and platelets. Rapamycin is hypothesized to rejuvenate their function, contributing to improved immune response.

Lee syndrome

A childhood mitochondrial disease model in mice used to study severe mitochondrial dysfunction, where rapamycin treatment roughly doubled or tripled survival and prevented neurodegeneration.

Ketogenic Diet

A nutritional strategy suggested as a treatment for Type 2 Diabetes due to its carbohydrate restriction, but not necessarily optimal for prevention, illustrating the difference between treating and preventing disease.

Sirtuins

A class of NAD+-dependent enzymes (mostly deacetylases) that play a role in aging. While activation is generally considered beneficial, evidence for strong lifespan extension in mice is mixed.

Hypoxia

A condition of oxygen deficiency, mentioned as an intervention that can rescue mice with Lee syndrome to a greater extent than rapamycin, consistent with an oxidative stress model.

People

Joan Mannick

A researcher who conducted clinical trials with everolimus (a rapamycin derivative) at Novartis, showing its ability to boost vaccine response in older adults, and later involved with RestoreBio.

Lloyd Klickstein

A researcher who, along with Joan Mannick, co-authored a 2014 paper on everolimus, influencing dosing strategies for rapamycin.

Judith Villen

A researcher at the University of Washington in genome sciences who collaborated on a phosphoproteomic study examining rapamycin's effects.

Dudley Lamming

A researcher who, when in David Sabatini's lab, contributed to the model suggesting rapamycin's metabolic side effects are linked to mTORC2 inhibition.

Cynthia Kenyon

A researcher cited for her perspective on disease-based definitions of aging, arguing that if 'everyone has cancer by a certain age, then it's normative aging, not a disease.'

Jonathan Ahn

A DDS/PhD student who researched periodontal disease in Matt Kaeberlein's lab, demonstrating its age-related nature and potential for reversal with rapamycin in mice. He is now faculty at the University of Washington.

David Sabatini

A leading researcher in the mTOR field, mentioned in the context of developing a model for rapamycin's side effects being due to chronic mTORC2 inhibition, and as someone to consult regarding Torin 2's discovery.

Matt Kaeberlein

A guest on The Drive podcast, a professor at the University of Washington, and a leading expert in the biology of aging, discussing his research on mTOR, rapamycin, and the Dog Aging Project.

Jay Olshansky

An academic who calculated that curing all cancers would only increase life expectancy by about three years, emphasizing the limited impact of disease-specific cures compared to targeting the biology of aging.

Leonard Guarente

Matt Kaeberlein's graduate advisor, recognized for establishing sirtuins as important in aging, specifically through work on the Sir2 protein in yeast.

David Sinclair

A researcher who has discussed sirtuins and their NAD+ dependence, likely contributing to the popular understanding of NAD+ precursors.

Nir Barzilai

A researcher whose work on centenarians shows they get chronic diseases later in life, rather than living longer with them, suggesting a 'phase shift' in disease onset.

Peter Attia

The host of The Drive podcast and a physician interested in longevity, discussing his clinical perspective on aging, personal use of rapamycin, and the challenges of studying aging in humans.

Books

Nature Metabolism

A scientific journal where a phosphoproteomic study on the effects of rapamycin in Lee syndrome mice was published, revealing insights into mTORC2 inhibition.

Science Signaling

A scientific journal where a 2009 paper from Panjgan's lab was published, detailing rapamycin's effect on boosting flu vaccine response in mice.

Studies & Research

TRIAD

The first clinical trial of the Dog Aging Project, testing rapamycin's effects on healthy lifespan in pet dogs, aiming to detect a 15% change in lifespan within a three-year window.

TAME trial

A clinical trial using metformin to delay the onset of a second age-related disease in people who already have one, representing a strategy for aging intervention trials.

Organizations

Pangang's lab

A research laboratory at the University of Michigan whose 2009 Science Signaling paper demonstrated that rapamycin boosted flu vaccine effectiveness in old mice, providing preclinical support for human trials.

University of Washington

An institution where Jonathan Ahn is a faculty member, pushing forward clinical trials related to rapamycin and periodontal disease, and also where the Dog Aging Project is based.

National Institute on Aging

A government organization that had a program in the 80s or 90s to identify biomarkers of aging, highlighting the historical challenge of validating such markers.

The Drive Podcast

The podcast hosted by Peter Attia, where Matt Kaeberlein is a guest, discussing topics on aging and longevity.

Dog Aging Project

A large-scale project at the University of Washington and Texas A&M to understand and intervene in the biology of aging in companion dogs, aiming to increase healthy lifespan.

FDA

The Food and Drug Administration, discussed for its regulatory approach to clinical trials for aging interventions, particularly concerning endpoint requirements and risk tolerance for healthy populations.

Companies

RestoreBio

The company conducting clinical trials for RTB 101 to gain FDA approval, which terminated its phase 3 trial early due to not hitting endpoints and subsequently merged with a cancer company.

Supplements

NAD

A coenzyme essential for sirtuin activity and many metabolic reactions, whose homeostasis is impaired with aging. Boosting its levels through precursors is a target for anti-aging interventions.

Nicotinamide Riboside

An NAD+ precursor or booster, one of two widely discussed forms used in studies of healthy aging. Efficacy and biological availability are subjects of debate and inconsistent reproducibility.

Nicotinamide Mononucleotide

An NAD+ precursor or booster, gaining popularity for its potential to increase NAD+ levels. Similar to NR, its efficacy and reproducibility in studies are inconsistent.