What caused the increased interest in longevity research around 2017-2018?

The speaker believes it was an inflection point, possibly triggered by Google's Calico focusing on longevity, which drew significant publicity and Silicon Valley interest to the field. Early efforts by researchers to emphasize healthspan and disease prevention also contributed significantly.

Are the Hallmarks of Aging an accurate model for targeting aging?

The Hallmarks of Aging, while helpful for driving interest and investment, can be misleading. Aging is not simply 12 distinct things to fix, but rather about maintaining a responsive, homeostatic network in the body. Interventions like rapamycin can impact all hallmarks, suggesting they are interconnected outputs rather than isolated causes.

How does chronic inflammation relate to aging and mTOR?

All interventions that extend lifespan tend to reduce chronic inflammation, and inflammation often appears as a primary driver in biological aging clocks. It forms a feed-forward loop with mTOR, where elevated baseline mTOR drives inflammation, and inflammation further drives mTOR, disrupting homeostasis.

How does rapamycin work and what are its longevity benefits?

Rapamycin dampens basal mTOR signaling, restoring its dynamic range. At low, intermittent doses for longevity (e.g., 5mg once a week), it's not immunosuppressant but dampens chronic inflammation, enhances autophagy, and changes protein translation, contributing to overall health span extension.

How can aging be mathematically modeled as a loss of resilience?

Aging can be modeled as a linear accumulation of undefined 'damage' or stochastic events that erode the body's resilience. This leads to a gradual lowering of 'hills' representing the energy required to fall into chronic disease or frailty states, resulting in an exponential increase in mortality, consistent with Gompertz law.

Can epigenetic reprogramming significantly extend human lifespan?

While certainly having an impact, the speaker is not convinced epigenetic reprogramming alone would cause a 'huge' difference in maximum lifespan. It's an open question whether reverting the epigenome can fully fix other accumulated damages (DNA damage, mitochondrial changes).

Is it possible for humans to achieve physical immortality?

The speaker is skeptical about physical immortality, considering the odds to be non-zero but close to zero. The current understanding and interventions suggest extensions of health span are feasible, but not an indefinite prevention of death from aging or disease.

Why is academic funding for basic aging research insufficient?

Despite significant private sector investment in biotech and supplements, academic funding for fundamental aging science is under threat. This imbalance prevents answering crucial basic science questions about stopping or reversing aging, diverting focus towards translational approaches.

Which chronic diseases are most inevitable with aging?

Cardiovascular and metabolic diseases are considered highly modifiable by lifestyle and interventions. Cancer, due to accumulation of mutations and unique immune system impacts, is seen as the most inevitable. Dementia remains an open question but might be highly modifiable.

How reliable are commercial biological aging clocks?

Commercial epigenetic clocks are often unreliable, with studies showing poor agreement between different tests, even when performed simultaneously. The speaker advises reconsideration for those looking to use them for personal biological age assessment.

What is alpha-ketoglutarate (AKG) and its role in longevity?

AKG is a central metabolite that declines with aging. Supplementation with time-release AKG in mice led to a 5-10% increase in lifespan and a dramatic reduction in frailty. Human trials are ongoing, with preliminary data suggesting it can reverse biological aging by a few years (oscillating effect).

What is the speaker's experience with sublingual NAD+ and exercise?

The speaker noticed an acute, significant enhancement in exercise performance (running faster, less breathlessness at higher heart rates) when taking sublingual NAD+ combined with apigenin (a CD38 inhibitor). This suggests improved cellular metabolic flexibility, but it's an N=1 observation.

Are GLP-1 agonists and SGLT2 inhibitors viable geroprotective drugs for healthy individuals?

These drugs might be comparable to rapamycin in their geroprotective potential, especially for individuals who are not 'perfectly' metabolically healthy. However, the speaker expresses concern about potential lean muscle mass loss with GLP-1 agonists and the need for more data in truly metabolically optimized people.

What are the risks of combining multiple longevity interventions?

The speaker cautions against combining many interventions simultaneously, as they are more likely to cancel each other out than have synergistic effects. Without controlled testing, there's no way to know what's working or if interventions are impairing each other, likening it to mixing 20 colors of paint to get an 'ugly gray outcome'.

Key Moments

357 ‒ A new era of longevity science: models of aging, rapamycin trials, biological clocks, & more

Peter Attia MD

Science & Technology3 min read133 min video

Jul 21, 2025|96,808 views|1,858|205

Peter Attia MD Dr. Peter Attia Early Medical The Drive Podcast The Drive Longevity Zone 2

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Key Moments

TL;DR

Longevity science explores aging models, rapamycin trials, biological clocks, and novel interventions like AKG and NAD+.

Key Insights

Aging can be modeled as both linear damage accumulation and exponential mortality risk.

Rapamycin, despite its immune-suppressive history, shows promise for longevity at specific intermittent doses.

Biological clocks, particularly those based on clinical chemistry, may become more predictive of mortality than chronological age.

Novel interventions like alpha-ketoglutarate (AKG) and sublingual NAD+ show potential for improving healthspan by supporting metabolic flexibility.

Understanding the precise mechanisms of aging interventions is crucial for designing synergistic combinations and avoiding detrimental interactions.

More research is needed into the long-term safety and efficacy of various longevity interventions, especially in human trials.

UNDERSTANDING THE MECHANISMS OF AGING

The conversation begins by questioning the fundamental causes of aging, moving beyond the "hallmarks" to a more integrated understanding. Brian Kennedy highlights the difficulty in defining aging precisely, suggesting that mathematical modeling, potentially through physics-inspired equations, is needed. He contrasts two aging models: linear accumulation of damage and exponential rise in mortality risk, emphasizing that interventions may need to address the underlying drivers of damage accumulation to truly impact maximum lifespan, not just improve function within the current damaged state.

THE PROMISE AND CHALLENGES OF RAPAMYCIN

Rapamycin emerges as a significant focus, with ongoing human trials exploring its potential for geroprotection. While historically known for immune suppression at high doses, intermittent dosing strategies are being investigated to harness its benefits for aging without severe side effects. The discussion delves into its mechanism via mTOR signaling, its impact on autophagy and protein translation, and its potential to restore youthful "dynamic range" in biological processes. However, the precise optimal dosing and timing for longevity remain subjects of ongoing research.

NOVEL INTERVENTIONS AND METABOLIC HEALTH

The conversation highlights promising new longevity interventions, including alpha-ketoglutarate (AKG) and sublingual NAD+. AKG, a metabolic intermediate that declines with age, shows potential in animal models to extend lifespan and reduce frailty. Sublingual NAD+ delivery, bypassing digestive degradation, is also being explored for its potential to enhance cellular metabolism. These interventions are investigated for their ability to restore cellular function and metabolic flexibility, offering a potential pathway to improve healthspan.

THE EVOLVING LANDSCAPE OF BIOLOGICAL CLOCKS

The utility of biological clocks in measuring aging and predicting health outcomes is discussed. While methylation-based epigenetic clocks have gained attention, the research presented suggests that clocks based on clinical chemistry parameters may offer better predictive power for mortality. These clocks, composed of standard, actionable biomarkers, have the potential to guide therapeutic interventions by identifying individuals at risk and revealing opportunities for intervention even in those appearing healthy by conventional standards.

ADDRESSING CHRONIC DISEASES AND RESILIENCE

The discussion touches upon the inevitability of aging-related diseases, with cardiovascular disease and metabolic dysfunction seen as more tractable than cancer or neurodegenerative diseases. The concept of resilience—the ability to return to a healthy state after perturbations—is central. Interventions are increasingly viewed not as fixing a single problem, but as restoring the body's capacity to maintain homeostasis and adapt to damage, thereby increasing resilience against various health threats.

THE FUTURE OF LONGEVITY RESEARCH AND CLINICAL APPLICATION

The conversation underscores the critical need for robust human clinical trials to validate longevity interventions. Challenges include developing reliable aging biomarkers, designing appropriate study endpoints, and navigating the complexities of combining interventions. There is a call for increased funding for basic and translational research, with a particular emphasis on interdisciplinary approaches involving physicists, biologists, and data scientists. The role of AI in accelerating discovery and optimizing experimental design is also highlighted as a rapidly advancing frontier.

Mentioned in This Episode

●Supplements

●Tools

●Companies

●Organizations

●Drugs & Medications

●Studies Cited

●Concepts

●People Referenced

Common Questions

The Buck Institute, established around 2000 in Marin County, was the first institute solely dedicated to understanding aging and longevity. It focused on basic science and grew significantly after 2017-2018 with increased interest and funding in the aging field.

Topics

Longevity Science Aging Research MTOR Pathway Epigenetic Clocks Alpha-ketoglutarate Urolithin A Spermidine Geroprotective Drugs Maximal Lifespan AI In Biology Resilience Theory Clinical Trials Biohacking Safety

Mentioned in this video

People

Matt Kaeberlein

A collaborator and researcher in the aging field, often debated with by the speaker regarding intervention effects and known for demonstrating the unreliability of commercial epigenetic clocks.

Josh Rabinowitz

A researcher who discussed intravenous NAD+ on a podcast, noting its effectiveness.

David Sabatini

Mentioned as a researcher familiar with mTOR, alongside Matt Kaeberlein.

Eric Burton

One of the faculty members at the Buck Institute, who later took over as CEO after the speaker left.

Peter Fedichev

A collaborator at Gero, described as a deep thinker in the aging field who views aging from a mathematical perspective, focusing on resilience and kinetic models.

Vadim Gladyshev

A researcher known for his focus on defining aging and the challenges in its scientific definition.

Software & Apps

ITP (Intervention Testing Program)

A program (primarily in mice) that tests interventions for their effects on lifespan and healthspan. The speaker's human studies aim to be an equivalent.

Concepts

Pillars of Aging

A framework proposed by the speaker after the 'Hallmarks of Aging' paper, also outlining pathways like inflammation and epigenetic changes, emphasizing their interconnectedness.

Gompertz Law

A mathematical model describing the exponential increase in mortality risk with age, compatible with the speaker's model of hills of resilience shrinking linearly.

Hallmarks of Aging

A framework proposed in 2013/2014 describing pathways in the cell thought to drive aging (e.g., inflammation, epigenetic changes). The speaker views them as outputs of aging, not distinct targets.

growth hormone

Supplements

alpha-ketoglutarate (AKG)

A central metabolite in the TCA cycle, which declines with aging. Time-release AKG supplemented in mice shows a 5-10% increase in lifespan and a dramatic increase in healthspan/reduced frailty.

Apigenin

A CD38 inhibitor, included in the sublingual NAD+ product, which increases NAD+ levels by blocking its consumption.

NAD+ (Nicotinamide adenine dinucleotide)

A central metabolite that declines with aging. The speaker was skeptical of NR/NMN but had a positive personal experience with sublingual NAD+ combined with apigenin, significantly enhancing exercise performance.

Spermidine

A robust molecule that extended lifespan and restored metabolism in mice, even in a calorie-challenged context. Optimistic about its potential.

Drugs & Medications

Cyclosporin

An immune suppressant often combined with rapamycin at higher doses for organ transplant patients to achieve a bigger effect and reduce side effects.

SGLT2 inhibitors

A class of drugs considered interesting for geroprotection, potentially comparable to rapamycin and GLP-1 agonists. The speaker notes their effect in metabolically healthy individuals is less clear.

Rapamycin

Organizations

Buck Institute

The first institute solely devoted to understanding aging and longevity, founded around 2000 in Marin County, California. The speaker was its second CEO in 2010.

NHANES (National Health and Nutrition Examination Survey)