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

Kennedy emphasizes that aging is not a collection of isolated phenomena but rather a networked process involving multiple interconnected pathways. He critiques the popular “hallmarks of aging” framework, suggesting that these hallmarks are more like outputs or markers of aging rather than independent causal drivers. Instead, he proposes that aging fundamentally reflects a decline in the body’s homeostatic network—the system that maintains equilibrium and responds dynamically to damage and stress. This network’s resilience diminishes over time, leading to the progressive loss of function that characterizes aging.

The Role of Inflammation and mTOR in Aging

A recurring theme in the conversation is the centrality of chronic inflammation in aging. Kennedy points out that nearly all interventions known to extend lifespan, from animal models to emerging human studies, share the common effect of reducing chronic inflammation. He discusses how inflammation might not be the root cause but is so deeply entwined with aging processes that modulating it yields significant benefits. The mTOR (mechanistic Target of Rapamycin) pathway emerges as a key regulator in this context. Kennedy explains that mTOR activity, which is essential for processes like wound healing and immune response, becomes dysregulated with age, leading to a loss of dynamic range and persistent low-level activation that fuels inflammation.

Delving deeper into mTOR, Kennedy recounts the discovery of its role in aging through yeast genetic screens, where reducing mTOR signaling extended lifespan. He explains that mTOR is a nutrient-responsive kinase that integrates signals from carbohydrates and amino acids, linking it to calorie restriction’s known effects on longevity. The conversation also touches on the dual nature of mTOR modulation: while high doses of rapamycin (an mTOR inhibitor) are immunosuppressive and used clinically in organ transplantation, intermittent low-dose regimens may restore youthful dynamic regulation without suppressing immunity, making rapamycin a promising geroprotector.

Models of Aging and the “Slope” of Lifespan

Kennedy introduces a conceptual model likening aging to a ball rolling in a valley, where youthful resilience corresponds to a deep valley that keeps the ball near a healthy state despite perturbations. As aging progresses, the valley’s walls erode, making it easier for the ball to roll into “failure states” such as chronic diseases or frailty. This model explains why mortality risk increases exponentially with age (Gompertz law), even though the underlying damage accumulates linearly. The exponential rise in risk reflects the increasing probability of crossing thresholds into irreversible decline.

This framework also clarifies why current interventions may only “tinker around the edges” by improving the oscillations or fluctuations around the damaged state rather than fundamentally altering the linear accumulation of damage. Kennedy suggests that to achieve a true shift in maximal human lifespan, the field must find ways to bend the slope of that linear damage accumulation, effectively slowing the underlying entropy or noise in biological systems. This remains a major challenge and a frontier for future research.

Rapamycin: Potential and Limitations

Rapamycin is discussed extensively as the “gold standard” small molecule with the most robust evidence for geroprotective effects across species. Kennedy expresses cautious optimism about rapamycin’s potential to extend healthspan in humans, especially when administered intermittently to avoid immunosuppression. He describes ongoing human trials, including a six-month study in Singapore involving 5 mg weekly dosing in middle-aged adults, which measures a broad range of biomarkers, including inflammatory cytokines, biological clocks, and functional outcomes.

However, Kennedy tempers expectations by noting that rapamycin’s effects in humans are likely to be more modest than in short-lived model organisms like worms or flies, where lifespan extensions can be dramatic. He also highlights complexities such as rapamycin’s transient negative impact on muscle recovery immediately after exercise, underscoring the importance of dosing timing and regimen. Ultimately, he views rapamycin as a valuable tool for improving healthspan but unlikely to dramatically change maximal lifespan on its own.

Biological Clocks and Measuring Aging

The podcast delves into the evolving landscape of biological clocks, particularly epigenetic clocks based on DNA methylation patterns. Kennedy acknowledges the excitement around these clocks but cautions against overinterpreting their significance. He points out that many commercial methylation tests lack reproducibility and that epigenetic changes may be more reflective of aging correlates rather than causal drivers. He also notes that other biological data—such as proteomics, microbiome profiles, and even facial structure—can produce similarly accurate age predictions, suggesting that methylation is not uniquely informative.

Kennedy and collaborators have developed clinical chemistry-based aging clocks using standard blood biomarkers, which outperform some methylation clocks in predicting mortality. These clocks are more actionable for clinicians because they rely on familiar parameters like blood counts and metabolic markers. He envisions biological clocks as tools to stratify risk and guide interventions rather than definitive measures of biological age, emphasizing the need for clocks that predict meaningful outcomes like mortality and disease rather than just chronological age.

Alpha-Ketoglutarate and Other Emerging Interventions

Alpha-ketoglutarate (AKG), a key metabolite in the Krebs cycle, is highlighted as a promising natural compound with geroprotective effects in animal models. Kennedy describes how AKG supplementation in mice extends lifespan by 5-10% and significantly reduces frailty, suggesting a “squaring” of the longevity curve by improving healthspan. He discusses ongoing human trials with time-release AKG formulations, aiming to validate these effects in people.

The conversation also touches on other emerging compounds such as urolithin, spermidine, and NAD precursors. Kennedy shares unpublished data on urolithin’s sex-specific effects in mice and its potential to enhance mitochondrial turnover. He expresses cautious skepticism about NAD precursors like nicotinamide riboside (NR), noting limited evidence for robust effects in humans despite widespread enthusiasm. The synergy between AKG and sublingual NAD supplementation is an intriguing anecdote from his personal experimentation, highlighting the potential for combinatorial approaches.

The Challenge of Translating Animal Research to Humans

Kennedy repeatedly emphasizes the difficulty of translating findings from model organisms to humans. He notes that short-lived species like worms and flies often respond dramatically to interventions that have more modest or uncertain effects in mammals. Even in mice, lifespan extension studies can be confounded by variability in control lifespans and environmental factors. He stresses the importance of robust, reproducible animal data before moving to human trials and the need for well-designed clinical studies with appropriate endpoints.

In humans, the complexity increases further due to genetic diversity, lifestyle factors, and the long timescales involved. Kennedy advocates for iterative translational research pipelines that integrate data from multiple model systems and carefully designed human trials. He also highlights Singapore’s unique position as a small, compliant population with strong government support, making it an ideal setting for pioneering longevity research.

The Role of Lifestyle and Conventional Medicine

While the podcast focuses heavily on molecular and pharmacological interventions, Kennedy underscores the enduring importance of lifestyle factors such as exercise, nutrition, and hormone replacement therapy (HRT). He notes that exercise, particularly resistance training to maintain lean muscle mass, is one of the most powerful modulators of healthspan, reducing frailty and improving metabolic health. He also discusses the underutilization of HRT in women worldwide, arguing that the benefits often outweigh the risks and that more education is needed to overcome lingering fears.

Kennedy also points out that many existing medications for cardiovascular and metabolic diseases—such as statins, antihypertensives, and metformin—may have geroprotective effects by managing preconditions and reducing the risk of failure states. He advocates for more aggressive optimization of these parameters in clinical practice, suggesting that improving healthspan through conventional medicine remains a critical and underappreciated strategy.

The Complexity of Combining Interventions

A significant cautionary note arises around the idea of combining multiple longevity interventions. Kennedy warns that mixing numerous compounds without understanding their interactions can lead to unpredictable and potentially counterproductive outcomes. He likens it to mixing many colors of paint, which often results in a dull gray rather than a vibrant effect. He advocates for systematic, factorial studies to identify synergistic combinations rather than ad hoc polypharmacy.

This complexity extends to lifestyle and pharmacological interventions alike. Kennedy stresses the importance of measuring individual responses and adjusting regimens accordingly, rather than adopting a “more is better” approach. He also highlights the need to understand mechanisms of action at a molecular level to rationally design combination therapies that target complementary pathways.

The Promise and Perils of Emerging Technologies

Gene therapy, stem cell treatments, and other cutting-edge biotechnologies are discussed as exciting but still experimental frontiers. Kennedy expresses interest in these modalities but urges caution due to limited safety data and the potential for adverse effects. He shares concerns about unregulated clinics offering unproven therapies, emphasizing the need for transparency, rigorous clinical trials, and patient education.

He also touches on the potential of AI and machine learning to revolutionize aging research. While current AI applications focus on data analysis and biomarker development, Kennedy envisions future AI systems that can help formulate experimental hypotheses and design smarter studies. However, he acknowledges that this remains an open question dependent on advances in computational power and algorithmic innovation.