#357 ‒ A new era of longevity science: models of aging, human trials of rapamycin, biological clocks, promising compounds, and lifestyle interventions | Brian Kennedy, Ph.D.
Brian Kennedy, a renowned biologist and director at NUS, discusses human aging research, including rapamycin's role, the limitations of current aging models, and promising compounds like AKG and sublingual NAD. He also highlights lifestyle's impact and the potential of GLP-1/SGLT2 drugs for healthy longevity.
Deep Dive Analysis
21 Topic Outline
Brian Kennedy's Journey from Buck Institute to Singapore
The Inflection Point in Longevity Research Funding (2017-2018)
Rethinking Aging: Linear Decline vs. Exponential Mortality Risk
The Role of mTOR and Inflammation in Aging
Rapamycin's Potential to Slow Aging and Enhance Immunity
The Concept of Resilience and its Decline with Age
Speculation on Future Longevity Interventions: Noise Reduction and Reprogramming
Evaluating Epigenetic Clocks and the Primacy of Epigenetics
Balancing Immortality Quest with Urgent Healthspan Improvement
Comparing Inevitability and Modifiability of Chronic Diseases
Human Clinical Trials for Aging Interventions in Singapore
Alpha-Ketoglutarate (AKG) for Healthspan Benefits
Urolithin A and Mitochondrial Health
Sublingual NAD Boosters and Exercise Performance
Other Promising Longevity Interventions: Spermidine, 17𝛼-estradiol, HRT
Biological Aging Clocks and Actionable Clinical Biomarkers
Evaluating Rapamycin, Metformin, GLP-1s, and SGLT2s for Longevity
The Role of Muscle, Strength, and Fitness in Healthspan
Risks of Combining Too Many Longevity Interventions
AI's Potential Impact on Aging Research
Concerns in Longevity Clinics and Biohacking Trends
7 Key Concepts
Hallmarks of Aging
These are cellular and molecular pathways (e.g., inflammation, epigenetic changes) thought to drive the aging process. While they drove interest in the field, they are interconnected outputs of a complex network, not independent targets to fix in isolation.
Homeostasis in Aging
This refers to the body's ability to maintain a responsive, equilibrium-seeking network that keeps it functional and healthy. Healthy aging is about maintaining this dynamic range, which deteriorates with age, making it harder to recover from stressors.
Resilience (in Aging)
This is the capacity of the body to resist and recover from stressors and maintain a healthy state. Brian Kennedy describes it metaphorically as living in a deep valley when young, with steep hills to failure states, where these hills become lower and easier to cross with age.
Linear Accumulation of Damage
This concept suggests that various subtle changes and stochastic events accumulate linearly over time, putting stress on the body's homeostatic network. This is distinct from the exponential increase in mortality risk, which is explained by the decreasing resilience.
Oscillating Component of Aging
This is a dynamic, age-related factor that fluctuates around the linear accumulation of damage, reflecting how well an individual is functioning at their current damaged state. Most current interventions are thought to impact this oscillating component, improving healthspan without necessarily extending maximum lifespan.
Longevity Normalizing vs. Extending
Longevity normalizing refers to interventions that restore a shorter-lived organism (e.g., mice in suboptimal conditions) to a normal lifespan. Longevity extending refers to interventions that genuinely prolong the maximum lifespan beyond what is typically observed in healthy controls.
Antagonistic Pleiotropy
This is the concept that genes or pathways beneficial early in life (e.g., for growth and reproduction) may have detrimental effects later in life, contributing to aging. Many long-lived mutants in simple organisms often exhibit fitness costs.
10 Questions Answered
The field reached an inflection point, possibly triggered by initiatives like Calico and increased publicity, leading to greater Silicon Valley interest and a growing understanding that aging could be slowed to prevent disease.
While they identify pathways involved in aging, they are interconnected outputs of a complex network, not independent problems. Targeting individual hallmarks in isolation is unlikely to fully address aging, which is more about maintaining overall homeostatic balance.
The linear accumulation of damage reduces the body's resilience (metaphorically, lowering the 'hills' to failure states), making it exponentially more likely for stochastic events to push the body into a disease or frailty state.
Most current interventions are thought to primarily impact the 'oscillating component' of aging, improving healthspan and functional well-being for 5-10 years, but likely not extending maximum human lifespan significantly.
Inflammation is consistently reduced by interventions that extend lifespan, and it frequently appears as a primary driver in biological aging clocks. It's often linked to an inability to turn off pathways like mTOR, creating a feed-forward loop of disruption.
mTOR is a nutrient-responsive kinase that, when turned down, extends lifespan across a wide range of species. During aging, baseline mTOR levels tend to creep up, impairing the dynamic range needed for healthy cellular function.
While some second-generation epigenetic clocks (like GrimAge and PhenoAge) predict mortality better than chronological age, a clinical chemistry-based clock using standard, actionable blood markers has been shown to predict mortality even more effectively.
Cardiovascular and metabolic diseases are considered highly modifiable. Cancer is seen as more inevitable due to mutation accumulation and distinct immune system impacts, while dementia's inevitability is less understood but may also be highly modifiable.
Combining multiple interventions without understanding their interactions is risky, as they are more likely to cancel each other out or produce unpredictable, potentially harmful effects rather than synergistic benefits.
High VO2 max, muscle mass, and strength are among the strongest predictors of healthspan and are super important for squaring the longevity curve, though their impact on maximum lifespan is less clear.
21 Actionable Insights
1. Prioritize VO2 Max, Muscle, Strength
Focus on achieving and maintaining high VO2 max, significant muscle mass, and overall strength. These factors profoundly reduce mortality risk, potentially more than avoiding other major health risks like smoking or diabetes.
2. Aggressively Manage Pre-conditions Early
Be proactive in managing early signs of metabolic and cardiovascular diseases, even if slightly outside conventional ‘healthy’ ranges. Early optimization through medication or lifestyle changes can lower biological age and extend lifespan.
3. Understand Aging as Resilience
Frame aging as a process where the body’s resilience, or ability to return to a healthy state after stressors, gradually declines. The goal of interventions should be to maintain or improve this resilience, keeping the ‘hills’ of health higher.
4. Focus on Homeostasis, Not Hallmarks
Avoid viewing aging as a collection of isolated ‘hallmarks’ to be fixed individually. Instead, concentrate on maintaining and improving the body’s overall homeostatic network and its inherent capacity for healthy function.
5. Break mTOR-Inflammation Feedback Loop
Recognize that chronic, low-grade inflammation and elevated baseline mTOR signaling create a destructive feedback loop in aging. Interventions should aim to restore the dynamic range of mTOR and dampen chronic inflammation.
6. Avoid Excessive Intervention Combinations
Exercise caution when combining many different longevity interventions (e.g., 20 pills), as they are more likely to cancel each other out or produce unpredictable, potentially negative outcomes rather than synergistic benefits.
7. Measure Personal Intervention Effects
When experimenting with new interventions, try one or two at a time, carefully observe your body’s response, and use simple measures to track effects. This approach helps identify what works for you and prevents confounding results.
8. Empower Self in Health Decisions
Actively educate yourself about health and longevity interventions, understanding their benefits, risks, and uncertainties. This informed approach allows for better personal health decisions and improved compliance.
9. Reconsider HRT for Women
For women, shift the perspective on Hormone Replacement Therapy (HRT) from ‘should I do it?’ to ‘is there any reason I shouldn’t?’. The value of hormone replacement is believed to significantly outweigh the risks for the majority of women.
10. Optimize Healthspan, Not Max Lifespan
Understand that current longevity interventions primarily improve healthspan (quality of life in later years), potentially adding 5-10 years of healthy life. They are less likely to fundamentally alter maximum human lifespan to extreme ages like 150 or 200.
11. Intermittent Rapamycin Dosing
If considering rapamycin for longevity, opt for an intermittent dosing regimen, such as once a week, allowing trough levels to come down. This approach is less likely to cause immune suppression compared to daily high doses.
12. Time Rapamycin Around Exercise
If using rapamycin, consider timing its intake to avoid hard exercise within 24 hours, as it might acutely impair performance. Optimal training might occur three to four days after taking rapamycin, suggesting a restored dynamic range.
13. Use Clinical Chemistry for Biologic Age
Utilize a comprehensive panel of standard clinical chemistry markers (e.g., from a complete blood count and routine metabolic panel) to derive an actionable biological age assessment. This approach provides insights into modifiable factors and suggests solutions for improvement.
14. Consider Time-Release AKG Supplementation
Explore supplementing with time-release Alpha-Ketoglutarate (AKG), potentially combined with Vitamin A (for males), as it has shown to increase lifespan and dramatically decrease frailty in mice. Time-release is crucial for its efficacy.
15. Sublingual NAD for Exercise Performance
Investigate sublingual NAD supplementation, especially when combined with apigenin (a CD38 inhibitor), as this delivery method bypasses digestion and may acutely enhance exercise performance by increasing NAD levels.
16. Spermidine for Metabolism
Consider spermidine as a robust molecule that may suppress metabolic dysfunction and extend lifespan, particularly in contexts of metabolic challenge, based on mouse data.
17. Urolithin A for Mitochondrial Health
Explore urolithin A, which has shown promise in reducing frailty in male mice and is believed to enhance mitochondrial turnover (mitophagy) and biogenesis, contributing to mitochondrial health.
18. SGLT2/GLP-1 for Metabolic Health
For individuals who are not perfectly metabolically healthy, SGLT2 inhibitors and GLP-1 agonists may offer benefits beyond their traditional use. These drug classes can optimize metabolic health and potentially contribute to geroprotection.
19. Avoid Unproven Gene/Stem Cell Therapies
Exercise extreme caution with unproven interventions like gene therapy (e.g., folistatin) and questionable stem cell therapies. These carry significant safety concerns and lack efficacy data, especially when offered by unregulated practitioners.
20. Distrust Commercial Biologic Age Tests
Be skeptical of commercial biological age tests, as many lack standardization and reliability. Different tests, and even duplicate runs of the same test, often yield inconsistent results.
21. Deepen Longevity Knowledge
Consider subscribing to resources like Peter Attia’s premium membership to deepen your understanding of health and wellness. This provides access to exclusive content and helps stay informed on the science of longevity.
7 Key Quotes
I think the hallmarks was good because it drove interest in the field... but it also is misleading because I think the idea that aging is 12 different things and you just need to fix all 12 of them is completely wrong.
Brian Kennedy
Healthy aging is about maintaining homeostasis. It's about maintaining a responsive network in your body that sort of keeps you in equilibrium, responds to the events that are happening during aging, the stochastic events, the damage that's happening, and it keeps you functional.
Brian Kennedy
I think that what we're doing right now is sort of working around the edges. We're doing things that may have five or 10 years impact on healthspan, which, by the way, is a revolution if that's successful.
Brian Kennedy
If anybody tells you they have the answers to that, they're lying to you or they're lying to themselves. We don't know. It's maybe the most important question in biology, and we should be throwing money at it.
Brian Kennedy
I think the question should not be, should a woman do HRT? The question should be, is there any reason a woman should not do HRT?
Brian Kennedy
If you're taking 20 pills, it's like mixing 20 colors of paint together. You're going to get some ugly gray outcome or at best, you're going to get an unknown outcome that we can't predict.
Brian Kennedy
It used to be that yeast and worms and flies were the model organisms for aging research and now billionaires are the model organisms.
Brian Kennedy
2 Protocols
Human Clinical Intervention Study for Aging (Singapore)
Brian Kennedy- Recruit 150-200 healthy individuals aged 40-60 (may have pre-conditions but not defined diseases).
- Administer rapamycin (5mg once a week) or placebo for 6 months.
- Measure a wide range of parameters including various aging clocks, inflammatory cytokine panels, functional measures (pulse wave velocity, DEXA, strength, cognition).
- Conduct a 3-month follow-up after the intervention to assess sustained changes.
Personalized Longevity Intervention Strategy (Brian Kennedy's Approach)
Brian Kennedy- Select one or two interventions to try at a time (e.g., AKG, NAD).
- Measure relevant parameters (even simple ones) before and after starting the intervention.
- Observe body's response, including exercise performance or other noticeable effects.
- Avoid combining many interventions simultaneously to understand individual effects and prevent potential negative interactions.