We doubled human lifespans in the last 200 years. Can we do it again? | Andrew Steele

Key Concepts

• Longevity Science/Medicine: Focuses on increasing healthspan (period of life free from disease and pain) rather than just lifespan or immortality.
• Healthspan vs. Lifespan: The distinction between living longer and living longer in good health.
• Biological Age vs. Chronological Age: Biological age refers to the physiological state of the body, while chronological age is simply the number of years lived.
• Hallmarks of Aging: Fundamental biological processes that contribute to aging, with 12 identified.
• Senescent Cells: "Old" cells that accumulate with age and are implicated in driving age-related diseases.
• Senolytic Drugs: Drugs designed to eliminate senescent cells.
• Cellular Reprogramming: The process of resetting the biological clock within cells, potentially reversing aging.
• Yamanaka Factors: Four genes identified by Shinya Yamanaka that can reprogram adult cells into stem cells, and also reverse aging.
• Epigenome: A layer of chemical modifications on DNA that controls gene expression, changing with age.
• Epigenetic Age Tests: Tests that measure changes in the epigenome to estimate biological age.
• Autophagy: A cellular process of "self-eating" where damaged proteins are consumed and recycled.
• Repurposed Drugs: Existing medications developed for other conditions that show potential for longevity benefits.
• Systems Biology Model: A comprehensive model of human biology that integrates various data points (DNA, gene expression, cell changes, protein levels) to understand aging.
• AI in Biology: The potential of Artificial Intelligence to accelerate biological research, contingent on sufficient data.

The True Goal of Longevity Science: Enhancing Healthspan

The video clarifies that longevity science and medicine are not about achieving immortality or preventing death, but rather about increasing healthspan. This means extending the period of life that is free from disease, pain, and cognitive decline like memory loss. The speaker, Dr. Andrew Steele, a longevity scientist, writer, and campaigner, emphasizes that this is a crucial distinction, moving away from the misconception of billionaires pursuing eternal life through extreme measures.

Economic and Societal Impact

The economic benefits of slowing down the aging process are substantial. Economists have calculated that even a single year of slowed aging, leading to healthier lives, could be worth $38 trillion. This would allow individuals to remain active, happy, and engaged in their lives and with their families for longer. Dr. Steele posits that this could represent the "greatest revolution in the history of medicine."

The Physics of Aging: An Exponential Risk

Dr. Steele, who transitioned from physics to longevity science, highlights a fundamental graph illustrating the relationship between age and the risk of death. For humans, this risk doubles approximately every eight years, demonstrating an exponential increase. This means that while a 39-year-old has a low risk of death (around 1 in 1,000), this risk escalates significantly with age, reaching approximately 1 in 6 by the 90s if no scientific advancements are made.

Contrasting Animal Aging

This exponential risk is contrasted with certain animals, such as giant tortoises, some fish, and salamanders, whose risk of death remains flat regardless of their age. By this statistical definition, these animals "literally do not age." This observation prompts a shift in perspective: viewing aging not as a terrifying inevitability, but as a fundamental biological "ticking clock" that drives age-related diseases like cancer, heart disease, stroke, and dementia. The core question becomes: can this ticking clock be understood and manipulated?

Measuring Biological Age: Beyond Chronology

In the last decade, scientists have developed methods to measure biological age, distinct from chronological age. While chronological age is simply the number of years lived, biological age assesses the physiological state of the body.

Methods for Assessing Biological Age

• Blood Tests: Analyzing various biomarkers in the blood.
• Epigenetic Tests: Examining changes in the epigenome.
• Functional Measures: Assessing physical capabilities like grip strength, which declines with age.

Epigenetic Age Tests: A Promising but Developing Field

Epigenetic age tests are currently generating significant interest. The genome is the body's DNA, the instruction manual. The epigenome is a layer of chemical modifications on top of the genome, acting like "notes in the margin" that dictate which DNA sequences are used and when. As we age, the epigenome changes. Measuring these changes allows for the assignment of a biological age.

However, Dr. Steele cautions that while these tests show correlation with age, their causal relationship is not fully understood. More experiments are needed to determine if intervening in these "biological clocks" can indeed influence aging.

The 12 Hallmarks of Aging and Targeted Interventions

Scientists have identified 12 hallmarks of aging, representing the fundamental biological processes underlying aging.

Senescent Cells and Senolytic Drugs

One significant hallmark is the accumulation of senescent cells. These are "old" cells that contribute to various diseases as we age. The hypothesis is that removing these cells could slow or even reverse aging. Senolytic drugs are being developed to target and kill these senescent cells.

Case Study: Senolytics in Mice Experiments in mice have shown promising results:

• Senolytic drugs made the mice biologically younger.
• They lived longer.
• Crucially, they experienced less cancer, heart disease, and cataracts, indicating a reduction in age-related ailments rather than just prolonging frailty. This demonstrates that targeting fundamental aging processes can address multiple age-related problems.

Cellular Reprogramming: A Futuristic Approach

Cellular reprogramming is another exciting area, described as a treatment "fallen through a wormhole from the future." This involves resetting the biological clock within cells.

Shinya Yamanaka's Discovery (Mid-2000s):

• Yamanaka aimed to revert adult cells back to an embryonic state to create stem cells for tissue repair.
• He discovered that using four specific genes, known as Yamanaka factors, not only turned back the developmental clock but also the aging clock. Cells treated with these factors became biologically younger.

Challenges and Progress:

• Naive Application: Continuously activating Yamanaka factors in mice led to organ failure and death because the cells became undifferentiated stem cells, losing their specialized functions.
• Transient Activation: Scientists found that activating these genes only temporarily, for example, "at weekends," was sufficient to reset the biological clock without causing developmental regression.
• Human Application: The challenge lies in delivering these four genes to every cell in the human body. This is a complex gene therapy requiring advanced biotechnology.
• Investment: This has attracted significant investment, with companies like Altos Labs, backed by $3 billion from investors including Jeff Bezos, focusing on this area.

Limitations of Reprogramming: Dr. Steele notes that while promising, epigenetic clock resetting cannot address all aging issues, such as DNA mutations or damage to extracellular components like collagen.

Repurposed Drugs: The Quickest Wins

The most immediate potential gains in longevity science are expected from repurposed existing drugs. These drugs have already undergone extensive development, their mechanisms of action in humans are understood, and their safety profiles are partially known.

Metformin: A Diabetes Drug with Longevity Potential

• Metformin, a common drug for diabetes, is being investigated for its potential to slow aging.
• A proposed human trial aims to observe if individuals taking metformin experience later onset of cancer, dementia, and heart disease, and if they live longer compared to a control group.
• Three to five years of data from such trials could provide significant insights.

Rapamycin: A Powerful Immunosuppressant with Anti-Aging Effects

• Rapamycin, originally isolated from bacteria on Easter Island, was found to be antifungal and later discovered to inhibit human cell growth.
• Mechanism: It targets a core component of cellular metabolism, initiating autophagy (Greek for "self-eating"). Autophagy is the process of breaking down and recycling old, damaged proteins.
• Landmark Study (2009): Giving rapamycin to mice late in life extended their lifespan by 10-15%, marking the first time a drug demonstrated aging deceleration in mammals.
• Broader Application: Rapamycin has since been tested in various organisms and contexts, showing consistent positive effects.
• Human Trial Potential: Due to existing knowledge about rapamycin, human trials could commence relatively soon, potentially leading to the first longevity drug within 5-10 years, provided sufficient funding.

The Ethical Landscape of Longevity

Dr. Steele finds it "fascinating" that longevity research often elicits more ethical questions than, for example, cancer research. He addresses common concerns:

• Boredom and Overpopulation: Questions about whether extended life would lead to boredom or overpopulation, resource depletion, and environmental damage.
• Moral Categorization: He argues that aging should not be placed in a separate ethical category but viewed as an extension of modern medicine.

The Global Burden of Aging and Underfunding

Aging is the leading cause of death globally. Over 100,000 people die daily from age-related diseases like cancer, dementia, and increased susceptibility to infectious diseases.

The Economic and Health Imperative

• Slowing the increase in mortality risk associated with aging could lead to the development of drugs that prevent multiple diseases simultaneously, rather than treating them individually.
• Despite this, longevity science receives shockingly little funding. In the US, government funding is just over $1 per American, which is considered "absolutely remarkable" given that aging contributes to 85% of deaths in the US.

The Need for a "Human Genome Project" for Aging

To truly understand aging, Dr. Steele advocates for a large-scale project akin to the Human Genome Project. This would involve:

• Comprehensive Data Collection: Measuring not only DNA but also gene expression, cellular changes, and protein levels in blood and between cells.
• Systems Biology Model: Feeding this data into a "giant computer model" to create a comprehensive systems biology model of a human being.

The Role of AI and Data

• While AI is often touted as a cure for all diseases, its effectiveness is dependent on the quality and quantity of data it's trained on.
• AlphaFold Example: The AI that predicts protein folding was only possible due to decades of protein structure data stored in the Protein Data Bank, a resource estimated to cost $21 billion to rebuild.
• To develop AI that can predict human biological processes, a similar level of investment in data collection and infrastructure is required.

Conclusion: A Transformative Era

With a potential economic benefit of $38 trillion (and likely more), the investment in understanding and intervening in aging is highly justifiable. Dr. Steele concludes that this is a "hugely exciting time to be alive," with the possibility of living "maybe for a little bit longer than we thought," and more importantly, living those extra years in good health.