#112 - Ned David, Ph.D.: How cellular senescence influences aging, and what we can do about it
Ned David, co-founder of Unity Biotechnology, explains cellular senescence and its impact on aging and age-related diseases. He discusses the development of senolytic medicines to treat conditions like osteoarthritis and macular degeneration, alongside entrepreneurial lessons.
Deep Dive Analysis
17 Topic Outline
Defining Longevity and the Indignities of Aging
Three Principles of Aging: Malleability, Control Knobs, and Turnability
Evolutionary Examples of Disparate Lifespans
Control Knobs of Aging: IGF-1 Pathway and Caloric Restriction
Other Control Knobs: Young Blood, Mitochondrial Dysfunction, and Methylation Clock
Introduction to Cellular Senescence as a Druggable Mechanism
The Senescence Paradox: Anti-Cancer Role vs. Aging Driver
Historical Context of Cellular Senescence Discovery
The Senescence-Associated Secretory Phenotype (SASP) and its Harmful Effects
The Dual Role of SASP: Harmful in Aging, Beneficial in Wound Healing
Ned David's Journey to Focusing on Senescence and Unity Biotechnology
Risk Analysis Framework for Biotech Company Creation
Identifying Senolytic Molecules and Targeting Senescent Cells
Senolytics for Osteoarthritis: Animal Models and Human Clinical Data
Senescence in Atherosclerosis and Cancer
Future Applications of Senolytics: Macular Degeneration and Brain Health
Lessons from Kythera and Advice for Aspiring Scientists/Entrepreneurs
6 Key Concepts
Cellular Senescence
A state where cells, after encountering unresolved stress, stop dividing permanently. These cells accumulate with age and contribute to various age-related diseases by secreting harmful factors, but also play a vital role in preventing cancer in younger organisms.
Senescence-Associated Secretory Phenotype (SASP)
A collection of over a hundred factors secreted by senescent cells into their microenvironment. These factors distort tissue function, driving inflammation and fibrosis, and contribute to the pathophysiology of aging and age-related diseases.
mTOR Complex
A master decision-maker biochemical system that regulates cell growth, division, and survival. It is influenced by nutrient availability (like in caloric restriction) and can be modulated by drugs like rapamycin to impact the rate of aging across species.
Methylation Clock
An ever-ticking clock based on the attachment or detachment of methyl groups to DNA over time. While its exact role is debated, changes in this epigenetic clock are correlated with aging and may contribute to noisy gene expression.
Yamanaka Factors
A set of four specific transcription factors that, when expressed in cells, can reprogram them into an embryonic-like state. This process can reset the methylation clock and induce features of youth in cells, though its application in whole organisms is complex.
Senolytic Molecules
Drugs designed to selectively target and eliminate senescent cells from the body. Unlike drugs that suppress cell secretions, senolytics aim to remove the source of harmful factors, potentially offering a more durable therapeutic effect with less frequent dosing.
8 Questions Answered
Ned defines longevity as the ability to live without the indignities of aging, such as profound degenerative disc disease or Alzheimer's, by using science and biology to change how we experience life.
Aging is flexible and malleable, nature uses biochemical 'control knobs' to adjust lifespan, and these control knobs are now identifiable and turnable by scientists.
Cells with DNA damage can either undergo programmed cell death (apoptosis) or enter a senescent state, but the specific factors that sway this decision are not yet fully understood.
Senescent cells exert their harmful effects by secreting a variety of pro-inflammatory and pro-fibrotic factors, collectively known as the SASP, which distort the function of surrounding healthy tissues.
The decision was based on the potential for senolytic molecules to be dosed infrequently (e.g., once a year) because they remove the source of the problem, leading to a potentially safer and more effective drug compared to continuous suppression of secretions.
While the ability to make senescent cells is an important anti-cancer mechanism in young organisms, in older individuals, senescent cells in the tissue microenvironment may paradoxically become pro-cancer, delaying tumor formation but not necessarily preventing it.
He focuses on picturing the simple, beautiful end-state of the idea, then identifying the fundamental existential risks to that vision, and systematically building work plans and budgets to address each of those risks.
He advises against creating a false choice between academia and entrepreneurship, encourages animating one's work with a single beautiful idea that truly excites them, and stresses the importance of learning from more experienced and patient mentors.
10 Actionable Insights
1. Identify Existential Project Risks
When pursuing a bold idea, picture the desired end state and identify the fundamental, existential risks to that vision. This allows for focused effort and resource allocation.
2. Streamline Project Risks (2-4)
For any project, distill potential failure points down to 2-4 primitive, durable risks to maintain focus and simplify complex decision-making over many years.
3. Budget Aligned with Risks
Budget and build work plans that systematically address and remove each identified risk, ensuring efficient use of time and money.
4. Implement Go/No-Go Decisions
In academic or project settings, explicitly define failure modes and set clear criteria for go/no-go decisions after a set period to conserve time and pivot to more promising endeavors.
5. Adopt Project Portfolio Approach
Manage multiple projects simultaneously, understanding that it’s acceptable for some to fail, as long as at least one demonstrates success and warrants continued focus.
6. Avoid False Career Choices
Do not perceive academia and entrepreneurship as mutually exclusive paths; many successful individuals blend both, so take time to consider all options without rushing.
7. Animate Work with Beautiful Idea
Pursue a ‘single beautiful idea’ that genuinely excites you and gives you goosebumps, as this passion fuels perseverance through challenges.
8. Learn from Experienced Mentors
Actively learn from people who are more skilled and experienced and who are patient enough to teach, as this is crucial for developing necessary intellectual and emotional toolkits.
9. Preserve Senescent Cell Creation
Do not genetically or otherwise interfere with the body’s natural ability to create senescent cells, especially when young, as this system is vital for preventing tumor formation.
10. Favor Source-Eliminating Therapies
When considering future health interventions, prioritize those that eliminate the source of a problem (e.g., senescent cells) rather than merely suppressing symptoms, as this may lead to less frequent dosing and potentially safer outcomes.
7 Key Quotes
Aging is not a rigid thing. So it's this flexible, malleable thing. And nature has throughout evolutionary history sort of bent and twisted aging for its own purposes to create creatures that have very different lifespans.
Ned David
The notion that you could essentially break the function of something or at least make it function a lot less well and double the lifespan of a creature was just a total mind warp for me and other people.
Ned David
If you want to know what the real biology is, it's the stuff that works in every lab, no matter who's doing it.
Ned David
The superpower of kids is the ability to make them, which prevents the replication of a cell that shouldn't replicate. And then it has the good sense to get rid of it before it harms anyone.
Ned David
The fact that eliminating these cells can produce a series of youth effects while not increasing cancer risk was very awesome and was actually kind of a theoretical validation of the picture in our minds about how this was all working.
Ned David
What motivated us was this would be a drug you would have to take all the time. And what we thought was so neat about the idea of making a molecule that could eliminate senescent cells, which we then named, we called them senolytic molecules. If you could make a senolytic molecule, you could dose it once.
Ned David
Cancer cells can divide and mutate and become anything to avoid death. They live under selective pressure, particularly in the context of drug. Senescent cells can't divide by definition. So their ability to access variation is dramatically reduced.
Ned David
2 Protocols
De-risking a Bold Idea in Biotech
Ned David- Picture the simple, beautiful end-state of the idea.
- Identify and write down the existential risks to that vision in the most primitive way possible (aim for 2-4 durable risks).
- Build work plans that systematically address and remove each identified risk.
- Develop budgets aligned with the work plans for risk removal.
- Politely seek funding from investors who understand and support the long-term vision.
Deciding Between Academic and Entrepreneurial Paths for Scientists
Ned David- Avoid creating a false choice; recognize that both paths can involve company creation and offer unique freedoms/responsibilities.
- Animate your work with a single, beautiful idea that genuinely moves you and gives you goosebumps.
- Actively seek to learn from people who are more experienced, skilled, and patient than you, allowing them to teach you.