#072 Morgan Levine, PhD, on PhenoAge and the Epigenetics of Age Acceleration — can we change the pace?
Dr. Morgan Levine, a founding principal investigator at Altos Labs and Yale, discusses biological aging, epigenetic clocks, and how lifestyle factors like smoking and body weight impact age acceleration. She also explores cutting-edge research in age reversal through partial reprogramming and plasma exchange.
Deep Dive Analysis
15 Topic Outline
Introduction to Dr. Morgan Levine and Epigenetics
Differentiating Chronological, Biological, and Functional Aging
Hallmarks of Aging and Potential Drivers: Focus on Epigenetics
Understanding Epigenetic Aging Clocks and DNA Methylation
Advantages of Epigenetic Clocks for Measuring Aging
Comparing First and Second Generation Epigenetic Clocks
Predictive Power of Epigenetic Clocks for Mortality and Disease
Epigenetic Age Acceleration and Lifestyle Factors
Impact of Sex and Menopause on Epigenetic Aging
Epigenetic Changes: A Developmental Program or Response to Damage?
Reversing Epigenetic Age with Partial Reprogramming
Plasma Exchange and Pro-Aging Factors in Blood
Reliability and Validity of Consumer Epigenetic Aging Tests
Future Directions in Aging Research and Epigenetic Clocks
Dr. Levine's Personal Lifestyle Habits for Healthy Aging
7 Key Concepts
Epigenetics
Epigenetics is described as the operating system of the cell, giving cells their identity (e.g., skin cell vs. neuron) despite having the same DNA. This program is rewritten with age, affecting a cell's characteristics and ability to withstand stress.
DNA Methylation (CPG Methylation)
This is a type of epigenetic modification where CPG sites (a C next to a G) on DNA can become methylated. Methylation in specific regions can repress gene expression, while its removal can activate regions, influencing which parts of the genome are accessible and expressed.
Epigenetic Clocks
These are tools based on machine learning that analyze patterns of CPG methylation across hundreds or thousands of sites in the genome. They predict an individual's age based on whether their methylation pattern resembles someone of a given chronological or biological age.
Age Acceleration
Age acceleration refers to the difference between an individual's chronological age and their predicted epigenetic age (e.g., from GrimAge or PhenoAge). A higher predicted age than chronological age indicates accelerated biological aging, which is associated with higher risk for disease and mortality.
Partial Reprogramming
This technique involves expressing Yamanaka factors (OSKM) to revert adult somatic cells to a younger state without causing them to lose their original cell identity. This process can reverse epigenetic age and improve functional aspects of cells, occurring before full conversion to an embryonic stem cell-like state.
Parabiosis
An experimental procedure where the circulatory systems of two mice, typically one young and one old, are surgically connected. This allows for the exchange of blood factors, showing that young blood can somewhat rejuvenate old mice, while old blood can accelerate aging in young mice.
Construct Validity
In the context of epigenetic tests, construct validity refers to the ability of a biological age measure (which is a latent, unobservable concept) to accurately predict or track with expected health outcomes. For epigenetic clocks, this means predicting mortality risk or disease risk even after accounting for chronological age.
8 Questions Answered
Chronological age is the number of years one has been alive, whereas biological aging refers to the physiological changes the body undergoes over time, affecting disease risk, functioning, and overall health, which can vary significantly between individuals.
Epigenetic clocks measure aging by analyzing patterns of DNA methylation at specific CPG sites across the genome. These patterns change with age, and the clocks use machine learning to predict an individual's age based on how their methylation profile compares to typical age-related patterns.
A major advantage is that epigenetic clocks can be used across almost any tissue or cell type, allowing for comparisons of aging rates in different organs within the same individual, unlike clinical blood tests which provide a single systemic measure.
Lifestyle and environment are major drivers, with smoking significantly accelerating epigenetic age, while exercise and a plant-based diet tend to decrease it. Genetics have a relatively small impact, estimated at 10-20% on epigenetic aging rate for most people, though it may be higher for supercentenarians.
Research into partial reprogramming using Yamanaka factors has shown that it's possible to revert adult cells to a younger epigenetic state without losing their cell identity, suggesting potential for age reversal at the cellular level.
Studies like parabiosis and plasma exchange suggest that factors accumulating in older blood can accelerate aging, while diluting these factors or introducing young plasma can lead to some rejuvenation, indicating a systemic influence on cellular and epigenetic aging.
Many consumer tests use older methods that are highly unreliable, showing significant variation (upwards of 8 years) if tested multiple times. Reliable tests incorporate statistical methods to reduce technical noise and should also demonstrate construct validity by predicting health outcomes like mortality risk.
Dr. Levine is most excited about understanding the mechanisms behind partial reprogramming and how it changes cell states and function, as well as figuring out what epigenetic clocks truly represent and the functional pathways linking them to mortality risk.
16 Actionable Insights
1. Maintain Active Lifestyle
Engage in regular exercise and maintain an active lifestyle, as exercise is considered the most powerful tool to intervene in and slow the aging process, offering benefits like reversing diabetes.
2. Avoid Smoking & Maintain Healthy Weight
To avoid unnecessary epigenetic age acceleration, prioritize avoiding harmful habits like smoking and keeping a healthy body weight, as these are significant factors in accelerated epigenetic aging.
3. Verify Epigenetic Test Reliability
Before using consumer-available epigenetic age tests, verify their reliability (consistency of results) and construct validity (predictive power for mortality/disease risk), preferring tests using second-generation clock methods.
4. Choose Sustainable Lifestyle Changes
Focus on lifestyle changes in diet and exercise that you can consistently stick to, as sustainability is more important than striving for perfection that cannot be maintained.
5. Make Informed Lifestyle Decisions
Use scientific knowledge about how lifestyle choices affect your health to make informed decisions about which interventions are personally worthwhile for potential benefits like increased healthy lifespan.
6. Eat a Plant-Based Diet
Consider eating a plant-based diet, as it is thought to decrease epigenetic age.
7. Practice Intermittent Fasting
Consider practicing intermittent fasting, for example, not eating until the afternoon, as it may offer benefits related to ketosis and metabolic switching.
8. Get Good Quality Sleep
Prioritize getting good quality sleep, as it is one of the general healthy habits that contribute to overall well-being and potentially slows aging.
9. Minimize Stress
Strive to minimize stress in your life, as it is one of the general healthy habits recommended for overall well-being and potentially slowing aging.
10. Avoid Heavy Drinking
Avoid heavy drinking, as it is among the general healthy habits recommended for overall well-being and to potentially minimize negative impacts on aging.
11. Combine Epigenetic & Biomarker Tests
When assessing health status, supplement epigenetic age tests with classical biomarker tests, as more data is always beneficial, especially given the early stage of epigenetic clock application for interventions.
12. Pre-order Dr. Levine’s Book
Pre-order Dr. Morgan Levine’s book, “True Age, Cutting Edge Research to Help Turn Back the Clock,” available May 3rd, 2022, on Amazon, to support her work and learn more about biological aging.
13. Listen to Dr. Horvath’s Episode
If intrigued by the discussion, listen to episode 62 with Dr. Steve Horvath, Dr. Levine’s former advisor, to learn more about epigenetic clocks and their potential forensic value.
14. Read Epigenetic Clocks Article
To learn more about epigenetic clocks, visit foundmyfitness.com/topics or search “found my fitness epigenetic aging clocks” on Google for a dedicated topic article.
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6 Key Quotes
Epigenetics in many ways is the operating system of the cell.
Rhonda Patrick
It's not the years you've been alive that's actually the problem. It's kind of how your body has changed over that time.
Dr. Morgan Levine
If you can actually quantify the process as best as possible, it's better than chronological age.
Dr. Morgan Levine
Smoking really accelerates your epigenetic age.
Dr. Morgan Levine
I don't think what we see with aging is just random stochastic damage or errors. I think we've always thought of aging as just this accumulation of errors. But it really might just be a program that kind of goes wrong...
Dr. Morgan Levine
If they could bottle the effects of exercise, it would be the biggest thing in aging research that, you know, exists.
Dr. Morgan Levine