Morgan Levine, PhD, on PhenoAge and the Epigenetics of Age Acceleration — can we change the pace?

Epigenetic Aging Clocks

Aging: Chronological vs. Biological

• Chronological aging: age according to time
• Biological aging: changes in the body over time
• Phenotypic/​​functional aging: observable changes in physical and cognitive abilities

Epigenetic Aging Clocks

• Measure CPG methylation or DNA methylation
• Compare methylation patterns to estimate biological age
• Can be used across various tissue and cell types

First vs. Second Generation Epigenetic Aging Clocks

• First generation (e.g., Horvath Clock): use machine learning to predict chronological age based on methylation data
• Second generation (e.g., PhenoAge, GrimAge): use machine learning to predict mortality or health span based on methylation data and clinical biomarkers

Comparing Epigenetic Aging Clocks to Clinical Biomarkers

• Epigenetic aging clocks provide a more comprehensive measure of biological age
• Second generation clocks are better at predicting mortality and health span than first generation clocks
• Epigenetic clocks can be used across various tissue and cell types, unlike some clinical biomarkers
  Epigenetic Age Acceleration
• Discordance between chronological age and predicted age based on epigenetic clocks 
• Indicates higher risk for disease or mortality
• Genes have a 10–20% impact on epigenetic aging rate
• Majority of impact comes from environment and lifestyle

Factors Affecting Epigenetic Age Acceleration

• Socioeconomic status
• Smoking
• Exercise
• Plant-​​based diet
• Moderate alcohol consumption
• Good quality sleep
• Minimized stress

Gender and Epigenetic Age

• Females generally have lower epigenetic age than males
• Menopause accelerates epigenetic aging in women

Stability of Methylation Patterns

• Not stable over the lifespan
• Most changes happen during development
• Epigenetic clocks do not mirror functional aging patterns
  Epigenetic Aging and Disease States
• Epigenetic age increases during development, becomes more linear around age 20, and slows down after age 80 
• Disease states like type 2 diabetes or cardiovascular disease may accelerate aging, but more longitudinal data is needed
• Aging and development are closely tied, with some studies showing that extending developmental periods can extend lifespan

Immortalized Cells and Epigenetic Age

• Immortalizing cells with telomerase can cause their epigenetic age to continue increasing over time
• Inflammation may be a major driver of epigenetic age acceleration in blood
• Epigenetic clocks can be tuned to measure different systems, such as inflammation

Inflammation and Epigenetic Age Acceleration

• Inflammatory biomarkers correlate with epigenetic age acceleration, especially in blood
• In a study of cancer patients, epigenetic age acceleration was seen after treatment, but normalized after six months to a year
• Second-​​generation epigenetic clocks may be better at capturing inflammation-​​related changes

COVID and Inflammation Epigenetic Clock

• Preliminary data shows that individuals with severe COVID symptoms have more accelerated inflammation epigenetic clock than those with mild or asymptomatic symptoms
• Further research needed to track how long it takes for symptoms to resolve and return to baseline
  Epigenetic Age Reversal and Partial Reprogramming
• Partial reprogramming aims to reverse the epigenetic clock without changing a cell’s identity 
  • Based on Yamanaka factors (OSKM) that can turn adult cells into embryonic stem cells
  • Epigenetic age can be reversed in cells, but the functionality and implications are still being studied
• Research on premature aging mouse models 
  • Reversal of some hallmarks of aging in multiple organs
  • Improved health span in mice with premature aging syndromes
  • Epigenetic clock reversal observed
• Questions and implications 
  • What happens to damaged mitochondria and DNA during reprogramming? 
    • Mitochondria seem to be rejuvenated, but the process is not well understood
    • Unclear what happens to accumulated cellular aggregates and byproducts
  • Is there a feed-​​forward loop in aging where epigenetic changes accelerate the process? 
    • Difficult to determine causality and whether epigenetic changes are central drivers of aging
    • Epigenetic clocks still have utility in tracking and understanding aging even if not the central cause
  • Can partially reprogrammed cells be used as a therapeutic approach in humans? 
    • Still in early stages of research, with much more to learn about functionality and potential applications
      Aging and Genetics
• Aging is not just random stochastic damage or errors 
  • May be a program that goes wrong without evolutionary prevention
  • Possibility of reprogramming to a better state
• Accumulation of damage plays a role in aging 
  • May not be the only cause
  • Could be a feed-​​forward loop accelerating aging

Plasma Exchange and Aging

• Parabiosis: connecting circulatory systems of young and old mice 
  • Young mice experience accelerated aging
  • Old mice experience some rejuvenation
• Plasma exchange: putting young plasma into old mice 
  • Rejuvenates old mice to some extent
• Epigenetic age can be affected by plasma exchange 
  • Indicates accumulation of factors in the bloodstream that may accelerate aging

Exercise and Epigenetic Age

• Exercise is associated with slowing of epigenetic age
• Genetics play a small role in epigenetic aging and lifespan (10–20%)
  • Supercentenarians and semi-​​supercentenarians may have more genetic control over aging
  • Most people cannot rely on genes for extreme longevity

Inflammation and Aging

• Suppression of inflammation can predict survival to older age groups
• Omega‑3 fatty acids may play a role in inflammation and aging 
  • Typical American diet has a low omega‑3 index compared to other countries like Japan
    Omega‑3 Index and Life Expectancy
• Study with Framingham data stratified people based on their omega‑3 index 
  • Low: lower than 4%
  • High: about 8%
• People with an 8% omega‑3 index had a 5‑year increased life expectancy compared to those with a 4% index
• Smokers with high omega‑3 indexes did not have the same low life expectancy as other smokers 
  • Smokers with high omega‑3 had the same life expectancy as non-​​smokers with low omega‑3

Omega‑3 and Methylation

• Study on women genetically predisposed to breast cancer 
  • Given 5 grams a day of fish oil (EPA, DHA) for six months
  • Methylation profiling of their peripheral blood mononuclear cells (PBMCs)
  • Hypomethylation in TNF alpha, a major controller of inflammation
  • Omega‑3 seems to change methylation patterns and regulate inflammation

Consumer Epigenetic Aging Clocks

• Important factors for epigenetic tests: 
  • Reliability: getting the same answer when taking the test twice on the same day
  • Construct validity: predicting or tracking with things we would expect (e.g., mortality risk, disease risk)
• First-​​generation clocks (trained to predict chronological age) are less reliable and less predictive of mortality risk
• Second-​​generation clocks (e.g., grim age, pheno age) are more reliable and predictive, but still in early stages

Interventions and Epigenetic Age

• Small study by Kara Fitzgerald and colleagues 
  • Participants underwent extreme dietary changes, meditation, exercise, and probiotics
  • Epigenetic age reversed by about three years according to the original clock
• However, the effect was shown to be noise when analyzed with newer statistical methods
• Epigenetic clocks are powerful tools for assessing health status, but not yet reliable for measuring intervention effects
• Better to also measure classical biomarkers and gather more data

Exciting Developments in Aging Research

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  Exciting Research in Aging and Epigenetics

• Transient or partial reprogramming of cells 
  • Understanding how changing the state of a cell affects its function and interaction with other cells
  • Exploring different ways to achieve this change
• Epigenetic clocks
  • Determining what drives changes in epigenetic clocks
  • Understanding the link between epigenetic clocks and mortality risk

Lifestyle Changes Based on Science

• Exercise
  • Most powerful tool to intervene in the aging process
  • Can reverse diabetes, improve health span, and slow epigenetic age
  • Hit (high-​​intensity interval training) is particularly beneficial
• Diet
  • Plant-​​based diet with some fish (Japanese-​​style diet)
  • Intermittent fasting (not eating until around 1:00 PM)

Caloric Restriction and Aging

• Caloric restriction has been shown to slow epigenetic age in mice 
  • However, benefits may be lost if restriction is stopped
  • Amount of restriction may depend on individual genetics
• Time-​​restricted feeding in mice may also play a role in the benefits of caloric restriction

Resources

• Dr. Morgan Levine on Twitter: @DrMorganLevine
• Dr. Morgan Levine on Instagram: @DrMorganLevine
• Book: “True Age” by Dr. Morgan Levine (available for preorder, release on May 3)