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Dr. Steve Horvath On Epigenetic Aging To Predict Healthspan: The DNA Phenoage And Grimage Clocks| Found My Fitness With Dr. Rhonda Patrick

Key Takeaways

  • The Horvath Aging Clock is collected through DNA sample and currently the most accurate estimate of chronological age
  • The epigenetic clock is under genetic control – evidence strongly suggests the epigenetic clock is a continuous readout that links prenatal tissue directly to disease and healthspan in older age
  • Some people inherit DNA which allows their epigenetic clock to progress slower
  • Early studies show DNA GrimAge is a good predictor of time to heart disease and chronic disease before clinical markers appear
  • Compared to the epigenetic clock, telomere length is a weak predictor of aging
  • In healthy people, even a “perfect” lifestyle won’t make a big dent in epigenetic age
  • The weakness of the epigenetic clocks is that we don’t understand the specific regulators of these clocks 


Steve Horvath, PhD, is a professor of human genetics and biostatistics at UCLA’s Fielding School of Public Health and creator of the Horvath Epigenetic Aging Clock. Dr. Horvath’s work focuses on predicting a person’s age and potentially lifespan, based on chemical modifications to DNA.

In this episode of Found My Fitness, Dr. Rhonda Patrick sits down with Dr. Steve Horvath to discuss all things epigenetic aging, DNA measurements of age, and lifestyle factors that impact aging.

Host: Dr. Rhonda Patrick (@foundmyfitness)

Horvath Aging Clock

  • Horvath Aging Clock: most accurate molecular measure of chronological age – applies to all cells with DNA, tissues, organs, prenatal samples, super-centenarians (100+ years of age)
  • Collected through DNA sample and accurately estimate chronological age
  • People age at different rates as evidenced by biomarkers
  • Some appear older or younger than chronological age
  • “Biologic age” relates to morbidity and mortality risk in addition to aging but is not well defined
  • Depending on how you measure biologic age you get different answers – i.e., maybe you’re only looking at glucose levels which are high but methylation is normal

Epigenetic Clock & Hispanic Mortality Paradox

  • The epigenetic clock is under genetic control: some people inherit DNA which allows the epigenetic clock to progress slower
  • Epigenetic clock and changes in methylation patterns are remarkably stable compared to other genomic measurements – how you age at 20 is how you will age at 60, barring significant lifestyle changes
  • “Epigenetic clock clearly relates to a process that plays a causal role [in aging]…is it the face of the clock or is it the clockwork?” – Dr. Steve Horvath
  • People of Hispanic ancestry often have a higher risk for diabetes and metabolic syndrome but age slower, according to the epigenetic clock
  • “Hispanic mortality paradox”: Hispanic people tend to live longer and age slower than expected epigenetic clock versus European ancestry
  • Offspring of super-centenarians have epigenetic clock advantage compared to those whose parents did not live to 100+ years of age

DNA GrimAge & DNA PhenoAge As Predictors Of Disease

  • We have some epigenetic clocks whose purpose is to measure chronologic age (DNA PhenoAge), others whose purpose is to predict healthspan (DNA GrimAge) as opposed to aging
  • DNA PhenoAge is accelerated in the brain tissue of people with Alzheimer’s and Parkinson’s disease
  • The immune system plays a role in Parkinson’s disease: blood cell counts in neutrophils were highly elevated in Parkinson’s disease
  • Early studies show GrimAge is a good predictor of time to heart disease and chronic disease before clinical markers appear
  • GrimAge is predictive of onset of cancer on a statistically significant level but studies are too small for clinical impact

Accuracy Of Using Telomere Length To Measure Aging

  • Telomere length is associated with aging: it generally correlates aging with shorter telomeres
  • Telomere paradox: some cancers lengthen telomeres but longer telomeres typically signal wellness and youthfulness
  • There’s a sweet spot to telomere length – it’s not a good biomarker to predict the onset of disease
  • If we compare telomere length versus the epigenetic clock, there’s no comparison: telomere length is actually a weak predictor of lifespan
  • Telomere length plays a role in some disease but is not a predictor of aging

Lifestyle Factors That Affect Epigenetic Clock

  • Factors that affect epigenetic clocks: diet, smoking, education, alcohol consumption
  • Lifestyle effects so far have been weak but there are associations
  • In healthy people, even a “perfect” lifestyle you won’t make a big dent in epigenetic age
  • You still want to avoid diabetes and lifestyle-related cancers but lifestyle won’t impact epigenetic age at a population level
  • Lifestyle interventions will only impact those who are unhealthy, e.g., obese, smokers
  • Obesity greatly accelerates epigenetic effect of aging on liver

What Is The Mechanism Of The Epigenetic Clocks?

  • The weakness of the epigenetic clocks is that we don’t understand the specific regulators of these clocks  
  • “Epigenetic clock is a continuous readout that links prenatal tissue directly to very old samples.” – Dr. Steve Horvath
  • Stronger and stronger evidence that clocks point directionally from birth, onward
  • We understand what contributes to changes in telomere length much more (e.g., obesity, chronic stress, etc.) than epigenetic clocks
  • Polycomb group proteins: proteins measured with epigenetics that play an important role in maintaining stem cells and gain methylation with aging
  • Enhancer regions: DNA sites that lose methylation with age
  • DNA methyltransferases add and remove methyl groups which clearly have an impact on epigenetic age – but we don’t know whether it correlates to lifespan
  • Some theories on what affects the epigenetic clock: stem cells, circadian rhythms, developmental processes (prenatal and in vitro factors), transposons (chromosomal segment), chronic inflammation, sleep disruption

Impact of Intermittent Fasting And Supplementation On Epigenetic Clock

  • Caloric restriction slows the epigenetic clock in mice
  • High-fat diet accelerates the epigenetic age of mice
  • More studies need to look at caloric restriction versus epigenetic aging in humans
  • If you start off as healthy, we don’t know whether we will see changes in the epigenetic clock
  • Vitamin D supplementation has been shown to reduce epigenetic age, but studies have only been on small sample sizes
  • Fish oil supplementation has also been shown to positively impact GrimAge – but observationally, not clinically

Senescence And Epigenetic Clocks

  • Epigenetic clocks are not simply markers of senescence
  • Removing senescent cells has an effect on epigenetic age
  • You can induce senescence many ways:
    • Split cells and let them grow (related to epigenetic clocks),
    • Radiation induced senescence (not related to epigenetic clocks),
    • Immortalizing cells (doesn’t stop epigenetic aging)

The Future Of Epigenetic Research

  • Clinical trials are expensive and government funding is always messy
  • We need the private sector to take interest in clinical trial research and fund studies
  • Primary outcomes are often far removed from processes targeted and yield confoundingly negative results – but that doesn’t mean the study didn’t find useful information
  • We need dozens or hundreds of clinical trials for proof and serendipity – the more we experiment, the more we’ll learn

Additional Studies And Reading:

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