Dr. Steve Horvath on epigenetic aging to predict healthspan: the DNA PhenoAge and GrimAge clocks

Horvath Aging Clock

• Developed by Dr. Steve Horvath, professor of genetics and biostatistics at UCLA
• Most accurate molecular measure of age
• Applies to all cells, tissues, and organs in the body
• Measures age in prenatal samples, children, and supercentenarians (110+ years old)
• Estimates chronological age based on DNA samples
• Error in estimation is biologically meaningful and related to biological age

Biological Age

• Vague term, not well-defined
• Different researchers use different methods to measure biological age
• Dr. Horvath’s method is based on DNA methylation
• Weak relationship between clinical biomarkers and epigenetic age
• Example: Hispanics have higher risk for diabetes and metabolic syndrome, but age more slowly according to the epigenetic clock

Epigenetic Clock and Lifespan

• Epigenetic clock correlates more closely with lifespan than with clinical biomarkers
• 40% heritability of epigenetic aging clock
• Offspring of centenarians have younger epigenetic age
• Longitudinal studies show consistency in aging rates over time

Stability of Methylation Patterns

• Methylation patterns are remarkably stable over a person’s lifetime
• More stable than gene expression, proteomics, and metabolomics measurements
• Stable even under suboptimal storage conditions

Changes in Methylation Patterns

• Epigenetic clocks track several hundred locations in the genome
• Some locations gain methylation, others lose methylation

• Changes may be random, but averaging hundreds of sites gives accurate age estimate
  Predicting Biological Age with Epigenetic Clocks

• Epigenetic clocks can predict chronological age, lifespan, and healthspan

• DNA methylation pheno age and DNA methylation grim age are biomarkers for predicting healthspan and lifespan
• Useful for human clinical trials of anti-​​aging interventions

Disease States and Epigenetic Age

• Parkinson’s disease: age acceleration effect in blood
• Alzheimer’s disease: age acceleration in prefrontal cortex, weak signal in blood
• Cancer: blood samples collected before cancer development show slight epigenetic age acceleration, but stronger signal in tumor tissue

Telomere Length and Epigenetic Clocks

• Telomere length is not a strong biomarker for predicting onset of diseases or lifespan
• Epigenetic clocks and telomere length measure different aspects of aging but have weak correlations

Lifestyle Factors and Epigenetic Aging

• Healthy lifestyle factors (diet, exercise, not smoking, education) have weak but significant effects on epigenetic aging
• Lifestyle interventions may not have a profound impact on aging at a population level
• Organ-​​specific effects of stress factors and anti-​​aging interventions

Obesity and Epigenetic Aging

• Obesity accelerates epigenetic age in blood and liver tissue

• Organ-​​specific effects of stress factors and anti-​​aging interventions
  Hormone Therapy and Aging

• Buckle epithelial cells (cells inside the mouth) show that women who took hormone therapy were aging more slowly

• Importance of measuring different tissue types to understand aging process
• Blood cells don’t have as many estrogen receptors as buckle epithelial cells, so hormone intervention studies should focus on susceptible cells

Bone Marrow Transplants and Aging

• Hematopoietic stem cell transplantation used for severe leukemia patients
• Young cells from a donor transplanted into an older recipient 
  • Reconstituted blood in the recipient has the age of the donor, and the effect persists for decades
• Stem cell niche in the bone marrow doesn’t seem to affect the aging rate
• Rejuvenation through transplantation not yet viable due to complications and graft versus host disease

Parabiosis and Aging

• Connecting young mice to old mice to study rejuvenation effects
• Young mouse connected to an old mouse ages faster according to an epigenetic clock
• No rejuvenation effect observed in the old mouse connected to a young mouse (more data needed)

Understanding Epigenetic Clocks

• Molecular mechanisms behind epigenetic clocks not yet fully understood
• Theories include stem cell biology, circadian rhythm, and developmental processes
• Epigenetic clocks work well in prenatal brain samples and in vitro studies

Methylation Patterns and Aging

• P16ink4a gene is methylated during early age, but demethylated as a person ages 
  • Plays a role in cell cycle progression and stem cell growth
• Enzymes that remove or add methyl groups (DNA methyltransferases) affect epigenetic age

• Inflammation and demethylases (e.g., Jumanji demethylases) may play a role in changing methylation patterns and aging
  Epigenetic Aging and Interventions

• Preliminary data suggests a connection between epigenetic aging and viral components, such as HIV

• Epigenetic age increases when stem cells differentiate into more mature cells 
  • However, the increase is not significant (1–2 years older)
• Trans-​​differentiation protocol preserves epigenetic age 
  • Turning a skin cell into a neuron maintains the epigenetic age of the skin cell

Reprogramming and Rejuvenation

• Administering certain factors (e.g., Yamanaka factors) can reset the epigenetic age to a prenatal stage
• Brief administration of these factors can rejuvenate cells without causing them to lose their identity
• Interrupted or transient reprogramming resets the age while maintaining cell identity, reducing the risk of malignancy

Epigenetic Aging in Mice and Humans

• Caloric restriction slows the epigenetic clock in mice
• High-​​fat diet accelerates the epigenetic age of mice
• No clear evidence of caloric restriction affecting epigenetic aging in humans
• Interventions that prevent metabolic syndrome or diabetes may be detectable by the epigenetic clock

Potential Interventions and Clinical Trials

• Vitamin D supplementation in obese African Americans reduced their epigenetic age by 1.8 years 
  • Larger studies needed to validate this finding
• Clinical trials are expensive, but necessary to test various anti-​​aging interventions 
  • Interventions could include vitamin D supplements, Yamanaka cocktail modifications, plasma transfusions, or hormone interventions

• Omega‑3 supplements or fish oil may slow down aging according to Grim Age
  Fish Oil Supplementation and Aging

• Large scale clinical trials found no benefits of fish oil supplementation

• However, an observational study (Women’s Health Initiative) found that women who took fish oil supplements aged more slowly according to Grim Age
• The Big Vital D study found no effect on primary outcome (combined cardiovascular events) but a strong effect on heart attack vs. stroke

Sleep Quality and Epigenetic Aging

• Sleep disturbances in the Women’s Health Initiative showed a slight acceleration of epigenetic age in blood
• Sleep expert Dr. Matthew Walker found that various diseases and all-​​cause mortality increase when sleep quality decreases
• However, the effect of sleep quality on epigenetic aging is weak compared to other factors

Growth Hormone Knockout Mice and Epigenetic Aging

• Growth hormone receptor knockout mice, which live longer, show slower epigenetic aging according to epigenetic clocks
• Relationship between senescence and epigenetic age is complicated, with different forms of senescence having different effects on epigenetic clocks
• Immortalizing cells by overexpressing telomerase component does not stop epigenetic aging

Methylation Patterns in the Genome

• Original epigenetic clock used 353 loci, while Grim Age uses over 1000 locations in the genome
• Methylation changes with age are almost global, with a quarter of the 28 million cytosines in the genome changing with age
• Sites that gain methylation with aging are often located in polychrome group protein target sites, which play a role in maintaining stem cells and cell differentiation
• Sites that lose methylation are often in enhancer regions
• Epigenetic clocks link development to tissue dysfunction in a direct manner, pointing to commonalities between development and aging processes