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Epigenetics

Epigenetic aging clocks featured article

Epigenetic clocks are predictors of biological age based on alterations in an individual's DNA methylation profile. Methylations – biochemical processes that modify the activity of a DNA segment without changing its sequence – occur naturally and regulate gene expression to control normal growth and development. With age, the methylation state of various genes may change. These changes are quantifiable and gauge epigenetic age, which often differs from chronological age.

The term "epigenetic clock" is also a collective designation referring to the natural biological mechanisms that drive DNA methylation. These innate mechanisms, which play critical roles in an organism's development and maintenance, leave a molecular "footprint" that reflects the biological life history of the organism. This overview focuses primarily on predictive epigenetic clocks, briefly mentioning the innate.

Overview of concepts underpinning epigenetic clocks

Epigenetics

Epigenetics is a...

Episodes

Posted on January 9th 2025 (5 months)

Dr. Rhonda Patrick discusses GLP-1 agonists, alpha-lipoic acid, ubiquinone vs. ubiquinol, calcium needs, and liquid biopsy cancer screening.

Posted on May 23rd 2022 (about 3 years)

In this clip, Dr. Levine shares the personal habits she's developed to slow the aging process including exercise, a plant-based diet, and time-restricted eating.

Posted on May 23rd 2022 (about 3 years)

In this clip, Drs. Patrick and Levine discuss the reliability of epigenetic age tests available to consumers.

Topic Pages

  • Epigenetic aging clocks

    Epigenetic aging clocks statistically summarise age-associated DNA methylation patterns, linking epigenetic modification dynamics to chronological ageing estimation.

News & Publications

  • While genes play a role in aging, lifestyle and environmental exposures—collectively called the exposome—may have a more robust effect on aging and longevity. A recent study found that the exposome contributes far more to premature death and age-related diseases than genetic risk alone.

    Researchers analyzed data from nearly 500,000 people enrolled in the UK Biobank to measure the exposome’s role in aging. They identified environmental exposures linked to early death and biological aging, then used a proteomic age clock—a tool that tracks molecular signs of aging—to confirm which exposures accelerate the aging process. Finally, they compared the exposome’s influence on disease risk to that of genetic predisposition.

    The exposome explained 17 percentage points more of the variation in mortality than genetic risk, which accounted for less than two percentage points. It was more strongly connected to lung, heart, and liver diseases, while genetic factors were more closely associated with certain cancers and dementias. The analysis identified three disease states and 22 biomarkers related to liver and kidney function, cardiovascular and metabolic health, inflammation, longevity, genetics, and vitamin and mineral status that independently drive biological aging and disease risk.

    These findings suggest that the exposome is critical in shaping health and longevity. While genes contribute to some diseases, environmental exposures throughout life greatly influence aging and survival. Air pollution is an exposome element contributing to disease and early death. Learn how wearable devices measure the air pollution exposome in this episode featuring Dr. Michael Snyder.

  • Androgens shape more than just male traits—they may also influence the pace of aging. A recent study found that an epigenetic predictor called the androgen clock can precisely track cumulative androgen exposure, offering new insights into how these hormones affect biological aging.

    To develop this model, researchers analyzed DNA methylation, a chemical modification that regulates gene activity and changes with age. They studied male-specific DNA methylation patterns in sheep and mice, identifying genetic sites that gradually lost methylation in males while remaining stable in females. Using this pattern, they created a clock that accurately estimates androgen exposure and tested whether altering hormone levels could change its ticking rate.

    They found that supplementing female mice with androgens accelerated the clock while removing androgens in male sheep through castration halted it altogether. The model estimated the duration of androgen exposure in both species with an accuracy of a few months, indicating that androgens directly influence epigenetic aging and can precisely regulate this process.

    These findings indicate that the androgen clock may be an effective tool for investigating how sex hormones influence aging. Learn more about epigenetic aging in this episode featuring Dr. Steve Horvath, one of the investigators involved in this study.

  • Rapamycin, a compound initially discovered as an antifungal agent, has garnered considerable interest in longevity research due to its ability to inhibit mTOR, a protein that plays a critical role in cellular growth and aging. Studies in animal models have demonstrated rapamycin’s potential to extend lifespan and improve healthspan. However, translating these findings into human applications has proven complex, as substantial risks often accompany the benefits.

    Bryan Johnson is an internet personality who has made a name for himself by talking about his sometimes extravagant n=1 biohacking attempts to reverse aging. Recently, Johnson announced a reversal on his position on rapamycin: He thinks it might be making him age worse.

    Johnson tested various rapamycin dosing protocols to explore its anti-aging potential while minimizing adverse effects. These protocols included weekly doses of 5, 6, and 10 milligrams, biweekly doses of 13 milligrams, and an alternating weekly schedule of 6 and 13 milligrams.

    Although data from preclinical trials were promising, Johnson concluded that the long-term use of rapamycin in humans does not outweigh its drawbacks. Side effects, including intermittent skin and soft tissue infections, impaired lipid metabolism, elevated glucose levels, and increased resting heart rate, persisted regardless of dosage adjustments. After ruling out other potential causes, he attributed these issues to rapamycin and ultimately decided to discontinue its use.

    Other research supports his observations, demonstrating that chronic rapamycin use can impair lipid profiles, induce insulin resistance, and contribute to glucose intolerance and pancreatic beta-cell toxicity. While anecdotal evidence suggests that rapamycin may slow tumor growth, its suppression of natural killer cells raises concerns about impaired immune surveillance and potentially increased cancer risk over time.

    Further complicating the picture, a recent pre-print study presented new findings about rapamycin’s effects on aging. The study assessed the effects of rapamycin across 16 epigenetic aging clocks and found that it accelerated aging markers in humans. This analysis is noteworthy because most assessments have relied on only one or two aging clocks, raising concerns about the reliability of the findings.

    As Johnson notes, longevity research is a rapidly evolving field that requires continuous scrutiny of emerging studies and biomarkers. For now, his experience underscores the importance of balancing potential benefits against risks when exploring experimental compounds like rapamycin. Learn more about rapamycin in our overview article.

  • From the article:

    The scientists examined blood samples from 278 women from the Grady Trauma Project, a study of low-income Atlanta residents with high levels of exposure to violence and abuse. They analyzed maps of DNA methylation, a modification of DNA that is usually a sign of genes that are turned off.

    […]

    “We knew that estrogen affects the activity of many genes throughout the genome,” […] “But if you look at the estrogen-modulated sites that are also associated with PTSD, just one pops out.”

    That site is located in a gene called HDAC4, known to be critical for learning and memory in mice. Genetic variation in HDAC4 among the women was linked to a lower level of HDAC4 gene activity and differences in their ability to respond to and recover from fear, and also differences in “resting state” brain imaging. Women with the same variation also showed stronger connections in activation between the amygdala and the cingulate cortex, two regions of the brain involved in fear learning.

    On top of that, experiments with female mice showed that the HDAC4 gene was activated in the amygdala while the mice were undergoing fear learning, but only when estrogen levels in the mice were low.

    View full publication

  • The DASH Diet slows epigenetic aging.

    The DASH Diet (Dietary Approaches to Stop Hypertension) is a dietary pattern that emphasizes heart-healthy eating. Widely recognized for its evidence-based guidelines, DASH is rich in fruits, vegetables, fish, poultry, legumes, and healthy fats and is low in saturated fats and sweets. Findings from a 2021 study suggest that the DASH diet slows epigenetic aging.

    Epigenetic age acceleration is a phenomenon that occurs when an individual’s epigenetic (biological) age exceeds their chronological age. Early research relied on measures of either intrinsic or extrinsic factors to measure age acceleration. Newer methods rely on clinical and functional biomarkers, which have stronger predictive abilities for the time to chronic diseases and death.

    The study utilized data from nearly 2,000 adults (average age, 67 years) who were enrolled in the Framingham Heart Study Offspring Cohort. Investigators collected information about the participants' usual dietary intake and assigned a score based on the overall quality and adherence to DASH guidelines. They also collected blood samples from the participants for analysis and determination of their DNA methylation status using three epigenetic age acceleration measures: Dunedin Pace of Aging Methylation, GrimAge acceleration, and PhenoAge acceleration.

    They found that all three age acceleration measures indicated that having a higher DASH score was associated with slowed epigenetic aging, even after taking age, sex, smoking status, body mass index, physical activity, alcohol consumption, and caloric intake into consideration. This slow aging translated to roughly one additional year of life. Higher intakes of vegetables, fruits, nuts, legumes, and whole grains were associated with slower aging, while higher intakes of red and processed meat and sodium were associated with faster aging.

    These findings suggest that the DASH dietary pattern slow epigenetic aging and underscores the importance of implementing lifestyle modifications to promote health and longevity. Learn more about epigenetic age acceleration in these clips featuring epigenetics experts Dr. Steve Horvath and Dr. Morgan Levine.

  • Higher BMI is associated with epigenetic age acceleration.

    Obesity exerts profound effects on the human body, ranging from alterations in the gut microbiota to an increased risk for many chronic diseases. Body mass index (BMI) is a proxy for body fatness and is strongly correlated with disease risk with aging. Findings from a recent study suggest that BMI is associated with epigenetic age acceleration.

    Epigenetic age acceleration is a phenomenon that occurs when an individual’s epigenetic (biological) age exceeds their chronological age and can be the result of either intrinsic or extrinsic factors. Intrinsic factors are largely driven by internal physiological factors such as normal metabolism and genetics. Extrinsic factors are those associated with lifestyle and environmental exposures, such as diet, smoking, or exercise.

    To rule out the effects of genetics and shared environments, the investigators used data from the Finnish Twin Cohort, an ongoing study of twins and twin families. They gathered BMI data and metabolic health parameters for more than 1,400 participants, including both monozygotic (identical) and dizygotic (fraternal) twins. They measured the participants' epigenetic ages using GrimAge, a type of epigenetic clock that predicts lifespan and healthspan in units of months or years, and tests the effects of lifestyle on biological aging.

    They found that for every one-unit increase in BMI, the twins exhibited approximately one month of accelerated epigenetic aging. In twin pairs where one twin was heavier than the other, the heavier twin’s epigenetic age was approximately 5 months older than the lighter twin. They also found that age acceleration was associated with insulin resistance, a risk factor for type 2 diabetes.

    These findings suggest that having a higher BMI accelerates epigenetic aging and underscores the importance of maintaining a healthy body weight throughout the lifespan. To learn more about epigenetics and accelerated epigenetic aging, check out these resources, including an overview article and these episodes featuring epigenetic experts Dr. Steve Horvath and Dr. Morgan Levine.

  • Genetic links between childhood cancer and accelerated epigenetic aging identified.

    Childhood cancer is relatively rare, affecting just one in 6,500 children each year. In recent decades, the overall survival rate for children with cancer has increased from 10 percent to 85 percent, due to early diagnosis and marked advancements in treatment. However, findings from a new study suggest that some survivors of childhood cancer are genetically susceptible to experiencing accelerated epigenetic aging.

    Epigenetic age acceleration is a phenomenon that occurs when a person’s epigenetic age exceeds their chronological age. Acceleration may be either intrinsic or extrinsic. Intrinsic aging is largely driven by internal physiological factors such as normal metabolism and genetics, whereas extrinsic aging is associated with lifestyle and environmental exposures, such as diet, tobacco use, ultraviolet radiation, and mental illness.

    The investigators performed a genome-wide association study, a type of observational study that associates specific genetic variations with particular diseases, using multiple epigenetic aging clocks. Their assessment was based on blood-derived DNA from approximately 2,400 childhood cancer survivors and 500 people who had never had cancer.

    They identified single nucleotide polymorphisms, or variants, in two areas of the survivors' DNA – the ¬¬SELP gene and the HLA region – that drive accelerated aging and are associated with age-related disease. The SELP gene encodes for a protein called P-selectin, a cell adhesion molecule that plays roles in atherosclerosis and peripheral artery disease. Its activity is increased in the setting of Alzheimer’s disease. The HLA, or human leukocyte antigen, region is an area on chromosome six that plays important roles in immunity. Mutations in the HLA region, which can occur following exposure to genotoxic drugs (such as chemotherapy) are associated with increased risk for autoimmune disorders, such as type 1 diabetes and celiac disease.

    These findings suggest that genetic variants increase the risk of accelerated epigenetic aging among childhood cancer survivors and underscore the importance of identifying children at risk. Learn about epigenetic aging acceleration in this clip featuring Dr. Steve Horvath.

  • Ketogenic diet and beta-hydroxybutyrate improve gene transcription and reduce intellectual disability in Kabuki syndrome.

    Kabuki syndrome is a debilitating inherited disorder caused by mutations in two genes involved in the regulation of chromatin remodeling, one of the first steps in DNA transcription. Ketones such as beta-hydroxybutyrate have been shown to enhance DNA transcription and gene expression. Findings from one group of researchers show that a ketogenic diet can alleviate some of the neurological deficits of Kabuki syndrome and improve memory.

    Kabuki syndrome is named for the facial features common to people with the disorder, which looked similar to Kabuki theatre makeup to the Japanese scientists who first researched the disease. In addition to distinctive facial features, the syndrome causes a wide range of health problems such as heart defects, difficulty eating, weak muscle tone, immune deficiency, and intellectual disability. This wide range of severe health issues is explained by the fundamental importance of chromatin remodeling to the body’s functioning, which is impaired in those with Kabuki syndrome.

    Chromatin is the name for the coiled structure DNA forms within the cells of plants and animals, which looks a bit like a tangled telephone cord. This coiled structure prevents DNA from being opened and transcribed (the first step in gene expression and DNA replication) randomly. Chromatin is wrapped around histone proteins that open or close the chromatin, based on whether the histone has a chemical tag called an acetyl group attached or not. As DNA accumulates epigenetic changes over the lifespan, histones become resistant to acetylation, chromatin is harder to open, and gene expression slows. Histone deacetylase (HDAC) inhibitors, such as the ketone beta-hydroxybutyrate (BHB), are compounds that help release histones, open chromatin, prevent loss of gene expression with aging, and may even lengthen lifespan.

    The researchers used a strain of mice that have the same DNA mutations that cause Kabuki syndrome in humans and fed them either a normal diet or a ketogenic diet for two weeks. The researchers fed a third group of mice a normal diet and gave them three daily injections of BHB for two weeks. To assess memory and cognitive performance, mice completed a water maze, a sensitive measure of hippocampal function, which is closely related to memory. The researchers measured changes in gene expression, HDAC activity, and neurogenesis.

    Compared to a normal chow diet, a ketogenic diet increased the concentration of serum BHB, normalized acetylated histone levels, and increased the expression of several genes that are downregulated in Kabuki syndrome. These changes in gene expression enhanced multiple markers of neurogenesis and improved performance during the water maze test. Mice eating a normal diet that received daily BHB injections achieved similar serum BHB levels as mice eating a ketogenic diet and experienced the same gains in neurogenesis.

    This comprehensive study provides insight into the potential of ketogenic diets and supplemental BHB to improve deficits in gene expression in mice with a debilitating genetic disorder. Future research is needed in order to translate these insights into clinically useful information for humans.

  • From the article:

    In mice, the scientists showed that learning ability was passed onto the next generation by epigenetic inheritance. When Fischer and co-workers exposed mice to a stimulating environment in which they had plenty of exercise, their offspring also benefited: compared to the mice of a control group, they achieved better results in tests that evaluate learning ability. These rodents were also found to have improved synaptic plasticity in the hippocampus, a region of the brain important for learning

    Both mental and physical activity of the parents matter:

    The researchers also found that miRNA212 and miRNA132 accumulated in the brains and sperm of mice after physical and mental activity. It was previously known that these molecules stimulate the formation of synapses in the brain, thus improving learning ability. Through the sperm, they are transmitted to the next generation. “Presumably, they modify brain development in a very subtle manner improving the connection of neurons. This results in a cognitive advantage for the offspring,” says Fischer.

  • From the article:

    The scientists discovered that after completing the endurance training program, the structure of many enhancers in the skeletal muscle of the young men had been altered. By connecting the enhancers to genetic databases, they discovered that many of the regulated enhancers have already been identified as hotspots of genetic variation between individuals – hotspots that have been associated with human disease.

    The scientists speculate that the beneficial effects of exercise on organs distant from muscle, like the brain, may largely be mediated by regulating the secretion of muscle factors. In particular, they found that exercise remodels enhancer activity in skeletal muscle that are linked to cognitive abilities, which opens for the identification of exercise training-induced secreted muscle factors targeting the brain.

  • A diet rich in plant foods, lean protein, and healthy fat is associated with a reduced risk of death from cardiovascular disease, cancer, and all causes; however, many of the cellular and molecular mechanisms of these relationships are unknown. One of the mechanisms that controls a person’s response to diet and risk of disease is epigenetic modification. Findings of a new investigation detail the relationship between healthy eating and epigenetic and biological age.

    While a person’s genetic code does not change over time, the pattern of epigenetic markers attached to DNA does change with age. Epigenetic modifications include the addition and subtraction of methyl groups, naturally occurring processes that regulate gene expression. These changes are quantifiable and serve as a means to gauge biological age, which is often different from chronological age. Epigenetic aging clocks use an organism’s DNA methylation profile biomarker of aging based on alterations in an organism’s DNA methylation profile and can be used to predict likelihood of death (i.e., mortality).

    The investigators utilized data from the Sister Study, an observational study of over 50,000 females in the United States who had a biological sister diagnosed with breast cancer, but were free from cancer themselves. These participants provided data about their dietary habits and provided a blood sample for the measurement of epigenetic age and other factors. Next, the authors analyzed the diet data and calculated four scores of diet quality that aligned with dietary recommendations from the USDA and other sources. The authors analyzed a subsample of almost 3,000 participants in order to calculate epigenetic age using the Hannum, Horvath, PhenoAge, and GrimAge clocks.

    The data revealed only a weak association between higher diet quality and epigenetic age as measured by the two aging clocks designed as predictors of chronological age (Horvath and Hannum clocks). However, there was a strong relationship between diet quality and epigenetic age calculated by the two clocks designed to estimate mortality (PhenoAge and GrimAge clocks). This highlights the differences between aging clock designs, but it also supports a relationship between diet quality and disease risk that is mediated by epigenetic changes. The relationship between increased diet quality and reduced mortality-related epigenetic age was strongest among participants who did not meet exercise recommendations. Smoking status and age did not significantly alter these statistical relationships.

    These findings demonstrate that higher diet quality is associated with a lower biological age as estimated by epigenetic clocks designed to predict mortality. Learn more about epigenetics from expert Dr. Steve Horvath, creator of the Horvath epigenetic aging clock, in this episode of the FoundMyFitness podcast.

  • Age-related diseases like heart disease, diabetes, dementia, and cancers are on the rise, placing a significant burden on the healthcare system and economy. Interventions that can slow the aging process by just two years could save almost $7 trillion over 50 years and increase health and quality of life. Authors of a recent report tested the effects of a diet and lifestyle intervention on the reversal of epigenetic aging.

    Epigenetic aging is a way to predict an individual’s risk of age-related disease by biological means instead of just chronology. Epigenetics is a biological mechanism that regulates gene expression (how and when certain genes are turned on or off). Diet, lifestyle, and environmental exposures can drive epigenetic changes throughout an individual’s lifespan to influence aging. The record of these changes can be used to predict biological age. Lifestyle interventions may be able to slow biological aging by reversing some epigenetic modifications.

    The authors of the study enrolled 43 healthy males between the ages of 50 and 72 years. They randomly assigned half of the participants to complete an eight-week diet and lifestyle intervention, while the other half did not. The intervention included a diet rich in vegetables (e.g., leafy greens, beets, and cruciferous and other colored vegetables), low-glycemic fruit (e.g., blueberries), seeds, animal proteins, liver, and eggs. The researchers advised participants to choose organic over conventional produce and meat; avoid eating between 7 p.m. and 7 a.m.; stay hydrated; cook with healthy oils (e.g., coconut, olive, or flaxseed oils); avoid sugar, dairy, grains, and beans; and avoid plastic containers. They gave participants a supplement rich in bioactive plant compounds (like quercetin or green tea extract) and a probiotic with the bacteria, Lactobacillus plantarum. They also asked participants to exercise for 30 minutes five days per week, sleep for at least seven hours per night, and manage stress with prescribed breathing exercises. They measured DNA methylation patterns before and after the intervention period to assess changes in the epigenome.

    The diet and lifestyle intervention significantly decreased epigenetic age by more than three years by the end of the eight-week trial compared to participants in the control group. Compared to their own baseline epigenetic age, participants who completed the intervention reversed their epigenetic clocks by almost two years, although this relationship was not statistically significant. The intervention also increased serum folate by 15 percent and reduced blood triglyceride levels by 25 percent.

    This study is the first randomized controlled trial to find that diet and lifestyle interventions may reverse epigenetic aging in healthy adult males. The authors note that large-scale trials with longer durations are needed to confirm their results.

  • The human immune system loses function with age in a process known as immunosenescence. Previous research has reported on the ability of a number of drugs to impact the aging process; however, these studies have not measured the ability to reverse epigenetic aging. Research from epigenetics expert Steve Horvath is the first to demonstrate the reversal of epigenetic aging and immunosenescence of the thymus with drug therapy.

    The thymus is an immune organ necessary for the development of T cell populations. After the age of approximately 63, a process called thymic involution severely impairs T cell function and is linked to increases in cancer, infection, autoimmune conditions, chronic inflammation, and heart disease.

    Nine participants between the ages of 51 and 65 years were given a drug protocol that included recombinant human growth hormone to reverse signs of immunosenescence. Because growth hormone can increase insulin production to a harmful degree, the authors used metformin, a common diabetes drug, and dehydroepiandrosterone, a steroid precursor, to control symptoms of diabetes. The investigators collected white blood cells to measure immune characteristics and epigenetic age.

    Following one year of treatment, the authors reported an average decrease in epigenetic age of 1.5 years over baseline, meaning they reversed epigenetic age by 2.5 years over the course of the study. Participants demonstrated an increase in t cell production and an increase in the leukocyte/monocyte ratio, a measure of immune cell populations that is associated with less inflammation and lower rates of several cancers. Monocytes use a lot of nicotinamide adenine dinucleotide (NAD+), which is an important energy source for cells. The authors suggested this decrease in monocytes and subsequent increase in NAD+ may be responsible for the reversal of epigenetic aging.

    The main purpose of this pilot trial was to determine the safety and efficacy of the study treatment. Larger studies with a control group are needed to expand on these results.

  • Obesity is a growing problem worldwide, especially among children and young adults. Many factors contribute to obesity, including environmental exposures, which can drive epigenetic changes. Findings from a new study suggest that maternal exposure to parabens may increase the risk of obesity among children.

    Parabens are widely used synthetic compounds that exert antibacterial and antifungal properties. They are commonly used in cosmetics, drugs, and some foods. Parabens can be ingested or absorbed through the skin. Some evidence suggests that parabens are endocrine disruptors.

    The study had multiple arms that included an analysis of epidemiological data from the German LINA study and an experimental study in mice that simulated paraben exposure during pregnancy. The epidemiological data revealed that the children of women who had high exposure to parabens during pregnancy (assessed by urinary excretion) were more likely to be obese, an effect that was more pronounced in girls. Findings from the mouse study suggested that this increased risk of obesity was driven by epigenetic mechanisms associated with the altered expression of the proopiomelanocortin gene (known as POMC), which plays critical roles in the neuronal regulation of appetite, satiety, and food intake.

    These findings suggest that prenatal environmental exposures to everyday compounds such as parabens may have far-reaching effects on the health of offspring.

  • Maintaining a healthy weight requires balancing energy intake with expenditure. A variety of elements influence how physically active we are, including genetic, cultural, and environmental factors. Evidence from a new study suggests that epigenetic changes in agouti-related proteins may regulate voluntary exercise behavior in mice.

    Agouti-related proteins are neuropeptides produced primarily in the hypothalamus. They regulate appetite, metabolism, and energy expenditure.

    Epigenetic changes are biological mechanisms that regulate gene expression (how and when certain genes are turned on or off). DNA methylation – the addition of methyl groups to the nucleotide bases of DNA – is a common epigenetic change. Previous research has shown that DNA methylation influences hypothalamic development in mice at specific time points early in life.

    In this study, transgenic mice that lacked the enzymes that facilitate DNA methylation in agouti-related proteins developed a sedentary phenotype later in life. This was manifested by low energy output in the form of voluntary exercise, with the transgenic mice running roughly half the distance on exercise wheels as their wild type counterparts.

    These findings point to the complexity of identifying ways to motivate people to exercise as a means to regulate body weight.