Important: The applications discussed in this article refer to research and exploratory clinical studies. Epigenetic clocks are not yet established routine clinical tests and are not recommended for individual self-diagnosis or health decisions. CD Genomics provides epigenetic clock analysis for research use only.

Epigenetic clock, as a breakthrough technology in the field of epigenetics, realizes the accurate evaluation of biological age by quantifying the dynamic changes of DNA methylation sites, and its application value has gradually extended from basic scientific research to clinical health management.

Compared with the traditional evaluation methods that rely on physiological indicators, the epigenetic clock provides a brand-new quantitative tool for health monitoring and disease intervention with its high specificity and time dynamic tracking ability, and becomes a key bridge connecting epigenetic mechanisms and clinical practice.

At present, with the deepening of the concept of precision medicine, how to turn the technical advantages of the epigenetic clock into a grounded health management tool has become the research focus in academic and clinical fields.

This paper focuses on four practical functions of the epigenetic clock in health management, aiming to systematically sort out its application logic in health care, and provide a theoretical reference for further promoting the clinical transformation and standardized application of this technology.

Predicting Mortality and Age-Related Disease Risk

Accurately predicting the risk of death and age-related diseases is the core research direction of aging biology and clinical preventive medicine. Traditional prediction models are often limited by static physiological indicators, and it is difficult to capture the dynamic risk changes in the process of individual aging. The new technologies, such as the epigenetic clock, provide key tools for constructing a high-precision risk prediction system by analyzing the time sequence law of epigenetic markers, such as DNA methylation, and their application is expected to promote the transformation of diseases from passive treatment to active prevention.

Epigenetic Age Acceleration and All-cause Mortality

In the field of aging research, the relationship between accelerated epigenetic age and all-cause mortality has attracted much attention. A large number of studies have revealed the close and complicated relationship between them:

• A meta-analysis of 41 studies showed that all-cause mortality increased significantly by 9% (95% confidence interval 1.07-1.12) with each year of accelerated epigenetic age.
• This association has been repeatedly verified in many studies, and studies in different populations show that epigenetic age has a significant impact on all-cause mortality.
• Long-term follow-up of the elderly shows that the risk of death of people with epigenetic age beyond their actual age is much higher than that of their peers, which shows that it is not only a biological index, but also an important tool to predict individual health and longevity.

In-depth exploration shows that the acceleration of epigenetic age reflects the complex physiological changes in the body:

• Decline of cell function
• Imparied repair mechanism
• Elevated inflammatory levels

These jointly promote the occurrence of diseases, and diseases are the direct cause of the rise of all-cause mortality. Therefore, the acceleration of epigenetic age can be regarded as an early warning signal, prompting the potential crisis of the body and reminding us to take measures to delay aging and reduce the risk of death.

Association with Specific Diseases

Cardiovascular disease is a global health killer, and its association with the acceleration of epigenetic age has attracted attention. Studies have shown that the acceleration of epigenetic age is related to the occurrence and development of cardiovascular diseases, and the DNA methylation pattern is very important.

The research on patients with cardiovascular diseases found that their DNA methylation pattern was abnormal, and the change of methylation level of specific genes affected gene expression and interfered with the function of the cardiovascular system. These genes are involved in key links such as vasodilation, blood lipid metabolism, and inflammatory response regulation. Abnormal gene expression would lead to vascular diseases, blood lipid metabolism disorders, inflammation aggravation, and trigger cardiovascular diseases.

Large-scale population research shows that the risk of cardiovascular disease increases significantly with the acceleration of epigenetic age, and the risk of cardiovascular disease increases by 40% with the acceleration of epigenetic age for 5 years, and this association is widespread among people of different sexes and races.

At the molecular mechanism level, the change of DNA methylation pattern affects cardiovascular health-related signaling pathways:

• In the Wnt/β-catenin signaling pathway, abnormal methylation of key genes affects the proliferation, migration, and differentiation of vascular smooth muscle cells, leading to vascular lesions.
• DNA methylation also affects the expression of inflammation-related genes and regulates the intensity of inflammatory response. In the occurrence and development of cardiovascular diseases, the change of DNA methylation caused by the acceleration of epigenetic age helps to aggravate inflammation.

Relationship between DNA methylation age estimated with Hannum's predictor and chronological age (Perna et al., 2016)

The Cancer Connection: Acceleration and Reversal

As a key tool to quantify biological aging, the relationship between the epigenetic clock and cancer has become the focus of current research. A lot of evidence shows that the occurrence and development of cancer are often accompanied by the acceleration of the epigenetic clock, which can not only be used as a potential marker of cancer risk assessment but also reflects the progress and prognosis of the disease.

Significant Acceleration of Epigenetic Age in Cancer

Cancer is a serious disease that threatens human health worldwide and is the focus of medical and biological research. Recent studies have shown that the acceleration of epigenetic age is very important in the occurrence and development of cancer, and this phenomenon is present in many cancers, such as colorectal cancer and head and neck cancer.

The incidence and mortality of colorectal cancer are high, and its relationship with epigenetic age is of concern. It was found that the DNA methylation pattern of colorectal cancer tissues changed, and the epigenetic age was significantly higher than that of normal tissues, which reflected the abnormal proliferation and differentiation of tumor cells and was related to the malignant degree, metastatic potential, and prognosis of patients.

Head and neck cancer also has the phenomenon of accelerated epigenetic aging. The results show that the EAA of most patients increases the most immediately after radiotherapy, reaching 4.9 years. EAA is related to more severe fatigue and inflammatory reaction, and with time, increasing EAA is related to increasing fatigue degree, which indicates that the accelerated epigenetic age of patients with head and neck cancer is an important feature of tumor occurrence, or affects tumor development and quality of life by affecting inflammatory reaction and patients' physical condition.

On the molecular mechanism, the accelerated epigenetic age of cancer is mainly due to the disorder of the DNA methylation pattern:

• DNA methylation in normal cells is balanced, gene expression is accurately regulated, and normal function and differentiation of cells are maintained. The balance in cancer cells is broken, and many gene promoter regions are abnormally methylated.
• The high methylation of the tumor suppressor gene promoter makes it unable to express normally and loses its inhibitory effect on cell growth and division, which leads to the uncontrolled proliferation of cancer cells. The methylation level of oncogenes is reduced and overexpressed, which promotes the invasion, metastasis, and malignant transformation of cancer cells.
• This process is complex, involving a variety of epigenetic regulatory factors and signal pathway abnormalities. The abnormal increase of DNA methyltransferase activity leads to the overall increase of DNA methylation level; the Demethylase is defective, which can not remove abnormal methylation modification normally, so that the abnormal methylation pattern can be maintained and accumulated.

New Perspective on Monitoring Therapeutic Effect

Accurate monitoring of cancer treatment efficacy is a top priority for both clinicians and patients.

• Traditional methods (e.g., imaging, tumor marker detection) only provide information on tumor size, shape, or marker levels.
• Limitation: These methods cannot comprehensively or timely reflect the internal biological changes of tumor cells (e.g., proliferation, apoptosis, drug resistance).

The epigenetic clock offers a novel approach for monitoring cancer treatment efficacy.

• It reflects the real-time DNA methylation status of tumor cells, which is closely linked to key tumor cell biological behaviors.
• By regularly measuring patients' epigenetic age, clinicians can assess in real-time how tumor cells respond to treatment and guide adjustments to the treatment plan.

Application in chemotherapy monitoring:

• Effective chemotherapy: Inhibits abnormal tumor cell proliferation, potentially slowing epigenetic age progression.
• Ineffective chemotherapy: Tumor cells continue to proliferate, leading to sustained acceleration of epigenetic age.
• Clinical evidence: In breast cancer patients, effective chemotherapy significantly reduces tumor tissue epigenetic age (associated with longer disease-free survival); non-responsive patients show no change or even increased epigenetic age.
• Value: Enables timely treatment adjustment, reducing unnecessary patient suffering and economic burden while optimizing survival chances.

In addition to chemotherapy, the epigenetic clock is also of great value in monitoring the efficacy of other cancer treatments, such as radiotherapy. After radiotherapy, if the epigenetic age of tumor tissue is obviously decreased and normal tissue is not excessively accelerated, it shows that radiotherapy is effective. If there is no obvious change in the epigenetic age of tumor tissue or abnormal acceleration of normal tissue, it may suggest that radiotherapy is not effective or has great damage to normal tissue, and doctors need to adjust the dose or mode of radiotherapy accordingly.

Multivariable linear regression models examining associations between biological aging measures and either frailty or myopenia in survivors (Gehle et al., 2023)

Neurological Health: Clocks for the Brain

The application of the epigenetic clock in the field of neural health provides a new perspective for dynamic monitoring of brain function. As a highly complex organ, the aging process of the brain is closely related to the occurrence of neurodegenerative diseases, and the brain-specific epigenetic clock can accurately quantify the aging rate of the brain and predict the risk of cognitive decline.

Development of Brain Tissue-specific Clock

As the most complex and mysterious organ of the human body, the aging process of the brain has always been the focus of scientific research. In recent years, the in-depth study of epigenetics has provided new ideas for the study of brain aging and related diseases.

The early research on epigenetic clock mainly constructed general clock models, such as the Horvath clock and Hannum clock. These models can predict the physiological age of individuals based on the whole genome DNA methylation data, but their accuracy and specificity are limited when applied to the brain, because they cannot fully consider the specific epigenetic changes of different cell types (neurons, glial cells, etc.) in the brain.

In order to accurately assess the degree of brain aging and predict the risk of related diseases, scientists began to develop brain tissue-specific clocks:

• Andrew Teschendorff's research group developed a statistical method to quantify biological aging by using DNA methylation data sets of blood and brain tissue, and constructed a brain cell type-specific DNA methylation clock to predict the actual age more accurately in purified neurons and hepatocytes.
• Scientists at the University of Exeter developed a new epigenetic clock and analyzed 1397 brain samples of people aged 1-108 to determine 347 DNA methylation sites. Combinatorial analysis can best predict the age of the human cortex, and the results show that it is better than the previous model in predicting the biological age of the human brain.

Different brain tissue-specific clocks have their own advantages and application scope in predicting the risk of brain aging and related diseases. The clock based on neuron-specific methylation sites is highly sensitive to predict the risk of neurodegenerative diseases. The clock for glial cells may play an important role in reflecting brain inflammatory response and glial-related diseases. These specific clocks provide tools for studying the mechanism of brain aging, and also provide new strategies for early diagnosis and intervention of nervous system diseases.

Relationship between Epigenetic Aging and Cognitive Decline

With the acceleration of global aging, cognitive decline has become an increasingly serious public health problem. Numerous studies have shown that epigenetic aging plays a key role in the development of cognitive decline, which involves complex molecular mechanisms and signal pathways.

• From the molecular level, DNA methylation, as an important epigenetic modification, is closely related to cognitive function. The pattern of DNA methylation in the brain changes significantly during aging, which affects the expression of cognitive-related genes.
• Histone modification is also an important way of epigenetic regulation and plays an important role in cognitive decline. Histone methylation and acetylation change chromatin structure and function, and regulate gene expression.
• Besides DNA methylation and histone modification, non-coding RNA (ncRNA) such as microRNA (miRNA) and long-chain non-coding RNA (lncRNA) are also involved in the regulation of epigenetic aging and cognitive decline. MiRNA regulates gene expression through complementary binding with target mRNA to inhibit translation or promote degradation.
• Environmental factors play an important regulatory role in the relationship between epigenetic aging and cognitive decline. Long-term exposure to adverse environmental factors such as heavy metal pollution and chronic inflammation will accelerate epigenetic aging and aggravate cognitive decline.

Acceleration of epigenetic age in AD mice compared to B6 mice in cortical and hippocampal tissue (Coninx et al., 2020)

The Immune System's Age: Inflammaging and Immunosenescence

The aging of the immune system is not a single process, but a complex pathophysiological process driven by inflammatory aging and immune aging. With the increase in age, a chronic low-grade inflammatory state continues to accumulate and gradually destroys immune homeostasis.

At the same time, the function and diversity of immune cells decline, which leads to a significant decline in the body's ability to resist infection and remove abnormal cells. The interaction between them is not only an important inducement of aging-related diseases, but also directly affects healthy life span and the aging process, and has become one of the core research directions in the field of gerontology and immunology.

Epigenetic Clock Reflects the Aging Process of Immune System

The immune system is the body's defense against diseases, and it will age with age. The epigenetic clock can accurately reflect the subtle changes of immune system aging. When the immune system is aging, the composition and function of immune cells change significantly, which is closely related to the acceleration of epigenetic age.

T cell function declines with age, the diversity of B cell receptors decreases, the ability of antibody production weakens, and age-related B cells accumulate, which affects the natural immunity and vaccine immune effect. The vitality of innate immune cells such as DC, macrophages, and NK cells decreased, which led to an insufficient initial immune response to the vaccine and a slow response of the immune system.

Interaction between Chronic Inflammation and Immune Aging

• Chronic inflammation is an important feature of immune aging: Aging makes immune function decline, aging cells and pathogens accumulate, aging cells secrete proinflammatory factors to cause inflammation, damage tissues and organs, and increase the risk of cardiovascular diseases and arthritis. The imbalance of intestinal microflora is also the cause of chronic inflammation. Aging, poor diet, and long-term use of antibiotics destroy the balance of microflora, and pathogens and toxins enter the blood to cause inflammation.
• Chronic inflammation aggravates immune aging: The stimulation of inflammatory factors damages the function of immune cells, inhibits the activation and proliferation of T cells, affects the production of B cell antibodies, promotes the apoptosis of immune cells, and also interferes with the differentiation and development of immune cells, which affects the differentiation of hematopoietic stem cells, and reduces the production of immune cells and has functional defects.
• Molecular mechanism: involved in nuclear factor-κ B (NF-κ B) and mitogen-activated protein kinase (MAPK) signaling pathways. The NF-κB signaling pathway is continuously activated in inflammation and immune aging, forming a vicious circle; the MAPK signaling pathway regulates immune cell function, and abnormal activation under inflammation leads to immune cell dysfunction and accelerates immune aging.

Multi-region methylation data recapitulates strong PCBrainAge acceleration associations in test data (Thrush et al., 2022)

Conclusion

Epigenetic age is a new research field. By studying the epigenetic clock constructed by DNA methylation patterns, we can accurately predict physiological age and reveal the real aging process of the body. Studies have shown that the acceleration of epigenetic age is closely related to all-cause mortality, cardiovascular disease, neurodegenerative disease, and cancer.

The epigenetic clock has great potential in disease prevention, diagnosis, and treatment. However, there are challenges in technology, biological mechanisms, and clinical application at present, such as high cost and low flux of detection technology, insufficient understanding of the mechanism of epigenetics and disease, and problems such as combining clinical transformation with existing standards and evaluating safety and effectiveness. In the future, further research is needed to tap its potential and promote the development of human health.

FAQ

1. If the epigenetic clock shows accelerated aging, does it mean I will definitely develop cardiovascular disease or cancer soon?

At present, the epigenetic clock has been verified to be effective in monitoring the efficacy of chemotherapy and radiotherapy, but its application in other cancer treatments (such as targeted therapy, immunotherapy) is still in the research stage.

2. Is the brain tissue-specific epigenetic clock only applicable to the elderly, or can it also be used for young people to predict the risk of cognitive decline?

The brain tissue-specific epigenetic clock is not limited to the elderly and can also be used for young people. By detecting the brain-specific epigenetic clock, young people can understand the aging state of their brains in advance.

3. How does the epigenetic clock reflect the aging of the immune system?

The epigenetic clock reflects the aging of the immune system mainly by linking the acceleration of epigenetic age with the changes in the composition and function of immune cells.

References

1. Perna L, Zhang Y, Mons U, Holleczek B, Saum KU, Brenner H. "Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort." Clin Epigenetics. 2016 8: 64.
2. Gehle SC, Kleissler D, Heiling H, et al. "Accelerated epigenetic aging and myopenia in young adult cancer survivors." Cancer Med. 2023 12(11): 12149-12160.
3. Coninx E, Chew YC, Yang X, et al. "Hippocampal and cortical tissue-specific epigenetic clocks indicate an increased epigenetic age in a mouse model for Alzheimer's disease." Aging (Albany NY). 2020 12(20): 20817-20834.
4. Thrush KL, Bennett DA, Gaiteri C, et al. "Aging the brain: multi-region methylation principal component based clock in the context of Alzheimer's disease." Aging (Albany NY). 2022 14(14): 5641-5668.