Epigenetic Factors That Influence Longevity

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Did you know that the number of individuals aged 90 years and older in the United States is expected to quadruple from 1.9 million in 2016 to 7.6 million in 2050?

This demographic shift highlights the urgent need to advance geriatric medicine and to focus on maintaining physical and mental well-being in older age.

One of the hallmarks of aging is epigenetic alterations that regulate gene expression, leading to changes in cellular function and tissue homeostasis. As such, epigenetics has gained increasing attention in longevity medicine as a biomarker of aging.

This article reviews the latest findings on epigenetics and longevity to elucidate the mechanisms underlying epigenetic alterations and their effects on human lifespan. We also highlight the current progress in developing novel interventions for promoting healthy aging.


Epigenetics and Longevity: How Epigenomes Determine Our Lifespan

Aging Is Not Natural but a Medical Condition


Aging is a complex and multifaceted process that has been the subject of scientific inquiry for many years. Historically, aging has been viewed as a natural process that occurs in all living organisms, leading to the decline of physiological functions over time.

However, recent scientific evidence suggests that aging is not simply a natural process but a medical condition that can be addressed and potentially reversed.

At the cellular level, aging is accompanied by physiological changes that occur over time, including DNA damage, telomere shortening, mitochondrial dysfunction, and a decline in stem cell function. Because these changes contribute to various age-related diseases, reversing them may provide a new avenue to delay aging.


What Is Epigenetics, and Why Is It Important?

Epigenetics refers to changes in gene expression (the process through which a gene’s encoded information is converted into a function) that are not caused by alterations in the DNA sequence but rather by modifications to the surrounding chemical structure.

In simple terms, epigenetics is like a light switch that can turn genes on or off without changing the DNA sequence, just like how a light switch can turn on or off a light bulb without changing the wiring in the house, but it changes how the house looks.

During development, epigenetics control which genes are turned on or off in stem cells, determining the cell’s fate or what type of tissue it will become. For example, a muscle cell has different epigenetics than a nerve cell, allowing it to perform its specific function.

In aging, epigenetics have been associated with changes in DNA methylation and histone modifications, observed in various age-related diseases. Therefore, developing interventions that manipulate these epigenetic patterns may allow us to improve our lifespan.


Epigenetic Alterations: A Hallmark of Aging

Epigenetics exist because our epigenomes can change as we age due to various reasons, such as environmental or dietary factors, causing changes in gene expression that may eventually impair cellular function and tissue homeostasis.

Due to its impact on human health, epigenetic alterations have been considered one of the hallmarks of aging that act in concert with other aging factors, contributing to the decline of organismal functions and the development of age-related diseases.

For example, epigenetic alterations in the brain can contribute to neurodegenerative diseases such as Alzheimer’s. In contrast, epigenetic alterations in immune cells can lead to an impaired immune system and increased susceptibility to infection and cancer.

An overview of the aging epigenome. Cells undergo several epigenetic alterations as they age and the emergence of cellular senescence. Source: Nature.


How Epigenetic Alterations Affect Longevity

Influence Stem Cell Functions


A stem cell is a type of cell that can develop into many different types of cells in the body. They can divide and renew themselves to create more stem cells or differentiate into specialized cells, such as muscle cells, nerve cells, or blood cells.

Epigenetic alterations can significantly impact stem cell functions, which is detrimental to maintaining tissue homeostasis and repairing damaged cells.

Also, these epigenetic alterations can lead to changes in the expression of genes involved in stem cell differentiation, proliferation, and self-renewal, ultimately exacerbating tissue regeneration and contributing to the development of various diseases.


Modify Telomere Length

Telomeres are the repetitive DNA sequences located at the end of chromosomes that protect the integrity of the genetic material during cell division.

Telomeres shorten in length after each cell division. When they reach a critical length, the cell enters senescence or programmed cell death.

Shortened telomere length has been associated with aging and age-related diseases, such as cardiovascular disease, diabetes, and cancer. Therefore, telomere length is a determinant of cellular lifespan, and its maintenance is crucial for an organism’s longevity.

Epigenetic alterations can modify the expression of genes involved in telomere maintenance, leading to telomere length and function changes.

For example, epigenetic alterations can affect telomerase – the enzyme responsible for maintaining telomere length. Epigenetic alterations can also affect the expression of genes that protect telomeres from degradation and retain their structural integrity.


Elevate DNA Methylation

Epigenetic alterations can modulate DNA methylation, a chemical modification of DNA that can affect gene expression without changing the DNA sequence.

Elevated DNA methylation levels have been associated with aging and age-related diseases. For example, DNA methylation of the tumor suppressor gene can increase with age, leading to a decline in regenerative ability and increased susceptibility to cancer.

Epigenetic alterations that elevate DNA methylation levels may also affect other cellular processes, such as mitochondrial function and inflammation.

For instance, DNA methylation changes in genes involved in mitochondrial function may contribute to mitochondrial dysfunction, leading to increased oxidative stress and cellular damage. Meanwhile, DNA methylation can cause inflammation to become chronic, a risk factor for various age-related diseases.


Cause Histone Modifications

Epigenetic alterations can also cause histone modifications, which can affect chromatin structure and the accessibility of DNA to transcriptional machinery.

Histone modifications, such as acetylation, have been linked to unhealthy aging. For example, decreased histone acetylation levels have been associated with a decline in gene expression and cellular function.

Moreover, histone modifications can influence the expression of genes involved in inflammation, oxidative stress, and apoptosis, all contributing to aging.

For instance, changes in histone modifications can affect the expression of genes involved in regulating immune response and inflammation, contributing to chronic inflammation and age-related diseases such as Alzheimer’s and cardiovascular disease.


Diseases Associated With Epigenetic Alterations



Many epigenetic changes can occur in cancer cells, such as aberrant DNA methylation and histone modification.

These changes can cause the activation or inactivation of genes that are involved in cancer development and progression, including tumor suppressor genes and oncogenes. Also, epigenetic alterations have been linked to the resistance of cancer cells to chemotherapy and radiation therapy, making them more challenging to treat.

Understanding the epigenetic mechanisms involved in cancer can potentially lead to the development of new therapies that target these alterations and ultimately improve patient outcomes. Furthermore, epigenetic changes may also be used as biomarkers for the early detection and diagnosis of various types of cancer.


Cardiovascular Disease

Epigenetic changes in the genes that regulate inflammation, oxidative stress, and lipid metabolism can lead to plaque buildup in the arteries. These changes can occur due to exposure to factors such as smoking, poor diet, and lack of exercise, which can affect the function of genes involved in cardiovascular disease.

DNA methylation and histone modification are the most common epigenetic modifications implicated in cardiovascular disease.

DNA methylation can affect the expression of genes involved in lipid metabolism, inflammation, and blood coagulation. Meanwhile, histone modifications can affect the regulation of endothelial function and vascular tone genes.

Epigenetic alterations can also change the behavior and function of vascular smooth muscle cells and endothelial cells, contributing to hypertension and vascular aging.


Type 2 Diabetes

One of the critical epigenetic alterations associated with type 2 diabetes is DNA methylation. Genome-wide DNA methylation studies have shown that individuals with type 2 diabetes exhibit differential methylation patterns compared to healthy individuals.

Specifically, genes involved in insulin signaling, glucose transport, and metabolism are often affected by DNA methylation changes in individuals with type 2 diabetes.

Histone modifications have also been implicated in diabetes. Histones are proteins that package DNA into a compact structure known as chromatin. Certain histone modifications, such as acetylation, can lead to changes in gene expression, insulin resistance, and impaired glucose metabolism, critical features of type 2 diabetes.


Alzheimer’s Disease

One of the epigenetic changes associated with Alzheimer’s disease is DNA methylation. DNA methylation patterns can be altered in the brains of individuals with Alzheimer’s, particularly in genes involved in neurodegenerative processes.

DNA methylation can also contribute to the dysregulation of genes involved in inflammation, oxidative stress, and synaptic plasticity, and all are critical factors in Alzheimer’s.

Histone modifications are also involved. Alterations in histone modifications can change gene expression patterns contributing to Alzheimer’s disease.

For example, a decrease in the level of histone acetylation has been associated with the upregulation of genes involved in inflammation and the downregulation of genes involved in synaptic plasticity, both of which are characteristic features of Alzheimer’s disease.


Epigenetic Interventions to Achieve Longevity

Calorie Restriction and Fasting

Studies have highlighted the positive effects of calorie restriction and fasting on epigenetics and longevity.

  • Calorie restriction involves reducing daily calorie intake by up to 40% while maintaining adequate nutrient intake.
  • Fasting involves abstaining from food for repeated periods. As such, intermittent fasting has been proposed to address epigenetics.


Research by the University of Chinese Academy of Sciences has shown that calorie restriction and fasting can, to variable degrees, extend the longevity of mice by reducing arterial dysfunction, enhancing skeletal muscle capacity, and reducing the loss of muscle fibers and motor neuron renewal.

Researchers suggested that the amelioration of age-related epigenetic alterations due to calorie restriction and fasting explains how these interventions affect longevity. Based on the epigenetic clock, the 40% calorie restriction therapy done in mice slows the molecular changes and lowers the epigenetic age (biological age).

Notably, a 20-year 30% calorie restriction study in adult monkeys has resulted in significantly longer lifespans and decreased aging-related diseases, suggesting that this intervention may have a similar effect on humans.

Indeed, caloric restriction has been shown to slow biological aging in humans, enhance liver function, lower oxidative stress, and lower the occurrence of age-related disorders.


Pharmacological Interventions

The same study from the University of Chinese Academy of Sciences has suggested some pharmaceutical approaches, many closely connected to epigenetics and longevity, based on the molecular mechanisms driving cellular senescence and aging.


For instance, senolytics can eliminate senescent cells to delay aging, while gero-protective drugs have been developed to prevent aging.

Some examples of gero-protective drugs are:

  • NAD+ precursors
  • Sirtuin-activating substances
  • HDAC inhibitors
  • Small molecules with potent anti-diabetic effects (e.g., metformin)
  • mTOR inhibitors (rapamycin)
  • Antioxidant chemicals (N-acetyl-l-cysteine)


Various animal models using small molecule compounds as gero-protective drugs. These substances prolong life or ameliorate aging effects in various organs. Source Nature.
Various animal models using small molecule compounds as gero-protective drugs. These substances prolong life or ameliorate aging effects in various organs. Source Nature.

Meanwhile, senolytic therapy, which selectively eliminates senescent cells in older people, is being researched as a possible therapy for anti-aging. The most widely suggested senolytic method combines pan-tyrosine kinase inhibitors dasatinib (D) with quercetin (Q).

D + Q has been demonstrated to increase lifespan and slow aging in various tissues and organs, including the heart, skeleton, brain, adipose, lung, and muscle.

Recent research has also shown that epigenetic regulation is a crucial mechanism by which D + Q eliminates aged cells. Further, D + Q treatment improves the cognitive function of old male rats by altering the epigenetic signatures in the hippocampus.

Other senolytic drugs include:

  • ABT-263
  • ABT-737
  • Digoxin
  • FOXO4-DRI (D-retro inverso)
  • Heat shock protein (HSP) 90 inhibitor 17-DMAG


These senolytic medications perform senolytic functions primarily by triggering apoptosis and mitochondrial malfunction. However, more investigation is necessary to establish their relationship to epigenetics.

Existing strategies to slow down aging in different creatures. Source Nature.
Existing strategies to slow down aging in different creatures. Source Nature.


Bottom Line

In conclusion, epigenetics plays a crucial role in aging and the development of age-related diseases. The accumulation of epigenetic alterations over time can lead to changes in gene expression, contributing to the onset of diseases and a decline in physiological functions.

However, interventions that target epigenetic alterations have shown promising results in mitigating the effects of aging and promoting longevity. For example, calorie restriction and fasting can induce epigenetic changes that protect against age-related diseases, while gero-protective drugs and senolytics target specific pathways involved in aging.

These interventions have demonstrated potential in reversing age-related changes and promoting healthy aging. As the number of people over 90 continues to rise, exploring the possibility of epigenetic interventions to achieve longevity is crucial.



Jain P. et al. (2022). Analysis of Epigenetic Age Acceleration and Healthy Longevity Among Older US Women. The Journal of the American Medical Association (JAMA).

Wang K. (2022). Epigenetic Regulation of Aging: Implications for Interventions of Aging and Diseases. Nature.


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