Epigenetic Alterations: The Third Hallmark of Ageing
Introduction to Epigenetics
Hidden switches in your DNA can make you biologically younger - or older - than your birth certificate suggests. This remarkable phenomenon stands at the frontier of epigenetics, a revolutionary field reshaping our understanding of human development and ageing. Whilst our genetic code remains fixed from birth, epigenetic mechanisms reveal how environmental factors and lifestyle choices influence which genes are expressed or silenced throughout our lives. This sophisticated interplay not only affects our own health trajectory but may extend to future generations, offering both sobering implications and unprecedented opportunities for intervention.
Epigenetics refers to changes in gene activity that don’t alter the DNA sequence itself but influence how genes are read and used [1]. Think of it as a set of dimmer switches that adjust how much a gene is “on” or “off.” These switches are essential for ensuring each cell type only activates the genes it needs - despite every cell carrying the same DNA.
Some epigenetic changes can be hereditary, influencing gene expression across generations. However, many epigenetic modifications are shaped by our own experiences and exposures throughout life. Certain lifestyle and environmental factors can trigger epigenetic changes by leaving chemical marks on DNA or the proteins it wraps around [2]. Over time, these epigenetic marks accumulate, influencing which genes stay active or silent. This reprogramming is thought to contribute to ageing, but the good news is, these changes are reversible. That’s why two 40-year-olds may have very different biological ages: one may function like a 34-year-old at the cellular level, while the other may appear biologically 46.
Types of Epigenetic Changes
The dramatic effects these epigenetic mechanisms exert on our health and ageing raise an important question: what specific changes occur at the molecular level, and how might we influence them? Research has identified four principal epigenetic modifications that orchestrate gene expression throughout our lifespan. Each represents a distinct biological pathway through which environmental factors - from nutrition and exercise to stress and pollutants - can literally reprogram our genetic activity. Understanding these mechanisms offers not merely academic interest but practical insights into how we might potentially optimise our biological ageing processes.
DNA Methylation:
This is when a small chemical tag, called a methyl group, attaches to parts of our DNA - usually at specific sites called cytosines. This tag acts like a switch, often turning genes off so they’re not used. As we age, these patterns of methylation shift - some areas gain tags, others lose them - changing which genes are active. This can affect how well our cells work and how our body ages [3].
Histone Modifications:
DNA is tightly wrapped around proteins called histones, helping to package it neatly inside our cells. These histones can be marked with chemical tags that tell the cell whether to open up the DNA (so genes can be switched on) or keep it tightly packed (so genes stay off). With age, these histone tags can get mixed up, which may shut down helpful genes or accidentally switch on harmful ones [4].
Chromatin Remodelling:
Chromatin is the combined structure of DNA and proteins (like histones) that make up our chromosomes. Cells can rearrange this structure to open up certain parts of the genome - allowing genes to be read - or close them off. In older cells, this system becomes disorganised: areas that should stay quiet might become active, and important regions might get locked down, throwing off normal cell function [5].
Transcriptional Alterations (Non-coding RNA):
Not all RNA in our cells is used to make proteins. Some types, like microRNAs, help control which genes are turned on or off. These ‘non-coding RNAs’ act as fine-tuning tools for gene activity. As we age, the levels and behaviour of these RNAs can change, affecting the balance of gene activity - especially in areas linked to inflammation, energy production, and cell repair [6].
Meeting the Hallmark of Ageing Criteria
Now, let’s refer back to Lopez Otin’s hallmarks of ageing criteria [7] to see how epigenetic alterations fits the brief:
1.It should naturally occur as part of the ageing process.
Epigenetic changes clearly accumulate during normal ageing. Studies in organisms from yeast to humans show that epigenetic modifications (DNA methylation and histone marks) shift steadily as individuals get older [8-11]. This age-related “epigenetic drift” means older cells have a different epigenetic landscape than younger cells, which can alter gene activity and cell function.
2. Experimental acceleration or increase of the biological process should measurably speed up the ageing process.
If epigenetic alterations occur faster or become excessive, signs of ageing appear sooner. In one experiment, scientists disrupted the epigenome in young mice (without altering any genes), and the mice rapidly began to exhibit old-age traits; their cells lost identity and organs faltered, essentially a premature ageing effect. In humans, researchers have observed similar patterns [12]. A study published in Aging Cell found that individuals with faster "epigenetic clocks" - a measure of biological ageing based on DNA methylation - were more likely to experience age-related conditions like cognitive decline, cardiovascular issues, and frailty, even if they were the same chronological age as others [13]. This reinforces the idea that rapid epigenetic changes can predict and potentially promote early-onset ageing and disease.
3.Mitigating the process (actionably reducing or slowing it down) should, in turn, slow down normal ageing.
Short answer: yes. Strong evidence shows that our environment and lifestyle choices directly affect the rate of epigenetic ageing.
A study published in Clinical Epigenetics found that individuals with consistently healthy lifestyles - characterised by a balanced diet, regular exercise, no smoking, and limited alcohol - had significantly younger epigenetic ages than those with unhealthy habits [12] . Of all factors, smoking had the most negative impact, while diet and exercise helped offset epigenetic changes. Other research has demonstrated that epigenetic ageing can be reversed with intervention. In a 2021 pilot study, participants following an 8-week lifestyle intervention, reversed their biological age by an average of 3.23 years compared to controls [14]. Similarly, a CALERIE intervention trial demonstrated that two years of moderate caloric restriction slowed epigenetic ageing in healthy adults [15].
Reducing exposure to environmental toxins can help decrease harmful epigenetic alterations. For example, a 2020 study published in Nature Communications found that long-term exposure to fine particulate air pollution accelerated DNA methylation ageing - linking polluted environments to premature biological ageing [16]. This suggests that limiting exposure to pollutants, such as air pollution, cigarette smoke, and industrial chemicals, may help preserve a healthier epigenetic profile.
Some of these benefits may be linked to the activation of sirtuins - a family of proteins that help regulate how DNA is packaged by modifying histones, which in turn influences which genes are switched on or off [17]. Sirtuins like SIRT1, SIRT3, and SIRT6 are known to support DNA repair, metabolic health, and healthy ageing. Encouragingly, sirtuins can be activated through lifestyle factors such as regular exercise, a nutritious diet, and calorie restriction or intermittent fasting. For example, activating SIRT1 is linked to improved cellular stability and energy metabolism [18], while SIRT6 has been shown to extend lifespan in animal studies when overactive [19]. These proteins work in part by keeping DNA properly wrapped and organised, helping to maintain youthful patterns of gene expression as we age.
A Hallmark We Can Influence
Epigenetic alterations meet all three criteria of a hallmark of ageing. The important takeaway: epigenetic modifications are dynamic and reversible, making them one of the more actionable targets for slowing biological ageing.
Ongoing research is now focusing on the mechanisms through which specific interventions - such as nutrient-rich diets, exercise, stress management, and emerging pharmacological agents - affect epigenetic markers like DNA methylation and histone modification [20]. Studies are also investigating how early-life exposures and cumulative lifestyle factors shape long-term epigenetic trajectories. While the field is still developing, current evidence strongly supports the role of modifiable behaviours in influencing epigenetic ageing - and by extension, age-related disease risk and longevity.
Lifestyle Steps to Tame Epigenetic Ageing
The bottom line: your daily choices can directly shape how your genes behave as you age. Here’s how to slow epigenetic ageing through simple, science-backed strategies:
1. Eat for Methylation Support
What to do: Eat leafy greens, legumes, eggs, whole grains, and cruciferous veg.
Epigenetic effect: Supports balanced DNA methylation and healthy gene expression.
2. Exercise Regularly
What to do: 150 mins of aerobic activity + 2 strength sessions weekly.
Epigenetic effect: Reverses age-related changes in genes linked to repair and inflammation.
3. Avoid Toxins
What to do: Don’t smoke, filter water, minimise chemical exposure.
Epigenetic effect: Reduces harmful methylation and chromatin disruption.
4. Manage Stress
What to do: Practise mindfulness, breathing, or yoga daily.
Epigenetic effect: Helps stabilise stress-sensitive gene activity.
5. Prioritise Sleep
What to do: Sleep 7–9 hours; reduce screen time at night.
Epigenetic effect: Maintains healthy patterns in repair and circadian genes.
6. Try Fasting or Calorie Awareness
What to do: Start with a 12:12 eating window.
Epigenetic effect: Activates longevity-linked genes (e.g. sirtuins).
Glossary of Key Terms
Epigenetics: The study of how gene activity is changed by lifestyle and environment - without altering the DNA code itself.
Epigenetic Marks/Modifications: Chemical tags added to DNA or histones (like methylation) that affect gene activity. Influenced by factors like diet, exercise, and pollution.
Histones: Proteins that DNA wraps around for structure. Chemical changes to histones control how tightly DNA is packed, influencing whether genes are active or silent.
Chromatin: The combined structure of DNA and histones. Loosely packed chromatin allows genes to be read; tightly packed chromatin keeps them off.
Gene Expression: Whether a gene is turned “on” or “off” - that is, whether it’s being used to make proteins. Controlled in part by epigenetics.
Transcription: The first step in using a gene: copying DNA into RNA, which is later used to make proteins.
Non-coding RNA (e.g. microRNAs): Types of RNA that don’t make proteins but help regulate which genes are active - especially those related to inflammation and repair.
Biological Age: How “old” your body is based on markers like DNA methylation, which may differ from your actual age in years.
Epigenetic Clock: A tool that estimates biological age by measuring patterns of DNA methylation across the genome.
CALERIE: Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy, a study designed to investigate the effects of calorie restriction on healthy human subjects.
Sirtuins: Proteins involved in DNA repair and ageing. They can be activated by exercise, fasting, and calorie restriction.
Inflammation
One of the body’s defence responses. Epigenetics can influence how inflammation-related genes behave.
References:
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Author: Georgia Pilling
