How do environmental factors impact epigenetic age?

Several environmental factors such as diet, exercise and stress can impact the epigenetic age and can be used to modulate and decelerate epigenetic aging in humans.

People are living longer globally resulting in a significant increase in aging populations – the number of people aged 65 years and above are expected to reach 1.5 billion by 2050. The population aging phenomenon initially began in high-income countries, but currently, it is middle and low-income countries are experiencing the greatest change [1]. As the distribution of a country’s population shifts towards older ages, there are resulting shortfalls in several socioeconomic areas due to loss of performance and disability during the later stages of life. Moreover, this demographic change poses a challenge to national economies since an increasing number of individuals retire and need increased healthcare and social support.

Such a scenario has led to an increase in the development of diagnostic and therapeutic tools that promote healthy aging. A Global Action Plan on Healthy Aging has been launched by the World Health Organization (WHO) to address the challenges due to aging populations.

Longevity.Technology: Addressing these challenges needs research, and recent advances in molecular technologies have made it possible for scientists to form hypotheses for decelerating and even reversing aging by studying its molecular mechanisms. Aging clocks are digital models that quantify the aging process and provide information on biological age, and they can be devised from any biological system that changes with age [2].

Now, a timely piece in Ageing Research Reviews aims to analyze the underlying aging mechanisms and efficacy of antiaging interventions, including diet, physical activity, and stress [3]; the authors are Fedor Galkin, Olga Kovalchuk, Diana Koldasbayeva, Alex Zhavoronkov and Evelyne Bischof.

Types of aging clocks

The release of the first aging clock took place in 2011, trained using 128 DNA methylation (DNAm) profiles, the clock was able to measure the chronological age of individuals with a mean absolute error (MAE) of 5.2 years. Using the same approach, Dr Steve Horvath created a multi-tissue DNAm clock in 2013. It used 353 CpG sites to produce accurate age prediction across multiple tissues, which in turn indicated epigenetic regulation plays an important role in aging [4].

Dozens of aging clocks have been developed since then that predict age using machine learning. Several aging clocks also use facial photos, clinical blood tests, and omics data. Recent aging clocks use alternative measures of age such as PhenoAge, which uses phenotypic age as its target variable, GrimAge uses the time to death, and DunedinPACE which uses the pace of aging. However, the first-generation clocks have not been completely replaced by these newer second-generation clocks [3].

Epigenetic aging

The common epigenetic factors that impact aging are chromatin remodelers and DNA modifiers such as DNA methyltransferases (DNMTs). Research also indicates that the accumulation of epigenetic stress also disrupts epigenetic profiles leading to aging phenotypes. DNA methylation levels at CpG sites were observed to lose their initial hypo- or hyper-methylated identity with age.

Age-related epigenetic changes lead to aging phenotypes through the promotion of cardiovascular pathologies, carcinogenesis and genomic instability. Recent studies have also reported that along with DNA methylation landscape alterations, noncoding RNA expression, and histone modifications were also reported to change with aging.

Epigenetic therapeutics

There has been an explosion in interest in the use of epigenetic therapies to delay or reverse aging-related changes. Several studies have indicated that epigenome modifications can improve the decline of cellular functions with age as well as delay the onset of age-related diseases, which suggests epigenetic changes to be a promising target for antiaging interventions.

And this focus on epigenetics is not just within the geroscience research community; James Brown, Cofounder and Nutrigenetics Director at epigenetics company Muhdo Health told us that interest in epigenetics is on the rise, and more and more people are turning to epigenetic testing in order to understand how their lifestyle, nutrition and environment can affect how their genes function and express themselves.

“Your day-to-day life and the daily choices you make can have a profound effect on your epigenome and the health and expression of your genes,” he said.

“Muhdo Health has already developed a data analytics research platform that connects and interrogates their entire dataset of over 30,000 DNA test results and 8,000+ epigenetic test results with data collected from lifestyle tracking and health questionnaires to better understand which lifestyle and environmental factors have the most positive effect on our genes.”

Negative impact on epigenetic age

Several studies have shown smoking to alter gene expression and DNA methylation levels. Such adverse effects of smoking are mostly mediated by epigenetic mechanisms. Smoking has been reported to increase the epigenetic age of lung tissues and airway epithelial cells by four to five years. Alcohol consumption is another factor that can accelerate epigenetic aging. Such aging accelerations are observed to be associated with polymorphism in the gene APOL2, which is linked to addiction and schizophrenia. UV rays and pollution also cause negative epigenetic changes.

Epigenetic diet

Although quitting alcohol and smoking can decrease accelerated aging, dietary factors have a wider reach. Caloric restriction (CR) is the most common dietary intervention that has been known to impact epigenetic age [3].

A recent methylation-supportive diet and lifestyle program which involved physical training, breathing exercises, intermittent fasting, as well as dietary and supplement prescriptions were reported to reduce epigenetic age. Moreover consumption of a diet rich in fish and poultry, fruits and vegetables, along with polyphenols such as curcumin have been reported to cause aging deceleration.

Physical fitness and epigenetic age

Physical fitness is an essential factor in human longevity. Studies have shown that people who undergo endurance training have a 3–5 times lower mortality rate as compared with those who do not undergo the training. People with a lifelong history of physical activity have been reported to show lower DNA methlyation levels on gene promoters in muscle tissue. Moreover, studies have also indicated that a drop in body mass index (BMI) is associated with a reduction in epigenetic age.

Physiological stress and epigenetic age

Recent studies reported that lifetime accumulated stress can have long-lasting effects on the epigenome. Moreover, psychological stress during childhood has been observed to impact the aging rate in later life. Being the direct victim of violence is also observed to be associated with higher epigenetic age in children. On the other hand, studies also reported mindfulness-based stress reduction to positively impact epigenetic aging [3].

Supplements and epigenetics

Research is ongoing for the development of supplements that can help people to live longer life in good health. Metformin is one such geroprotector that can extend lifespan by 3 to 4 years when the course starts at 75 years of age. Other popular supplements that have been examined in clinical trials include polyphenols, polyamines and NAD+ boosters. Moreover, the integration of aging clocks into the practices of the pharmaceutical industry can help in the discovery of new classes of geroprotectors.

Going forward…

Dietary changes, increase physical fitness, and stress reduction are a few factors that can help to reduce epigenetic aging in individuals and promote healthy aging. Aging clocks are effective tools that help to predict such changes associated with epigenetic age. However, there are a few challenges to integrating aging clocks, including their high cost and variety.

Such challenges can be overcomed by the development of multi-omic clocks. These clocks will help us to reach a new level of understanding regarding the process of aging and help to fight the problem of global population aging.

[1] https://www.who.int/news-room/fact-sheets/detail/ageing-and-health
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9245174/
[3] https://www.sciencedirect.com/science/article/pii/S1568163723001150
[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015143/