Real time unlocks how DNA methylation impacts aging

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Innovative research from Vilnius University sheds light on how DNA methylation impacts cellular aging and healthspan.

A research team from Vilnius University (VU) has developed a non-invasive method to track DNA methylation changes in live cells. This advancement allows researchers to observe epigenetic modifications over time – a process that could hold the key to an improved understanding of cellular aging and longevity [1]. By examining these changes, scientists hope to develop new strategies for promoting healthy aging, potentially offering insights into how lifestyle factors, such as diet, influence our health as we grow older.

Longevity.Technology: Epigenetic changes involve chemical modifications to DNA that do not alter the genetic code itself but can influence how genes are expressed. Among these changes, DNA methylation plays a crucial role, acting as a cellular switch that can turn genes on or off. Factors like lifestyle and diet contribute to methylation patterns, and over time, accumulated modifications can impact the aging process and overall health. This latest research offers a window into how these processes occur in living cells, shedding light on how we might target them to extend healthspan.

Monitoring DNA methylation in real-time

The method developed by the VU team, led by Professor Saulius Klimašauskas, offers a way to monitor DNA methylation non-invasively within living cells. This enables researchers to capture real-time epigenetic changes, a breakthrough that could enhance our understanding of how cellular processes evolve with age.

This method uses engineered methionine adenosyltransferase cascades, which allow for the metabolic labeling of DNA. By modifying methionine – a key amino acid in the methylation process – with an extended molecular ‘tail,’ the team created a methionine analogue that can act as a methyl donor in place of the native molecule. This engineered analogue integrates with DNA methyltransferase enzymes within the cell, allowing the researchers to label and track methylation activity over time.

“The method we’ve developed allows us to explore processes that have been scarcely studied until now,” Klimašauskas explained. “It marks a significant step forward in investigating epigenetic changes that could profoundly impact human health.”

This new technology, based on cellular uptake of modified methionine analogues, enables real-time tracking of DNA methylation without the need to alter the cell’s natural state. The analogue passes through cell membranes and incorporates into cellular DNA methylation processes as a non-toxic substitute for natural methionine, minimizing potential disruptions to cell function.

L-R: Paper authors, Dr Vaidotas Stankevičius, Dr Liepa Gasiule and Professor Saulius Klimašauskas

Methionine: a dietary component with epigenetic influence

Central to this research is methionine, an essential amino acid vital for numerous cellular processes. Methionine is converted into S-adenosylmethionine (SAM), a molecule that serves as a universal methyl donor for DNA, RNA, and protein methylation. SAM is crucial for transferring methyl groups, which act like molecular switches to turn genes on or off.

“Methylation of biomolecules is a universal biochemical process that occurs in every human cell,” explained Dr Liepa Gasiulė, one of the researchers on the team. “You can think of DNA modification like a sentence with punctuation, where the words represent DNA and the punctuation marks are the methylation modifications – they determine how the sentence is read and understood.”

Imbalances in methylation can affect various cellular functions, including metabolism, neurological health and immune response, all of which are important for maintaining vitality and health over a lifespan.

Non-invasive tracking with modified methionine analogues

By using CRISPR/Cas9 technology, the team engineered mouse embryonic stem cells to express enzymes that incorporate the modified methionine analogue, allowing for real-time observation of methylation activity. This approach enables tracking of how specific epigenetic changes unfold over time in living cells.

“What’s important is that the developed method is non-invasive – the stable and non-toxic methionine analogue freely passes through cell membranes and enters the cells,” explained Klimašauskas. “This opens up opportunities to apply this technology in in vivo studies, for example, with mice, to observe changes in living organisms.”

This innovation allows for the assessment of DNA methylation dynamics under various physiological conditions without disrupting the cell’s natural methylation processes. By facilitating in vivo tracking, the technology could help identify how different factors influence epigenetic patterns, potentially leading to lifestyle recommendations for healthier aging.

Looking to the future

Research into the role of dietary methionine has highlighted its potential impact on lifespan and healthspan. Studies suggest that methionine restriction can support cellular health and may contribute to a longer, healthier life [2,3], and the VU team’s method could provide valuable insights into how methionine levels in the diet influence aging at the molecular level, informing dietary recommendations that support long-term health.

As well as exploring the link between methionine and cellular function, this research holds potential for cancer treatment, as cancer cells are known to be highly dependent on methionine. “It appears that the stronger the cancerous properties of the cell, the more dependent it is on methionine,” Gasiulė added, noting that preclinical studies have shown that a low-methionine diet can enhance the effectiveness of chemotherapy and radiotherapy, reducing metastasis risk.

With clinical trials on methionine restriction diets already underway, this research could pave the way for innovative strategies to fight cancer and other diseases linked to epigenetic changes, potentially marking a significant breakthrough in treatment approaches.