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Diet, DNA and destiny

For some, living longer brings opportunities, but for others it heralds ill health. Ameliorating deficits in healthspan requires deeper understanding of the complex changes in biological functions that lead to ageing. Dr Gavin Kelsey, Head of the Epigenetics programme, talks about the programme’s science, ambitions for the next four years, and shares a small secret about what helps fuel his research.

Epigenetics describes the systems that control our genes’ activity throughout our lives. Key epigenetic ‘marks’ are established early in development, defining the body’s different cell types and keeping cells working correctly. As we age, epigenetic information can change and deteriorate, partly due to lifestyle factors, affecting cell function and renewal. The ������Ƶ’s Epigenetics programme focuses on how the epigenetic control of gene expression helps maintain and support lifelong health, opening up new ways to promote healthy ageing.

“The big theme of the programme is to link two areas of biology, metabolism and epigenetics, so we're trying to investigate how much some aspects of our metabolism and our diet affect how our genes are controlled,” says Dr Gavin Kelsey. This is important because we know that all of the processes that go on around the DNA to ensure that genes are regulated correctly depend upon metabolites within cells, and these metabolites are also shared by other processes in the cell, as part of the cell’s normal metabolism.”

DNA is not a simple molecule. Within the nucleus of our cells, DNA is wrapped around histone proteins, organised into chromatin and packaged to form chromosomes. The DNA itself is modified or ‘decorated’ with chemical tags, and the histone proteins are also highly modified by chemical tags made available by the pool of metabolites within in the cell. These reversible modifications control subsequent gene expression, locking away some genes while leaving others accessible to the gene reading machinery at the appropriate time.

“Although part of this is probably hardwired and unlikely to be affected by changes in nutrition, some metabolites may be helping genes respond to environmental or nutritional change,” he explains. “This is the area we're particularly interested in, and how the interface between metabolism and epigenetics changes as we age.”

One key question is how these epigenetic changes—the sum of the various modifications to particular genes—are set up early in development and affect how our genes are programmed throughout our lives.

As a result, the programme does much work at this development stage and is learning much from early human embryos.

“We have wonderful model systems, but they don’t always perfectly recapitulate exactly what goes on during human development,” says Kelsey. “That’s why it's vital we translate what we know from models, such as mouse, into human systems; looking at the epigenetic processes happening in the very early embryo, as different cell types start to emerge from what is otherwise a ball of identical cells, is really exciting and transforming what we know about early human development.”

Answering these questions over the next four years depends on the best scientists – research and technical, a bold vision, and the capability to realise it, which is what makes the ������Ƶ world leading in the field. “What's really exciting, particularly in Peter Rugg-Gunn's group, is the development of single-cell technologies and these amazingly sensitive methods that allow us to map epigenetic marks over genes in individual cells. Until now, we've only been able to do this for individual epigenetic marks, but his team has developed a technique to look at multiple different modifications in a single cell, which will be a game changer,” he explains.

The Epigenetics programme has also been strengthened by strategic appointments in 2022 when Dr Sophie Trefely and Dr Teresa Rayon joined the ������Ƶ. Rayon’s group is interested in the rate at which organisms develop and how this might be linked to lifespan. The mechanisms underlying biological timing remain largely unknown so, by comparing what happens during development in mice versus humans, she is working on what controls biological timing and whether we can modulate developmental timing and extend lifespan.

Trefely is interested in metabolism and the fact that within the cell, metabolites are not uniformly distributed. Some are produced in particular organelles, such as mitochondria, but to impact DNA regulation, metabolites must act in the cell’s nucleus. “She is using elegant methods to examine the metabolic profile of a nucleus, altering the cell’s metabolic regime to discover how metabolites change in the nucleus. Using these new technologies, we can discover what happens at the interface between metabolites and gene regulation," explains Kelsey.

Trefely and Rayon are joint appointments, bridging the Epigenetic and Signalling programmes, and an example of how the synergies between the ������Ƶ’s three programmes mean advances in one translate into advances across the others.

On a personal level, Kelsey—who joined the ������Ƶ in 1995—is trying to age healthily. “I’m going to the gym regularly for the first time in my life and enjoying it. I try to eat healthily and maintain a healthy weight. I try to be less sedentary, hence my standing desk. But I’ve never tried intermittent fasting,” he concludes. “I think I’d find fasting quite difficult. I'm already begging for a croissant at 9am, despite having had breakfast. It’s habit, rather than necessity!”