Rewiring Biological Time and Aging with Epigenome Editing

What if we could turn back the clock on our cellular age? The prospect of cell or gene therapies that alter the consequences of aging may seem like science fiction, but we are edging ever-closer to that reality. 

Over the last decade, the CRISPR-Cas9 revolution has driven countless advancements in our fundamental understanding of gene function and regulation, in turn unlocking long-held secrets of cellular activity and aging.

We have long known that the epigenome is a complex system—one that regulates the shape of our DNA, and the activity of the genes that lie therein. But of late, we have begun to wonder: could it also hold the keys to a long and healthy lifespan?

Packaged for purpose

In one sense, the epigenome is a packing system. It is the structure that allows the entire blueprint of life to fit within the nucleus. 

The amount of DNA contained within each of our cells is staggeringly large. Each cell in a human body contains around 6 feet of DNA. If you were to extract it all and lay it out end to end, the DNA from a single person would stretch to around 60 trillion feet (or over 10 billion miles)—roughly half the width of our solar system. 

Clearly, it would be physically impossible for all our DNA to exist in open, uncoiled threads within our cells. Instead, the DNA is tightly coiled and woven around proteins called histones. These histones are neatly bundled into clusters of eight (called nucleosomes), which are further packed into stacked fibers of chromatin, condensing the DNA exponentially.

But within this structure lies a sophisticated control system. The epigenome also includes a series of reversible chemical marks which adorn the DNA and histone proteins, directing changes to local shape and function. 

In effect, the epigenome does more than just package DNA—it also regulates which genes are open for transcription and active use, and which are rendered closed, inaccessible, and inactive.

The epigenome and age

So how does this relate to aging and age-related disease? 

Your DNA sequence remains largely stable throughout your lifetime. But the epigenome is dynamic. Some epigenetic marks and signatures endure over time, but others are dramatically altered across the length of human life. 

Such age-linked shifts in the epigenome have been associated with a broad range of cancers, neurological diseases, and age-related inflammation and immune disorders. The onset of age also includes increased cellular senescence and the buildup of fibrotic scar tissue—both of which are accompanied by unique epigenetic signatures. 

Given its core relationship to age-related disease, the ability to precisely manipulate the epigenome has profound implications for the possibility of correcting these conditions.

Opportunities for epigenome editing

The targeted manipulation of gene expression, known as epigenome editing, could transform our approach to in vivo gene therapy for age-related diseases. 

On the one hand, epi-editing can be more precise than small-molecule drugs (which typically alter gene functions less discriminately), and unlike nuclease-based gene editing, epi-editing does not cut DNA or alter its core coding sequence in any way—a critical safety advantage in many therapeutic contexts.

Beyond this, epi-editing could also catalyze the ex vivo cell therapy space. Cell therapy, which uses entire cells as a therapeutic agent, is a powerful approach to correcting age-related diseases. Here, epigenetic editing can be used in the manufacture of more precise and consistent cell products, providing the essential substrates to regenerate tissues lost to age-related fibrosis and senescence. 

Using epi-editing to re-tune the aging immune system could also help arrest the aging process at a global level. The immunological dysregulation that occurs with age is tightly correlated with epigenetic changes—changes that could be reversed with epi-editing, along with the symptoms of chronic “age-flammation.”

 The epigenetic age

This bright, new future of therapeutic epi-editing is already on our doorstep. It is already showing promise in the generation of advanced CAR T-cell therapies that are epigenetically primed for tumor-clearing success. The field is already working to upregulate the expression of tumor-associated antigens for more effective cancer treatments; to repress key proteins and rescue neuronal damage around amyloid plaques in Alzheimer’s Disease models; to epi-edit the Scn9a gene, with a view to turning off the pathway for chronic pain. And this is merely the beginning. 

Epigenetics has led us to the understanding that neither age nor susceptibility to age-related disease are attributes written in stone. They are manipulable processes. And as our newfound ability to edit the epigenome becomes more precise and more tunable, we can start to imagine a world in which human health spans are extended for the benefit of all.