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Reprogramming 101: How To Reset The Ageing Clock

Posted on 5 June 2023

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Imagine if children inherited the age of their parents – if you had a child at age 25, that baby’s cells would be functionally 25 years old. Humanity wouldn’t survive for very long. The fact that the ageing process renews at each generation is essential for the survival of any sexually reproducing species. This facet of our biology is taken for granted, but it’s pretty remarkable when you think about it. Every cell in your body can trace an unbroken lineage going back billions of years. During that time, its ancestors repeatedly underwent ageing, only for the clock to be reset at each new generation and for the ageing process to begin anew.

What exactly is this ‘ageing clock’ that keeps getting rewound, and what purpose does it serve? Most importantly, if this clock is capable of resetting each generation, could we deliberately reset it in an adult human, and what would happen if we did?

A Crash Course In Epigenetics

Two chefs might be reading from identical cookbooks, but if each book has different sections scribbled out, they aren’t going to be preparing the same meals. A similar state of affairs explains how our bodies contain so many different types of cell, despite them containing the same DNA.

Almost every cell in the body contains the same genetic code, the instruction book for making every protein a cell might need. Yet just as the chef can’t read random sentences of their cookbook and expect to produce a tasty meal, each cell needs to read some parts of its genetic code while ignoring others. B cells need to access the genes required for antibody production, but would do well to ignore those involved in laying down bone tissue.

Enter the epigenome. The epigenome is, simply put, all of the modifications to the genome that influence how it is read, without changing the content of the genome itself. For example, modification to the DNA packaging proteins known as histones can change how tightly or loosely the DNA is packed, which in turn affects how accessible that DNA is to be read by the cell’s protein-synthesising machinery. In this way, entire segments of the genome can be made ‘off-limits’. To continue our analogy, this would be like striking out entire pages of the book.

Depiction of DNA methylation and histone modification, two forms of epigenetic alteration.

Other epigenetic modifications can further fine-tune how the genetic code is interpreted, allowing individual genes to be enhanced or suppressed as needed. This is like adding a small annotation to a particular sentence in the metaphorical cookbook. Perhaps the chef might want to go a bit lighter on the chillies this time. OK, we’ve taken this analogy far enough – the point is that the epigenome allows different cells to have their own individual identity, despite having exactly the same set of genes.

Another important piece of information about the epigenome is that it acts like a kind of interface between our genome and our environment. While the genetic code is relatively resistant to change, everything from the food that you eat to the air that you breathe can change the way that code is read by changing the epigenome. This could have important consequences for our health and that of our children, but it’s still an area of ongoing research and probably requires its own dedicated article.

Ageing And The Epigenome

So what has the epigenome got to do with ageing? The epigenome isn’t stable throughout life – within each cell, new epigenetic alterations can be randomly acquired for various reasons. These changes are bad news, because they change the way genes are expressed. Important genes could be turned off, thereby causing cells to function poorly or die. Alternatively, a gene can become overactive at the expense of other, more important genes. Research has linked these changes to several processes thought to be important components of ageing, such as inflammation and faulty mitochondria (the structures that convert nutrients into energy for the cell).

Chronological age vs biological age estimated based on DNA methylation, using three different algorithms.
Genome-wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates

Scientists can now measure these epigenetic alterations and use them to predict someone’s age pretty accurately. They have also found that not everyone accumulates epigenetic alterations at the same rate, and that people with lower rates of ‘epigenetic ageing’ tend to be healthier and feel younger than similarly aged people with faster rates of epigenetic ageing. What’s more, when scientists have given animals treatments that extend their lifespan (such as restricting their caloric intake), their rate of epigenetic ageing slows down.

To what extent epigenetic changes cause ageing in humans is still debated – a portion of epigenetic alterations could just be a consequence of some other underlying process. However, it’s clear that they are at least closely linked to ageing and age-related disease. The only way we can know the nature of this relationship for sure would be to slow down or reverse epigenetic changes and see what happens.

What Is Reprogramming?

At conception, the embryo is an epigenetic blank slate. It needs to be, because it needs to be able to produce any type of cell in the body, and big changes to the epigenome are mostly a one-way process. To ensure that epigenetic changes are not inherited, a process called reprogramming occurs when the gametes (sperm and egg) are produced, and then again upon fertilisation. This erases any epigenetic modifications in the parents’ cells (although research suggests that some changes can actually persist – that’s the subject of another article).

A few decades ago, it was not possible to artificially reproduce this epigenetic reprogramming. In 2006, however, Takahashi and Yamanaka discovered a set of molecules that could rewrite a cell’s epigenetic identity. These molecules, now known as Yamanaka factors, can reprogram a fully specialised cell into an unspecialised one, similar to an embryonic stem cell.

This depiction of cell specialisation is known as Waddington’s epigenetic landscape. The ball at the top of the hill represents a stem cell with the ability to become any type of cell in the body. The valleys represent increasingly specialised cell fates. Once the cell has rolled down the ‘blood cell valley’, it is still free to become a red or white blood cell, but can never hop over to the ‘muscle cell valley’, as the necessary parts of its genome have been locked away. Reprogramming factors, however, can push this ball at least part of the way back uphill.

The breakthrough with respect to the ageing process came a few years later, however. Scientists took senescent human cells (cells that have divided the maximum number of times) and cells from centenarians (people who have reached age 100). They then used Yamanaka factors to reprogram the epigenome in those cells. Remarkably, they found that this procedure completely reversed most signs of ageing in both types of cell. Senescent cells were able to divide again, and the length of their telomeres was reset. Abnormal gene expression was corrected, and mitochondria started to function normally again. The cells became essentially indistinguishable from embryonic stem cells, and were able to divide normally and specialise again.

These findings have now been reproduced many times: epigenetic reprogramming reverses ageing. But if that’s the case, why haven’t scientists cured ageing by simply resetting the age of all of our cells? Unfortunately, reprogramming has a significant limitation: it erases the cell’s identity, causing it to become an unspecialised stem cell. Even if we managed to reprogram every cell in someone’s body, they wouldn’t survive very long. Their heart muscle wouldn’t contract and their neurons wouldn’t fire – they’d just be a lump of stem cells.

Partial Reprogramming – The Holy Grail?

It seems like a cruel joke – we’ve discovered a way to reverse ageing, but we can’t use it. If only we could reprogram a cell in a way that reset its age, but didn’t reset its identity. Well, it turns out we can: it’s called partial reprogramming.

When a cell is exposed to reprogramming factors, but only for short periods of time, it’s possible to restore the epigenome to a ‘youthful’ state without turning it into a stem cell. This has been shown to work not only in single cells, but also in living animals. In one such study published in Nature last year, researchers used genetic techniques to increase the expression of Yamanaka factors in mice. They found that this had various rejuvenating effects, including reduced inflammation, reduced senescence and a more youthful metabolism. What’s more, the mice did not appear to suffer any negative health impacts, even though the treatment lasted a long time.

What’s Stopping Us From Trying Partial Reprogramming In Humans?

It’s probably going to be quite a while before we even think about testing partial reprogramming in humans. There are a few reasons for this, the foremost among them being safety. We still don’t really know exactly how partial reprogramming works, which makes it difficult to gauge the risk involved. Since reprogramming restores a cell’s ability to proliferate, it could increase the risk of cancer. While the study we mentioned above didn’t find any negative effects in mice, a human lives a lot longer than a mouse. Perhaps problems associated with partial programming take longer to emerge.

Another major problem is simply figuring out how to carry out partial reprogramming in an ageing human. When working with animal models, an animal can simply be genetically modified to express reprogramming factors under certain conditions. To treat a human, we would need to develop a drug (or, more likely, a gene therapy) that could induce reprogramming. There would be many factors to consider when developing such a treatment. What’s the optimal combination of reprogramming factors, and for how long should cells be exposed to them? Do younger people respond differently to them than older people? Even when these questions are answered, the treatment would still need to reach the target cells, and in the correct quantities – some cells are easier to reprogram than others.

Since ageing seems to be driven by many different processes, scientists believe that multiple different approaches will be needed to reverse ageing in humans. One of the things that makes reprogramming enticing is that it seems to hit most of these processes at the same time. Unfortunately, even the most optimistic estimates anticipate that we won’t see clinical trials involving partial reprogramming for another 5 years, which means that clinically approved treatments could be several decades away.

Even then, unless regulators’ attitudes towards rejuvenation change, it is unlikely that partial reprogramming will be available for general anti-ageing purposes, but rather for specific diseases in which its effectiveness has been proven.

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    Genome-wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates

    Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state

    In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice

    YouthBio CEO: The time is right to develop epigenetic reprogramming therapies

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