Targeting Ageing With Gene Therapy – Part 2: How Might It Work?

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In part 1, we built a baseline understanding of the key gene therapy techniques and delivery methods. Now it’s time to look at how these techniques can actually be applied to target the ageing process. Once again, this is a summary based on a recent review discussing our current progress in this area.

Why Gene Therapy?

Before we get into the details, it’s worth mentioning why we might want to use the relatively new and emerging gene therapy technologies over traditional drugs when targeting ageing. When it comes to achieving a specific biological outcome like suppressing a molecular pathway linked to ageing, gene therapy is like a scalpel compared to the hammer of traditional drugs. A drug might work by binding to a receptor on the surface of a cell, triggering a series of chemical reactions inside the cell that eventually result in a set of genes being activated. A lot can go wrong here – the drug might bind to other receptors or influence other molecular pathways that produce unwanted and unacceptable results. When it comes to targeting a specific pathway, there’s also no guarantee that a safe and effective drug target actually exists in the first place.

Gene therapy techniques give us much finer control by allowing us to bypass a lot of this complex molecular machinery and influence a specific gene that will produce the desired outcome. This also makes gene therapies a lot easier to design – rather than trying to reverse engineer a chemical that will interact with the target pathway in the desired way, we can use gene therapy to instruct a cell to make more or less of any protein. In summary, so long as we understand a biological mechanism to be driving ageing, we should be able to design a gene therapy that will target that mechanism much more directly and cleanly than any drug.

As we get in to the various ways in which gene therapy might be used to target ageing, it’s important to note that these strategies are speculative. No gene therapy has yet been proven to slow ageing in humans, and receiving gene therapy comes with risks such as acute immune reaction.

The Genetic Approach

One way in which gene therapy could be used to slow ageing is by targeting and restoring the integrity of the DNA itself. As we age, the stability and function of our DNA is degraded in several ways.

Telomere attrition:

Each time a cell divides, the protective caps known as telomeres on the ends of each chromosome shorten. This eventually prevents the cell from dividing any further, causing it to enter a state called senescence. Humans posses an enzyme called telomerase that is capable of repairing telomeres, but most cells within the human body do not produce enough telomerase to maintain the length of their telomeres. Some adult stem cells do produce appreciable levels of telomerase, but production declines with age due to decreased activity of a gene called TERT (telomerase reverse transcriptase).

One potential approach to slowing human ageing would be to use gene therapy to enhance telomerase production, thereby restoring telomere length. Experiments already exist suggesting that this is possible in mice. Delivering copies of the mouse TERT gene to 2 year-old mice significantly improved their health, physical fitness and average lifespan.

DNA repair:

We all know that random genetic mutations accumulated throughout life can lead to cancer. While not all genetic mutations contribute to cancer, they can be harmful to us in other ways, as mutated genes may produce faulty proteins that don’t function as effectively as they should. As we accumulate large numbers of these mutations over time, they gradually impact the function of our tissues and organs as a whole.

Our cells possess mechanisms to repair genetic mutations, but the capacity and fidelity of these repair systems declines with age. One strategy is therefore to use gene therapy to enhance these repair systems, helping them promptly correct genetic mutations as they occur. Enhancing the expression of certain genes has been shown to enhance DNA repair in cells in the lab, but it’s currently unknown whether delivering these genes via gene therapy has benefits in animals.

Epigenetic alterations:

In addition to accumulating damage, the way in which the genetic code is read also changes with age. This is due not to modifications of the genetic code itself, but rather the way in which the DNA is packaged.

DNA is coiled around proteins known as histones, and modifications to these histones influence how tightly the DNA is packed. Tightly packed DNA (known as heterochromatin) becomes inaccessible and cannot be used to produce proteins. The specific parts of the DNA that are locked away is one of the factors that makes different cell types function differently, even though they all contain the same genetic code. With increasing age, histone modifications are added or removed, which can lead to the disassembly of the heterochromatin and to the expression of genes that should not be expressed in that cell type.

We know of multiple genes that are involved in maintaining heterochromatin, and there are now several studies in animals showing that boosting the expression of those genes using gene therapy is not only effective for preventing heterochromatin disassembly, but also regenerates aged tissues. A similar treatment in humans could be one way of targeting ageing. There are also certain human genes that could be suppressed epigenetically to delay the ageing process. For example, a study found that Cdkn1a and Ccng2, two genes that become activated in aged cells to suppress cell division, could be inactivated in mice using RNA from human stem cells. When delivered to aged mice, this treatment significantly improved health in multiple organs, improved memory and reversed hair loss.

The Energy Approach

Ageing involves significant disruptions in how the body handles energy intake, storage and expenditure. Targeting the pathways that control these processes could potentially delay or prevent many age-related diseases.

Insulin resistance:

Insulin is the blood sugar-lowering hormone. It is released by the pancreas and prompts other tissues (mainly muscle and liver) to take up glucose from the blood where it can be used, stored, or converted into other forms. With increasing age, cells stop responding to insulin as strongly as they once did, which contributes to many age-related diseases through multiple mechanisms.

We already have diabetes drugs that can improve insulin sensitivity. While these might have some benefit for ageing, a better approach might be to use gene therapy to directly influence existing systems that regulate insulin sensitivity. For example, fibroblast growth factor 21 (FGF21) is a hormone secreted by liver cells that regulates both glucose and fat metabolism. It’s under investigation as a target in type II diabetes, but research also shows that delivering DNA encoding FGF21 to muscle tissue has wide-ranging benefits in mice, including an increase in average lifespan.

Klotho:

Klotho is a family of proteins that have produced quite a lot of excitement over their potential role in the ageing process. They regulate many aspects of metabolism including the handling of calcium, phosphate, vitamin D and glucose. Mice that are deficient in Klotho appear to age at an accelerated pace and die younger, and there is some evidence that this might also be true in humans.

Using gene therapy to boost Klotho production is a potential strategy for delaying ageing. Studies show that delivering DNA encoding forms of α-Klotho (a subfamily of Klotho) improved both cognitive and physical function in mice.

The Immune Approach

One key characteristic of ageing is the dysfunction of the immune system. This results not only in increased susceptibility to infection, but also the activation of inflammation even when no infection is present. There are numerous ways in which this dysfunction could be targeted with gene therapy.

Inflammageing:

Ageing is accompanied by increased chronic inflammation throughout the body, known as inflammageing. Inflammation exists to suppress infections while the immune system ramps up its more precise, targeted responses such as antibody production. But in older age, inflammation persistently occurs at low levels when and where it shouldn’t, contributing to a wide range of age-related diseases.

Research shows that gene therapy can be used to target key molecular pathways involved in inflammation and thereby reverse some age-related changes in mice. Researchers were able to deliver a mutant form of the gene encoding NF-κB, a key regulator of inflammation. This resulted in the reversal of muscle atrophy in mice and an increase in their maximum lifespan.

Antibodies:

There is evidence for a correlation between accelerated ageing and the accumulation of a specific type of antibody called IgG. IgG is important for resisting infections, but in old age it appears to negatively impact the function of white blood cells and trigger inflammation.

RNA gene therapy has been used to lower IgG levels inside cells in mice, which appeared to mitigate ageing in some organs. However, this might not be a viable option in humans as it may increase susceptibility to infection.

The Senescence Approach

Senescence is thought to be a fundamental driver of ageing. Senescence is a state in which cells are no longer able to divide, either because their telomeres have become too short or because the cell has sustained too much damage. Senescence is generally beneficial in young age because it shuts down division in a small number of diseased cells, keeping tissues healthy. However, when many senescent cells build up in old age, they begin to become a problem.

Cell Cycle:

Senescence involves the activation of genes leading to cell cycle arrest – the halting of cell division. These genes are potential targets for gene therapies to prevent cell cycle arrest. For example, delivering the Sirt2 gene (which suppresses senescence through multiple pathways) to the hearts of aged mice improved cardiac function.

This strategy does come with some risks, as senescence plays a role in preventing cancer by shutting down replication after too many divisions have occurred. However, large numbers of senescent cells can also promote cancer in old age through the harmful signalling molecules they release. Indeed, they are thought to be major contributors to cancer recurrence after successful chemotherapy, which tends to trigger senescence in cells surrounding the cancer. It may turn out that the benefits of suppressing senescence in old age outweigh the risks.

Partial reprogramming:

It is possible to turn any cell into a stem cell by delivering certain gene regulators known as Yamanaka factors or reprogramming factors. These reprogramming factors erase many epigenetic alterations to the DNA and also extend the telomeres, leading to a reversal of senescence.

We wouldn’t want to turn all of our cells into stem cells – we need our heart cells to be heart cells and our brain cells to be brain cells. However, by exposing cells to Yamanaka factors for only a limited duration, many of the benefits of reprogramming can be gained without causing cells to become stem cells. This is known as partial reprogramming, and could be achieved using gene therapy. Numerous studies have shown that using gene therapy to activate Yamanaka factor expression in mice reduces cellular senescence and can improve the function of various tissues.

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While none of these strategies are proven in humans, we can see that there is a great variety of different strategies ripe for exploration. Some clinical trials have begun to investigate the safety of gene therapies in the treatment of age-related diseases, such as the delivery of the human TERT gene. Even so, putting these strategies into practice in humans will be challenging. In the next and final part, we’ll explore why.