As genetic sequencing technology has improved, we’ve identified an increasing number of genes that are linked to the ageing process. Gene therapies work by delivering genetic material to cells. Through the information encoded by that material, gene therapies can tell a cell to make more of a protein, block the production of a protein, turn genes on or off or even alter the genetic code itself. Gene therapy gives us a new weapon against the ageing process, allowing us to precisely fix problems that would be hard or impossible to solve with conventional drugs. Here are some of the treatments that could one day be used to treat ageing and age-related diseases in humans.
Often abbreviated to telomerase, TERT is a protein that elongates the protective caps known as telomeres on the ends of our chromosomes. When cells divide, some genetic material is lost from the ends of each chromosome. Telomeres are pieces of genetic material that don’t encode anything useful, and are there to preserve our genetic code when a cell divides. Once telomeres become too short, a cell can’t divide any further and enters a state called senescence, a process that is considered to be one of the hallmarks of ageing.
Telomerase rebuilds telomeres, allowing cells to divide indefinitely. However, most human cells produce very little telomerase. Using gene therapy, we could introduce copies of the telomerase gene (also called TERT) into our cells. This has already been done in animal models, and has been shown to extend lifespan and to treat multiple age-related diseases including myocardial infarction and neurodegenerative disease. There are even a few ongoing phase 1 clinical trials for TERT gene therapy in humans, notably for Alzheimer’s disease.
While telomere shortening is related to ageing, it also serves to protect us against cancer. Many scientists think this and some other mechanisms of ageing evolved to help us survive in early life, with the tradeoff that we become more susceptible to disease in later life. Thus, treatments based on TERT need to be explored with caution.
α-Klotho is a protein encoded by a gene called KL. It was discovered about 25 years ago, when rodents with defects in the KL gene were found to age at an accelerated pace. α-Klotho can exist in two different forms and has a variety of functions. It affects the handling of phosphate, one of the key ingredients of life. It also plays an important role in regulating growth, preserving stem cell populations, and helps cells to get rid of waste products among other effects thought to be related to slower rates of ageing.
Gene therapy can be used to enhance KL expression. In mice, enhancing KL expression has boosted both lifespan and the amount of time spent free of age-related diseases by as much as 30%. Enhancing KL expression using gene therapy has also been used to treat neurodegenerative diseases, kidney diseases and cardiovascular diseases in animal models. We know that levels of α-Klotho in humans decline throughout life, and that klotho deficiencies are linked to age related diseases. Unfortunately, the effect of targeting KL or α-Klotho in humans hasn’t been investigated in clinical trials.
FOXOs (forkhead box sub-group O) are a family of transcription factors – proteins that regulate the activity of genes. FOXOs become activated under conditions of stress, such as when nutrients are scarce or when DNA becomes damaged, and help protect cells against these conditions. Decreased FOXO activity seems to be involved in neurodegenerative diseases and in cancer. FOXO genes could be targets for gene therapy at some point, but we need a greater understanding of their role in the ageing process.
Sirtuins are a family of proteins encoded by SIRT genes. They have various functions, notably in repairing damaged DNA and regulating epigenetic modifications – alterations to the DNA and associated molecules that change how the DNA is read, without changing the genetic code itself. Both of these are thought to be primary drivers of ageing, and altering SIRT expression via gene therapy has been shown to have beneficial effects in age-related diseases in animal models. Delivering SIRT7 using gene therapy slowed ageing in a mouse model of accelerated ageing, while suppressing SIRT6 was able to suppress cancer in another mouse model.
Apolipoprotein E (APOE) is a molecule that controls how the body handles lipids (fats). While it might not be the most promising target on this list for general ageing, it does have a strong association with human longevity, and is one of the only targets of gene therapy to have reached human trials. It is encoded by the APOE gene, and is especially important when it comes to the risk of developing Alzheimer’s disease. In fact, which variant of the APOE gene you carry is the most powerful genetic predictor of Alzheimer’s disease, with the APOE e4 variant being the strongest risk factor, while APOE e2 is the best genetic protector against Alzheimer’s.
The aim of the first gene therapies targeting the APOE gene is to introduce the more favourable APOE e2 variant into the cells where it matters most, notably the microglia (the ‘janitors’ of the central nervous system, responsible for keeping the brain free of dead cells and debris). A clinical trial is currently preparing to test this in Alzheimer’s patients who carry two copies of the APOE e4 variant.
Vascular endothelial growth factor (VEGF) is an important protein for the formation of blood vessels. It protects the cardiovascular system and is negatively correlated with ageing. Gene therapy aimed at restoring VEGF function could have the power to delay ageing in many organs, since adequate blood supply is vital for the health of any tissue. Some animal experiments suggest that VEGF gene therapy can extend lifespan, but as in the case of TERT, VEGF also has the potential to promote cancer. That’s because tumours require a higher blood supply than normal tissue.
Gene therapy technology makes targeting genes related to ageing a lot easier. Rather than having to find a drug molecule that affects the target the way we intend, then having to worry about unintended side effects and whether the drug will reach its target, gene therapy theoretically bypasses these problems by telling the cell exactly what proteins to make (or what not to make). However, there’s still much work to be done before most of this research reaches the clinical trial stage.
Title image by Sangharsh Lohakare, Upslash
Gene Therapy Strategies Targeting Aging-Related Diseases https://doi.org/10.14336/AD.2022.00725