Alternatively, like a safecracker, you can x-ray the lock that you wish to open and work out the probable shape of the key from the pictures that you receive. This is much more effective for discovering drugs, as you can use computer models to identify promising compounds before researchers go into the lab to locate the best one. Now a study, published in Nature, presents detailed images of a crucial anti-aging enzyme called telomerase – raising hopes that we can slow down aging and cure cancer.
Every organism packages its DNA into chromosomes. In simple bacteria such as E.coli this is a single small circle. More complex organisms have far more DNA and multiple linear chromosomes (22 pairs plus sex chromosomes). These most likely appeared as they provide an evolutionary advantage, but they also come with a disadvantage.
At the end of each chromosome is a protective cap that is known as a telomere. However, most human cells cannot copy them – meaning that every time they divide, their telomeres become shorter. When telomeres become too short, the cell enters a toxic state called senescence. If the senescent cells are not disposed of by the immune system, they start to compromise the function of the tissues in which they reside. For millennia, humans have perceived this gradual compromise in tissue functioning over time without understanding what causes it. We simply just called it aging.
Enter telomerase, a specialized telomere repair enzyme in two parts – able to add DNA to the chromosome tips. The first part is a protein called TERT that does the copying, while the second component is called TR which acts as a template. Together, they form telomerase, which trundles up and down on the ends of chromosomes, copying the template. At the bottom, a human telomere is roughly 3,000 copies of the DNA sequence TTAGGG – laid down and maintained by telomerase. However, sadly, production of TERT is repressed in human tissues with the exception of eggs, sperm, and some immune cells.
Aging versus Cancer
Organisms regulate their telomere maintenance in this way because they are treading a biological tightrope. On one hand, they need to replace the cells that they lose by cell division, but, on the other hand, any cell which has an unlimited capacity to divide is a tumor risk. As it turns out, the majority of human cancers have active telomerase and shorter telomeres than the cells surrounding them.
This indicates that the cell from which they came divided normally but then picked up a mutation which turned TERT back on. Cancer and aging are flip sides of the same coin and telomerase, by and large, is the one doing the flipping. Inhibit telomerase, and you have a treatment for cancer, activate it and you prevent senescence. That is the theory, at least.
The researchers carrying out this new study were not just able to obtain the structure of a proportion of the enzyme, but of the entire molecule as it was working. This was involved using a beam of electrons to take thousands of detailed images of individual molecules from different angles and combine them using a computer.
Elixir of Youth
TERT itself is a large molecule and although it has been shown to increase lifespan when introduced into normal mice using gene therapy, it’s challenging and fraught with difficulties. Drugs that can turn on a particular enzyme that produces it are much better, easier to deliver, and cheaper to produce.
We are already aware of a few compounds that inhibit and activate telomerase – discovered through the cumbersome process of randomly screening for drugs. However, they’re not very efficient.
Some of the most provocative studies involve the compound TA-65 (Cycloastragenol) – a natural product that lengthens telomeres and supposedly helps to improve macular degeneration. As a result, TA65 has been sold over the internet and has prompted at least one lawsuit over claims that it caused the user to get cancer.
However, the telomerase inhibitors that we know of so far have genuine clinical benefit in various cancers, particularly in combination with other drugs. However, the doses required are high.
This new study is extremely promising because, by knowing the structure of telomerase, we can use computers to identify the most promising activators and inhibitors and then test them to find out which ones are more effective. This is a much faster process than randomly trying different molecules to see if they work.
So how far could this go? Well, in terms of cancer, it’s hard to tell. The body can easily become resistant to cancer drugs, including telomerase inhibitors. Prospects for slowing down aging where that is not cancer are somewhat easier to estimate. In mice, deleting senescent cells or dosing with telomerase both increase lifespan. It might be that at some point other aging mechanisms, such as the accumulation of damaged proteins, come into play.
If we did manage to stop the kind of aging caused by senescent cells using telomerase activation, we could start devoting all our time to tackling these additional aging processes. There is now every reason to be optimistic that we could soon be living much longer and healthier lives.