Aging and what to do about it

Have you ever wondered why we age as we get older? Or why older people can’t heal as fast as younger people can? These are the questions I had when I started researching about what causes aging.

Some factors that cause aging are genomic instability, epigenetic alterations, telomere attrition, stem cell exhaustion, loss of proteostasis, mitochondrial dysfunction, deregulated nutrient sensing, altered cellular communication, and cell senescence (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/). Many of these factors are related to cell senescence, which is a major cause of cellular aging, and ultimately, human disease and death.

In this article, I shall be concentrating on cell senescence. Cell senescence is when cells stop replicating, which can be caused by telomere attrition, or shortening. Telomere shortening happens when a cell reaches the limits of its telomere, which is protecting the cell’s gene from being harmed during replication, and is at the verge of cutting into its DNA and causing mutations. If the cell is not shut down and it does not senesce, it can lead to cancer and other genetic mutations, which is equally harmful.

If we could find a way to extend these telomeres in normal cells, i.e., have them regenerate, we could possibly extend life, allowing us to benefit more from the knowledge of older people. This already occurs naturally in some cells, such as stem cells. In these cells, an enzyme called telomerase maintains the telomeres of the cell. This must occur because DNA cannot replicate to the very ends, as DNA polymerase requires a primer to start. In one study, in which mice were infected with a virus that encodes a telomerase that is always on, scientists found that the lifespans of the mice increased by 13 to 24 percent (https://www.embopress.org/doi/full/10.1002/emmm.201200245). Their cells were rejuvenated, making their bodies work as if they were younger. For example, they found that muscular coordination improved and insulin sensitivity increased.

Surprisingly, they didn’t find any increase in cancer, although one might expect it. Telomerase is expressed inappropriately in over ninety percent of human cancers. (https://jcp.bmj.com/content/jclinpath/72/4/281.full.pdf ) As most cancers start when cell division gets out of control, this is not surprising. Normally, when a cell starts to divide in an uncontrolled manner, chromosome shortening would fairly quickly kill the descendants of that cell. This is why when we have a telomerase activity increase, we might expect to see an increase in cancer. Because the chromosomes would no longer shorten — and, in fact, may well grow — and the cells could, in principle, divide forever.

This possibility to make cancer more likely to occur is a major worry of scientists (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815611/). Thus, they have considered ways to prevent this from happening. Among the possible solutions they have considered is to express telomerase only briefly in the targeted cells. The paper written in 2012 by de Jesus and others (https://www.embopress.org/doi/full/10.1002/emmm.201200245) tried this method.

As I mentioned above, they showed substantially reduced aging in mice expressing extra telomerase but did not see an increase in cancer. They used a virus that they engineered to get the telomerase into the cells of live mice. The virus, derived from an adeno-associated virus (AAV), was expressed when put into these mice. It can be expected that when the cells divide they lose the gene as the cells divide (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548848/). The engineered virus does not replicate when cell division happens, so when a cell divides, there is less and less of a chance that that specific cell will have the virus in them. Therefore, cancers seem unlikely to develop. That de Jesus’ group didn’t see cancers in their mice gives us hope.

However, these scientists might be incorrect. Mice don’t live long, so cancer may not have had enough time to develop in their study. Also, some cells will still have the virus in them, unless they expire, because even though the virus doesn’t replicate, it doesn’t disappear either. If the telomerase works, all of the cells will be able to replicate many times; it is irrelevant if they have the virus in them or not. During this time, they might develop new mutations that will result in cancer. We might be able to address this issue using gene editing methods to turn off oncogenes that might be turned on during this process.

One method that offers a lot of promise for fixing age related errors is CRISPR-Cas9. This system comes from a bacteria’s defense system against viruses, and as now developed allows the specific mutation, inactivation or even deletion of any gene in a living organism. It uses an RNA guide that the scientists design to find specific sequences in the genome to cut. On its own, this will generally inactivate the targeted gene. The cell’s own DNA repair systems, though, can then be manipulated to either mutate or replace the gene instead. This has huge promise in gene editing’s future and our ability to extend our life span.

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