Aging Genes

Aging May Mostly be Due to Genes and not Wear and Tear in the Worm, C. elegans
Scientists don't know for sure why we get old. But some researchers from Stanford have provided evidence that some animals may be programmed to die at a certain time. In this case, they studied the lowly worm C. elegans. The researchers compared which genes were on and to what extent between young and old worms. What they found was that the genes affected by aging were all controlled by at least three other genes. And that these genes change as we get older and aren't affected by wear and tear. What this suggests is that worms die when they do because it is programmed into their DNA. Interesting, but what does that have to do with people? It might be an important part of why humans age too. Scientists still don't know why humans age. But they have at least two theories.
Programming or Wear and Tear?
The first aging theory is that our genes get damaged over time. And this damage leads to our cells working a little worse year after year, which makes us age. There is a lot of evidence for this theory from many different mammals. Basically environmental abuse ages us. The other theory is that animals are genetically programmed to age. In other words, our genes have the instructions for making us grow older. This is why a mouse lives two years and a human 75. And C. elegans only two weeks. Scientists need to know which theory is correct if they want to extend human life. If it is DNA damage, then people need to damage their DNA less. And figure out how to fix the damage better when it happens. If humans are programmed to die at a certain age, then scientists need to muck with people's genes. They can accomplish this with medicines or perhaps by directly tinkering with human DNA. Most likely with something as long-lived as a person, both theories come into play. In other words, humans age because of DNA damage and because humans are programmed to die at a certain age. This would mean that to increase human lifespan as much as possible, scientists need to work on both problems. The new research may help scientists home in on why people are programmed to die at a certain age. It is important to understand how genes work in order to understand the findings. Genes are Controlled by Transcription Factors Remember, genes are simply recipes for proteins. And proteins are the worker bees of the cell. Almost everything that gets done in a cell is done by proteins. Not every protein needs to be made all the time in every cell though. For example, making a protein in our eyes that helps to digest our food would be useless. So our cells have ways of turning genes on and off. Cells can also turn genes up or down depending on how much of a certain protein they need. For example, when people are in a dangerous situation, they make adrenaline. This makes the heart race, blood pressure increase, etc. These effects are dangerous if they go on for too long. So it makes sense for a person to just make adrenaline when he or she needs it. There are many ways to control a gene. One of the main ways is with proteins called transcription factors (TFs). Cells read genes using a protein called RNA polymerase. This protein is great at reading a gene. But is terrible at finding where one starts. TFs help the polymerase find the start of a gene. Cells use these TFs to control how often a gene is read. The more often a gene is read, the more of its protein gets made. So one way to control how much protein gets made is by controlling how much TF is at the gene. The more often a TF is there, the more protein a cell makes. This is an important way that cells control how much protein they make. Each TF is specific for only a certain set of genes. So you might have a TF that is responsible for turning on all of the genes for making adrenaline. Or for all of the genes that lead to aging.

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These mice are the
same age. The one
on the left has
more DNA damage.
How much protein gets made
is partly determined by
transcription factors.
At Least Three Transcription Factor Genes are Involved in Aging
The researchers used microarrays to look at what aging does to the expression of the 20,000 or so C. elegans genes. They found 1254 genes that changed as the animals aged. They confirmed that these genes were significant by looking at different stages of the worm and different mutants that increase or decrease the worm's lifespan. The next step was to look at the promoters of the genes they identified as changing. Promoters are simply the part of the gene that transcription factors (TFs) stick to or bind. The researchers found that many of these genes had a binding site for a particular class of TFs called GATA TFs. The next step was to nail down which particular GATA factor was involved in aging. There are 14 different GATA TFs in C. elegans. The researchers used a technique called RNA interference (RNAi) to turn down ten of these TFs in the worm. The researchers saw no effect. But they saw an effect with three of them when they looked at what happened in mutants that lived longer. This is the expected result if the GATA TFs extend lifespan. Basically what happened in the mutants was that when each of these three TFs was taken away, the worms no longer lived a longer life. In other words, getting rid of each of these three TFs caused the worms to have a normal lifespan. In this study, the researchers focused on one if these three GATA factors. They focused on elt-3. The researchers showed that the amount of elt-3 protein decreased as a worm got older. They showed that when they got rid of elt-3, genes were less affected by aging. They also showed that elt-3 is not affected by various kinds of DNA damage. These results suggest a couple of things. First off, elt-3 is probably involved in the aging of a worm. And second, the aging is not happening because of the wear and tear of every day life. Instead, a decrease in elt-3 is just a natural part of worm aging. Human Aging It is unclear whether this research has any direct implications for human aging. A big reason why is that people are not worms. C. elegans normally lives about two weeks in the lab. This really isn't enough time to build up much DNA damage. So aging in C. elegans is mostly programmed into its genes. Humans on the other hand live 70 years or more. This is plenty of time to build up DNA damage. And there is a lot of data to support that DNA damage is a big part of why humans age. But even in humans damage probably isn't the whole story. This research can teach researchers how to look for similar pathways in humans. And once scientists find them, they can then invent ways to tweak them to increase human life span. Next researchers will need to work on preventing or fixing DNA damage. Then maybe we can routinely live past 100. Or even older.
Old worms like these
make less elt-3.
People age because of
wear and tear and
programming.