On this episode of X10, we talk about the different ways in which DNA is damaged, how our bodies naturally repair it, and how we might be able to help this repair along.
In our video about genomic instability as a hallmark of aging, we said that DNA repair mechanisms deserve a video of their own. So, let’s dig into that now. How exactly does DNA get repaired, and how does that relate to aging?
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The first thing to know is that DNA can get damaged in a variety of ways – and so, of course, there are different repair mechanisms for the different types of damage. For example, a single nucleotide base – a single letter in the DNA – could be damaged. In a process known as Base Excision Repair (BER), a suite of proteins recognize the trouble, snip out the problematic base – and sometimes also a bit of DNA around it – and then copy the correct sequence from the other strand.
There’s also a proofreading system called DNA Mismatch Repair to detect and correct mistakes that happen during replication, such as an addition or deletion or the wrong base being put in. But rather than listing all the different types of damage and how they get repaired, let’s focus on a couple that were the topic of a recent paper about DNA damage and aging.
The researchers started from the general understanding that DNA repair seems to affect lifespan and then tried to find out which repair mechanisms might be important. They used 18 rodent species with maximum lifespans ranging from four years – mice and hamsters – to thirty-two years for naked mole rats.
They designed experiments to measure the efficiency of two DNA repair mechanisms, nucleotide excision repair (NER) and double-strand break repair (DSB). The idea was to see if the efficiency of either system correlated with the lifespan of the different species.
They didn’t find a link between NER and lifespan. That makes sense, because NER repairs a type of DNA damage that’s mainly caused by UV light, so there isn’t really a reason to expect it to be involved in age-related decline. In keeping with that idea, the study showed that NER efficiency does correlate with how much sunlight exposure a species gets. The DSB mechanism can be further subdivided into two repair pathways. The efficiency of both pathways correlated with maximum lifespan, meaning that species with better DSB repair systems tend to live longer.
The researchers didn’t stop there. They went on to look at a gene that regulates both DSB pathways, SIRT6 – a member of our old friend the sirtuin family. When they increased the expression of SIRT6 in mice, the mice had more efficient DSB repair and lived longer than usual. They even managed to figure out exactly which part of the protein encoded by SIRT6 was affecting DSB repair. In a pretty amazing experiment, they showed how important this segment is for longevity.
They engineered a version of mouse SIRT6 to include the DSB segment from the beaver version. They also made a beaver SIRT6 that had the mouse segment. Then, they introduced either one of the engineered versions or the original versions into fruit flies and measured their lifespan. All of the introduced SIRT6 genes increased the fruit flies’ lifespan because they ended up with higher SIRT6 than normal, but the beaver version and the mouse-with-beaver-segment version increased it the most.
So, this study didn’t just show that DSB affects lifespan and NER doesn’t. It identified the exact segment of a specific gene that increases DSB efficiency and thus lifespan. There are doubtless other genes that also affect DSB, as well as other DNA repair mechanisms involved in aging, but it’s still an important discovery. In the long run, it might be possible to find or create drugs to tweak SIRT6 and increase DSB efficiency to delay or prevent age-related decline from DNA damage. And even if that doesn’t happen, this is pretty cool science.
Thanks for watching! If you’ve got any questions about DNA repair, post a comment and we’ll do our best to answer. And don’t forget to subscribe if you’d like to keep up with X10. Finally, thanks to the Lifespan Heroes who make our work possible. If you want to be part of promoting and supporting longevity research, head to lifespan.io/hero and make a pledge.