For about the past fifty years, popular theory has held that the process of
aging is caused in large part by an accumulation
of mutations. There’s growing evidence, however, that aging has a significant epigenetic component. That is, the process by which stretches of
DNA – or the genes – are turned on and off. My colleagues and I believe that not only are epigenetic changes a primary
cause of aging, but these changes are driven by the ongoing
process of DNA breakage and repair. Why do we think this? Here we have two mice from the same litter
– essentially twins. We checked, so we know that they have the
same DNA sequence. The only difference between the two is that, for the older-looking one, the break and repair
process was accelerated. And this caused epigenetic changes. Part of the epigenetic process involves the
packaging of DNA. When genes are not active they’re packed
tightly in chromatin but sometimes this packaging loosens, giving the cell access to appropriate genes. This process happens all the time, and it has to for a cell to function properly. Certain areas of the DNA structure within
a liver cell, for example, need to loosen to allow access to liver-specific
genes. Unfortunately, naturally occurring DNA breaks cause changes in the chromatin structure. And over time, this happens a lot. Our bodies experience a million DNA breaks
a minute. And as cells try to repair the broken DNA, the chromatin structure loosens in some areas, including the area around the break,
and it tightens in other areas. And if it loosens an area that it’s not
supposed to, a wrong gene might be expressed. This is important because if, for example, liver cells accidentally activate wrong
genes, the organ as a whole will begin to show signs
of aging. We wanted to test our theory that aging results
from DNA break and repair, so we engineered a new strain of transgenic
mice. These mice are genetically altered to let
us turn on and off a special enzyme. When we turn the enzyme on, the DNA within many of the mouse cells
are cut at a number of locations – at a rate that is about three times the natural
frequency of DNA breakage. And each breaking of the DNA initiates a repair. Special proteins that regulate chromatin structure and gene expression move to the cut DNA. The proteins loosen the chromatin and recruit other proteins that repair the DNA. When their work is done, the proteins usually move back to their original locations, and
the chromatin structure – the packaging – usually resets to its original
tightness. In our mouse, as long as the enzyme is on, cuts are initiated in the DNA. With many breaks happening, the repair proteins are very busy. And this is an issue. With each successive fix, the proteins don’t always return to their
original locations, and the chromatin structures at the repair
locations don’t always reset to their original tightness. Actually, the process is a bit more complicated. There are other proteins involved, and these
proteins, in addition to assisting with DNA repair, are also responsible for turning genes on
and off. With each successive fix, the proteins become
more jumbled. This jumbling results in some genes that were initially turned on to turn off and other genes that were turned off to turn
on. Changes like these alter the cells enough to cause them to become more dysfunctional. By the way, just to be sure we weren’t
disrupting the function of cells, we didn't cut in random places. Instead, we avoided locations that code for genes. So what did we find? Here are the two mice I showed you earlier. They are both 10 months old. The older-looking mouse had the cutting enzyme
turned on for three weeks when it was young. The other didn’t. To verify that the aging we see isn’t the
result of mutations, we sequence – or “read” – the entire
chromosome of each mouse. So really, the only difference between these
mice is epigenetic. To test our theory further we experimented with resetting epigenetic
structures in our aged mice, and we found that we could safely reverse
blindness and rejuvenate kidneys and muscle. We used to think that aging was like parts
of a recipe being erased – once a mutation occurred, the DNA code was lost forever. But now we know that cells still have the DNA intact, we just need to teach them how to read that code again. And if we can do that, aging may be much more reversible than we ever thought.
