As we age, our bodies break down. One explanation for this is that oxidation from the constant chemical reactions in our bodies eventually causes our cells to rust, just like old metal. But geneticist Stuart Kim of Stanford University has another explanation: an imbalance between cell proteins, which control the transfer of genetic information. These so-called transcription factors bind to DNA. Those that turn genes "on" are called activators and repressors turn genes "off."
Kim and his colleagues studied how aging in worms affects transcription factors, especially one activator and two repressors that control the development of the intestine and skin. He found that in the young worm, a balance of these transcription factors is critical to the development of the skin and intestine. As the worms aged, the repressors increase in concentration and eventually turned down the activator. So, the genes that were supposed to be "on" were turned "off."
Kim says this means that "the intestine no longer functions very well and the skin no longer functions very well, and that was contributing to why the worms were dying at two weeks."
Turning back the genetic clock
When Kim restored the balance between the activator and the repressors, the worms lived 50 percent longer. He suspects that many additional proteins are involved in aging, and proper control of them could extend a worm's life even more.
So why do these transcription factors become unbalanced? Kim says there is no way to answer this from an evolutionary perspective.
Worms usually live only five days in the wild before getting eaten by a predator. Kim's investigations happen much later, near day 18. Kim notes, "for worms the whole game is to try and be the fittest healthiest worm but for five days-make as many babies as you can in five days." So the age-related deterioration occurs only when worms are grown in the lab, free of predators. "So everything we're looking at has not been seen by nature."
Kim points out his findings do not imply that molecular damage is not contributing to aging, but they do raise questions about how much of an impact that damage has on our life span. While worms live only two weeks in the lab, flies live two months and mice live two years. Humans share 99% of their DNA sequence with chimpanzees but live about 40 years longer. Whales can live as long as 200 years and clams can live for 400 years.
Molecular damage common to all species
Kim explains that in such a wide variation in life span, the molecular damage is identical. Similar reactions occur in humans, whales, and mice. Kim asks, "If molecular damage was driving life span and aging, why is it occurring at such different time scales across different animals?"
The transcription factors in the worms do not have an obvious human equivalent. Yet, Kim says his work represents a conceptual change in how we think about aging.
His study appears in the July 25th edition of the journal Cell.
