Old age is a killer. Scientists have known for a long time that incidence rates of all of the deadliest chronic diseases — cancer, diabetes, dementia — increase dramatically as we age. But what are the underlying biological mechanisms that drive age-related diseases, and can they be slowed, stopped, or even reversed?
Researchers in England believe they’ve found a genetic switch that potentially resets the biological clock in old cells, causing them to look and behave just like spry younger cells. The discovery, published in the journal BMC Cell Biology, focused on a class of genes called splicing factors that play a critical role in translating genetic information into proteins within a cell.
Lorna Harries, a professor of molecular genetics at the University of Exeter and lead author of the paper, told Seeker that the job of splicing factors is to cut up sequences of messenger RNA and assemble the specific proteins that cells need to function properly. That includes proteins that help cells respond to environmental stressors like infection or damage from free radicals.
“As you age, your ability to respond to the environment decreases,” said Harries. “Those splicing factors are one of the key things that help your cells adapt. They can take one gene and make a lot of different proteins from it, essentially change the gene’s output according to your environment.”
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Earlier research has shown that splicing factors definitely become less active as we age, leaving cells more vulnerable to outside threats, but it was unclear to Harries if lower levels of splicing factors were a cause of age-related decline or just another effect.
To figure it out, Harries started with a culture of senescent human cells. Senescent cells are ones that have reached their maximum limit of cell divisions and essentially gone inactive. In a young, healthy body, the immune system targets senescent cells and destroys them. As we age and the immune system weakens, more and more of these senescent cells build up in our bodies, which has been linked to decreased longevity.
Harries and her colleagues wanted to see what would happen if they boosted the levels of splicing factors in a senescent cell to those of a young, active cell. To do that, they synthesized novel versions of a compound called resveratrol, which naturally occurs in chocolate, blueberries, and red wine. Resveratrol had shown promise in previous research for altering the expression of splicing factors.
“To our amazement, all of the splicing factors basically reset,” said Harries. “They returned more or less to the levels we see in young cells.”
But even more incredible was that the old, senescent cells treated with the synthetic analogs of resveratrol were indistinguishable from young cells. They actually started dividing again, and their telomeres — the caps on the ends of chromosomes that shrink with old age — grew longer.
“When my post-doc brought me pictures of the cells, I said, ‘No, you’ve got the wrong ones. Those must be the young cells,’” said Harries. “She redid the experiment quite a few times before I started to believe her.”
Does that mean that the key to living a longer, healthier life is to eat an entire box of chocolates washed down with a bottle of cabernet? Far from it, said Harries. The naturally occurring form of resveratrol isn’t very bioavailable, meaning very little of the compound actually makes it into your cells. The synthetic molecules made in the lab performed much better.
The biggest takeaway from the research is that splicing factors clearly play an active role in the breakdown of the body as we age.
“Those changes that we’re seeing in splicing factors are causal,” said Harries. “They’re driving aging; they’re not just an effect of it. Because you can reverse the effects of aging if you reset them.”
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Like other researchers, Harries is quick to distance her discovery from anything close to a “fountain of youth.” Her goal isn’t to increase human lifespan, but to improve “health span,” the number of years that people can live free of chronic, debilitating diseases associated with old age. A longer health span not only improves quality of life, but lowers the overall cost of healthcare.
Splicing factors are the latest addition to a growing scientific understanding of the underlying mechanisms of aging, which includes the critical role of adult stem cells in continuously renewing tissue and repairing organs. When these discoveries are taken together, it’s fair to ask whether we’re fast approaching a time when the frailty and decline associated with old age are no longer a given.
“That’s the hope,” said Harries. “We’re not there yet, and I don’t think we’re going to be there in the next 10 or 20 years. The important thing is understanding the basic mechanics of this. It’s absolutely key. I think we’re starting to get to a position now where we’re beginning to uncover those nuts and bolts. And by doing that, we can work out some ways to tweak them.”
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