September 24, 2015 | by Chase Doyle
Eating decadently and living longer: There must be some sort of catch, right? Well, according to one recent study, it might be possible to have your cake and eat it, too, after all.
The research, based on experiments in mice and published in the September issue of Cell Metabolism, is extremely provocative, suggesting that diabetes and lifespan may be linked in more ways than previously thought, with efforts to prevent the disease and open the door to a dramatic extension of life.
“We were studying these mice as a model for diabetes prevention,” said the study’s senior author, Debbie C. Thurmond, Ph.D., founding chair of the Department of Molecular and Cellular Endocrinology within the new Diabetes & Metabolism Research Institute at City of Hope, “and we noticed that the animals that we had manipulated to prevent insulin resistance just lived longer... It was an unanticipated, but remarkable, byproduct of our research.”
The researchers had set out to prevent type 2 diabetes by increasing the expression of a gene to improve insulin sensitivity. What they discovered, however, was that, in addition to helping the animals resist diabetes, the genetic modification also significantly increased the animals’ lifespan.
The laboratory animals that were manipulated to overproduce a protein, called Syntaxin 4, lived more than 33 percent longer than mice without the gene modification, according to the paper.
“This process works very well when we’re young,” said Thurmond, “but when we’re middle-aged, it becomes less efficient. This is often referred to as ‘insulin resistance.’ What that means is that their blood sugar levels are staying a little higher than normal.”
Too much insulin and glucose in the blood for prolonged periods of time can be a problem, leading to health complications, including type 2 diabetes. In addition, there’s anecdotal evidence that humans with less insulin resistance seem to live longer.
“When you eat a meal, you want your body to respond to that rapidly,” said Thurmond. “There’s a correlation in the literature between extended lifespan and reduced circulating insulin and glucose levels… Thus, we believe these mice might be living longer because their cycle of response to eating a meal is accelerated.”
This acceleration was made possible by genetically changing the DNA of mice to overexpress Syntaxin 4 in the pancreas and skeletal muscle. The protein promotes clearance of excess glucose from the blood and was highly effective in the modified animals. The genetically modified, or transgenic, mice showed increased insulin sensitivity, despite being fed a high-fat diet.
They also had a 33 percent increase in median lifespan.
“We made the mouse model to examine diabetes,” said Thurmond, “and what we ultimately found was, in addition to preventing diabetes, it ended up increasing their lifespan substantially.”
“While the control mice developed the age-induced skeletal muscle insulin resistance as expected, these mice did not," Thurmond said. "They lived longer and were much healthier, despite the high-fat diet.”
Although such increases in lifespan are not unheard of, previous animal studies of life extension have involved severe caloric restriction.
“Basically,” said Thurmond, “the only other way to get animals to live a really long time is to starve them... But, I don’t think that’s a practical way to extend lifespan, especially in the U.S. population.”
Most surprising of all, perhaps, was the notable absence of negative side effects.
“These mice were normal in every regard,” said Thurmond, “except they lived longer and were more insulin sensitive… That was the most amazing thing to me — it was all benefit.”
Thurmond and her team at City of Hope are currently seeking novel ways to enrich tissues with this protein without using genetic modification.
“We’ve identified the target (Syntaxin4); now we have to figure out how to activate that target,” Thurmond concluded. “We’ve already proven that it is feasible by gene therapy, but for a large portion of the population, that’s not an option. We are in the process of developing strategies that will hopefully lead to better drug development.”
Learn more about diabetes research at City of Hope.