Scientists say they have discovered a key aspect of how the aging process works, raising prospects of new treatments for aging-related diseases such as Alzheimer's, and potentially leading to significantly increased life expectancy.
A study led by scientists at the Sanford-Burnham Medical Research Institute found how to rev up a cellular repair mechanism associated with increased longevity. While the research was performed in worms and mice, the scientists said the mechanism appears fundamental to much of animal life, presumably including humans.
The repair process is turned on by a protein called HLH-30, found in the nematode worm C. elegans. In mammals, the process is regulated by a close relative called TFEB. The scientists say they are now looking for compounds that can regulate this molecular switch.
A paper describing the findings was published Thursday in Nature Communications. Malene Hansen of Sanford-Burnham is its senior author. Louis R. Lapierre, also of Sanford-Burnham, is the first author. Scientists from the Salk Institute and Massachusetts General Hospital also contributed.
The repair process eliminates waste and debris that would otherwise accumulate in cells and clog them up. Called autophagy, the process is activated in C. elegans by restricting its caloric intake, which also makes the worm live much longer.
Caloric restriction has also been found to extend the lives of mice. Since mice and humans are far more closely related to each other than either are to nematodes, any life-extending mechanism common to worms and mice is presumably active in people, Lapierre said.
Hansen and other scientists have found that autophagy is essential for increased longevity; and HLH-30, and its mammalian equivalent, TFEB, is the main contributor to the process, Lapierre said.
In the study, researchers demonstrated the role of HLH-30 in transgenic C. elegans and that of TFEB in mice. Worms genetically engineered to have higher levels of the protein lived 15 to 20 percent longer than control animals. And mice subjected to caloric restriction had higher levels of TFEB activity in the liver and pancreas, which are especially responsive to changing levels of nutrients.
If autophagy is necessary for life extension, then turning on autophagy with a drug might also treat human aging-related diseases such as Alzheimer’s, Lapierre said. Alzheimer's disease is characterized by an abnormal accumulation of cellular debris in brain cells that slowly destroys them. So turning on the cellular garbage disposal may treat or prevent the damage, said Lapierre, who studies Alzheimer's.
A malfunctioning autophagy process has also been implicated in cancer and cardiovascular diseases, both also aging-related.
HLH-30 and TFEB are transcription factors, proteins that turn genes on and off. These proteins bind to DNA in the nucleus, and to other proteins.
"The logical next step for this is to try to find compounds that can recreate that activation in C. elegans," Lapierre said. "We want compounds that would send the transcription factor to the nucleus. We know when that happens, we see autophagy."
However, just because a compound works in animals doesn't mean it's suitable for humans, Lapierre said. For example, an immunosuppressant drug called rapamycin extends the life of mice but isn't well tolerated by people, he said. Rapamycin is used to prevent transplant rejection, where the benefit is worth the side effects.
But to treat aging-related diseases, researchers are looking for a drug that's less harsh, Lapierre said. Right now, researchers are examining the molecular pathway to find a target that's downstream the target rapamycin activates, he said. Such a drug would presumably be more specific and produce fewer side effects.
Another goal is to make autophagy work more effectively.
"Since autophagy is a cleansing mechanism, the idea is also to increase the capacity of the cell, particularly the organelle called the lysosome, to degrade materials," Lapierre said. "That's one of the issues in aging, and a lot of age-related disorders."Copyright © 2017, The San Diego Union-Tribune