Study is first to show such governance, reveals protein’s possible anti-aging link
A formerly underappreciated member of the sirtuin family of proteins may hold the key to youthfulness and is the first sirtuin shown to specifically govern the activity of genes, scientists report.
Researchers from Stanford University report in the Jan. 9 Cell that SIRT6, a sibling of the aging-related protein SIRT1, is an important regulator of gene activity in mice.
“This is a big, big discovery,” says Raul Mostoslavsky, a chromatin biologist at the Massachusetts General Hospital Cancer Center and Harvard University Medical School in Boston. And one, he adds, that could shift some of the limelight away from SIRT1, a molecule implicated in the aging process.
“I’d say 95 percent of the literature is on SIRT1. I think that is going to change,” Mostoslavsky says. “People will start realizing that other sirtuins are probably important for regulating many biological functions.”
Mostoslavsky was not involved with the current study, led by Katrin Chua and Howard Chang of Stanford University, but he is familiar with all seven of the sirtuins found in mammals. He was the first to genetically engineer mice to lack each individual member of the sirtuin family. Mice missing SIRT6 develop normally for the first weeks of life, but then rapidly decline as if they are prematurely aging. The mice die by one month of age, ultimately of low blood sugar.
Last year, Chua’s group showed that SIRT6 is an enzyme that specifically removes a chemical called an acetyl group from a specific spot on a histone protein. Histones wrap DNA into a package that can fit inside the cell and are also important for controlling which genes turn on and off. Removing acetyl groups from histones generally shuts genes off.
Chua’s group has also previously shown that SIRT6 helps keep genomes stable and protects the ends of chromosomes, known as telomeres, from damage.
Now Chua’s and Chang’s groups together show that SIRT6 works with a master regulatory complex called NFkappa-B to govern activity of genes associated with aging, inflammation, immunity and metabolism. When SIRT6 is missing, NFkappa-B becomes hyperactive and turns up activity of aging-linked genes.
Reducing the amount of NFkappa-B in SIRT6-deficient mice restores normal life span and corrects many of the premature aging symptoms. But the mice still have low blood sugar, and many other genes not regulated by NFkappa-B show abnormal activity when SIRT6 is absent.
Chua thinks that drugs targeting SIRT6 may provide new treatments for some aging-related diseases such as osteoporosis.
Mostoslavsky believes many important body systems are affected by SIRT6, but cautions that the enzyme is not necessarily an anti-aging protein. The mutant mice lacking the protein have severe metabolic disturbances that could account for premature aging. Researchers have not yet detected any change in SIRT6 levels or activity with age.
“Whether this has a role in the normal aging process, we still don’t have enough information to answer that,” he says.