Well, this sounds familiar: Researchers have identified a member of the sirtuin family that affected longevity.

Across 18 different rodent species, those with more effective double-stranded break DNA repair – but not in nucleotide excision repair – by Sirtuin 6 (SIRT6) also had longer life spans.

"I suspected that double-stranded break repair is important for longevity," senior author Vera Gorbunova told BioWorld, "but I was really surprised that the correlation between double-stranded break repair efficiency and longevity was so strong."

Gorbunova is professor of biology and associate professor of oncology at the University of Rochester.

The focus of her laboratory is on "life span and health span," she explained, and the goal of the current studies, which were published in the April 18, 2019, issue of Cell, was to see "whether there is a connection between double-stranded break repair and longevity."

Other studies had shown that DNA repair efficiency, in the most general sense, appears to affect life span. But the molecular mechanisms, both in terms of the specific DNA repair pathways and the proteins involved, had not been worked out.

Gorbunova, co-corresponding author Andrei Seluanov and their colleagues looked at SIRT6 because mutations that render the protein nonfunctional lead to shorter life spans in mice.

But the mechanism "wasn't entirely clear, because it has many roles," Gorbunova said.

The team looked at multiple rodent species which, they wrote in their paper, "are an ideal group to pursue comparative aging studies... because rodents are closely related phylogenetically, yet their [maximum life spans] are extremely diverse."

They showed that there was an "almost perfect" correlation between a given species' longevity, and the ability of that species' version of SIRT6 to repair double-stranded DNA breaks.

Leave it to the beaver

Somewhat to their surprise, the difference in enzyme efficiency was due to differences in very few amino acid residues – five, to be exact.

By substituting those five amino acids in the SIRT6 of the mouse (average life span of two years) with those of the beaver, which lives 10 times as long, "we could make a mouse protein work three times better," she said.

The sirtuin family comprises seven proteins, some of which are located in the nucleus while others are found specifically in mitochondria. They are histone deacetylases that fulfill diverse molecular roles, depending on their individual targets.

As a family, though, sirtuins' collective celebrity status stems mostly from the SIRT1 activator, resveratrol, a substance found in red wine and dark chocolate that spawned a cottage industry based on the fanciful hope that longevity could be achieved through self-indulgence.

In the biopharma community, they are also known as the subject of a bad bet by Glaxosmithkline plc., which paid $720 million for Sirtris Pharmaceuticals in 2008, closed the company as an independent unit in 2013, and is currently not working on any sirtuin activator programs. (See BioWorld Today, April 24, 2008, and March 14, 2013.)

Gorbunova downplayed the connection between SIRT6 and SIRT1.

The antics around resveratrol, she said, "gave a bad name to this whole connection between sirtuins and life span."

She noted that "in mammals, we have several homologs of the yeast protein, and it was not very clear which one was responsible" for life-span effects. Her team's hypothesis is that mammalian SIRT6 may be more related to yeast SIRT2, whose connection to life span is "proven and very reproducible."

The team plans to map out the link between SIRT6 and life span beyond rodents, continuing to use a broad range of species.

"We were able to find all these cool things because we looked at many species that most people don't study," Gorbunova pointed out.

The findings now published in Cell suggest that activators of SIRT6 could affect life span. Targeting SIRT6 could possibly have a role to play in diseases of aging. DNA repair defects contribute to genomic instability and, ultimately, to many forms of cancer. SIRT6 activates PARP, the target of four approved and multiple experimental cancer drugs whose inhibition is synthetic lethal with DNA repair defects, especially those in BRCA1 and BRCA2.

Given those connections, the team also plans to look for activators of SIRT6.

Just not wine or chocolate.