A rare gene variant identified in people who have lived to 100 or more appears to slow down the fundamental processes that cause ageing. The team behind the research says the findings could boost efforts to develop anti-ageing drugs.
Numerous animal studies have shown that the activity of a protein called SIRT6 is strongly linked with maximum lifespan. at the University of Rochester in New York and her colleagues set out to find variants in the gene for SIRT6 that extend human lifespan.
They compared the gene sequences in 500 Ashkenazi Jewish centenarians with another 500 Ashkenazi Jews whose families aren鈥檛 especially long-lived. They found that 1 per cent of the centenarians had a variant they named centSIRT6, compared with 0.5 per cent of the comparison group.
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The numbers were too small for this to be statistically significant, but in a large database of 150,000 people from diverse ethnic backgrounds, the team also found that longer-lived people were more likely to have the centSIRT6 variant.
In a series of lab experiments in human cells, the team found that this variant has a number of effects expected to slow ageing. One is its superior ability to prevent the build-up of genetic mutations by increasing DNA repair.
Ageing may also be caused partly by a gradual loss of control over what DNA does, and one of the ways DNA activity is controlled is by the way it is packaged. When we are young, the DNA in our cells is packaged very neatly, but as we get older it starts to get messier, Gorbunova says.
鈥淭his packaging really deteriorates and becomes disorganised,鈥� she says. 鈥淚t鈥檚 like if you fold your laundry in a drawer it鈥檚 very neat, but then as you keep going in and out of the drawer it gets messy.鈥�
The centSIRT6 variant is better at keeping DNA tidy, Gorbunova says. 鈥淚t keeps this packaging together more efficiently.鈥�
Another way that this variant could extend lifespan is by suppressing the activity of parasitic sections of DNA called transposons that copy and paste themselves all over the genome. As we get older, this suppression gradually fails.
This can lead to harmful mutations building up in cells as transposons paste themselves into key sites. What鈥檚 more, high transposon activity can trigger an inflammatory response by making cells think they are being attacked by viruses 鈥� and long-term inflammation is linked to many age-related diseases. The centSIRT6 variant is better at suppressing transposons.
鈥淚 think with all this evidence together, it is very likely that this variant contributes to longer lifespan,鈥� says Gorbunova.
鈥淚 agree,鈥� says at the Albert Einstein College of Medicine in New York, whose own team has also been looking for rare variants associated with longevity in centenarians. 鈥淭his assessment is supported by their strong experimental functional studies.鈥�
The SIRT6 protein exerts all of these effects by catalysing two chemical reactions. It removes acetyl groups from some proteins and adds ribose groups to others, which affects the activity of these proteins.
The centSIRT6 variant is less efficient at removing acetyl, but better at adding ribose, Gorbunova鈥檚 team found. That is important because efforts to develop drugs that boost SIRT6 activity have focused on boosting the acetyl activity, whereas ribose activity now appears to be the key.
If they can be created, such drugs might even be able to reverse ageing to some extent, Gorbunova says. 鈥淲e see some evidence that SIRT6 can rejuvenate.鈥�
Of the other human gene variants linked to longer lifespans, the strongest evidence relates to a variant linked to cholesterol that reduces the risk of heart disease, she says.
鈥淚t doesn鈥檛 address the underlying mechanism of ageing, it鈥檚 more an associated condition,鈥� she says. 鈥淚 think with our SIRT6 study, for the first time we are addressing something that drives the ageing.鈥�
Reference: bioRxiv,
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