Does SIRT6 hold the key to human longevity?

Longevity focused biotech SIRTLab emerges from stealth, aiming for first human trials of SIRT6-boosting therapeutic in 2024.

Last week, US-Israeli startup SIRTLab announced the appointment of leading geroscience researcher Nir Barzilai as its Chief Medical Adviser. The company is focused on the development of therapeutics that boost levels of a key protein called sirtuin 6 (SIRT6), which is heavily implicated in longevity.

Sirtuins are a group of proteins found in all living organisms, including humans, that play a vital role in regulating various cellular processes. There are seven different types of sirtuins, numbered from SIRT1 to SIRT7, each with its own unique functions. In recent years, SIRT6 has gained particular attention for its potential role in promoting healthy aging, and SIRTLab has put the protein at the center of its work.

Longevity.Technology: The SIRT6 protein has been shown to regulate several critical cellular pathways, including glucose metabolism, DNA repair and inflammation – all of which play key roles in aging and longevity. One of the world’s leading authorities on SIRT6 is SIRTLab co-founder and Bar-Ilan University professor Haim Cohen, whose research is behind the company’s work to develop therapeutics with longevity-boosting potential. To learn more about SIRTLab’s longevity-first approach, we spoke to its co-founder and CEO Boaz Misholi.

The link between SIRT6 and longevity may sound like exciting new progress, but Misholi points out that this area of research stems from the discovery in 1935 that caloric restriction extended lifespan of rats by a third.

“At the time, the researchers were shocked because there was no scientific explanation for this phenomenon,” says Misholi. “That led to a huge amount of interest and further research, but it wasn’t until about 60 years later that two Harvard researchers, David Sinclair and Haim Cohen, discovered that the effect of calorie restriction was mediated by sirtuins.”

SIRT6 and lifespan extension

Following his work at Harvard, Cohen returned to Israel to head up his own lab at Bar-Ilan University, where he continued his interest in sirtuins and their role in human aging and longevity – and SIRT6 in particular.

Does SIRT6 hold the key to human longevity?
Prof Haim Cohen is Chief Scientist at SIRTLab.

“He discovered that SIRT6 mediates many facets of calorie restriction to improve metabolism and extend healthy lifespan in animal models,” says Misholi. “By generating mice with overexpression of SIRT6, he demonstrated average lifespan extension of 30%, and positive impacts on frailty.”

The mice in Cohen’s study also exhibited significant improvement in overcoming a variety of age-related diseases, such as cancer and blood disorders, and were able to conduct the same level of vigorous activity as young mice.

“It appears that high levels of SIRT6 also boosts physical performance and improves memory and cognitive function – even in young mice,” says Misholi. “But, while the longevity and healthspan benefits of SIRT6 are well-known, no one has yet developed a therapeutic way to increase SIRT6 levels at a cellular level in the body. Until now.”

Translating SIRT6 results to humans

Of course, therapeutic approaches that have worked in animal models don’t always translate into results in humans, but SIRTLab believes that SIRT6 expression has a good chance of delivering on its promising results in mice.

“With SIRT6, we’re seeing an ancient mechanism at work – you can find it in the simplest lifeforms like worms and yeast, all the way through to birds, mammals and humans,” says Misholi. “For example, in our experiments, we’ve also taken human cells and shown that our method for expressing SIRT6 works well and delivers good results.”

Building on the work of Prof Cohen, SIRTLab has created a SIRT6-focused therapeutic platform, with multiple approaches to increasing SIRT6 levels in cells.

“We have developed four different ways to therapeutically target SIRT6 production: messenger RNA (mRNA), small molecules, adeno-associated viruses (AAVs), and antagonists for micro-RNAs that control SIRT6 levels,” says Misholi. “There are different benefits to each approach, and it’s even possible that a treatment could use a combination of two or more. We’ve seen in our experiments that our mRNA therapeutic boosts cellular levels of SIRT6 by 20 times, which is very exciting.”

To help achieve its goal of creating the first longevity drug, the company has assembled a strong team of scientists and advisors.

Dr Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine

“Alongside our head of R&D Dr Hagit Ashush, we have Prof Haim Cohen, the world’s leading SIRT6 researcher and Prof Dan Peer, a world leader in targeted drug delivery,” says Misholi. “And, of course, we now have Prof Nir Barzilai, a leading voice on the biology and genetics of aging, on our Board of Directors.”

Misholi says that because longevity is at core of the company’s work, it potentially has a platform for targeting many diseases of aging.

“We have many potential indications to consider,” he says. “We have demonstrated that we can treat mice with fatty liver disease, and within three weeks we have reversed it – the liver has become totally healthy. In our mouse studies, we found that increasing the level of SIRT6 in the liver alone had a very strong impact on the activity on the energy level of and the overall health of the mice.”

SIRTLab also believes SIRT6 can play a role in frailty, inflammatory diseases and neurodegenerative disease.

“Take osteoporosis, for example – we believe that an injection of our technology to the affected area will impact the inflammation there,” says Misholi. “If you look at inflammation of the pancreas, for example, there’s no drug, there’s no solution for that. We believe that if increase the level of SIRT6 in the pancreas, it may reverse the inflammation there. And there is also a lot of work showing a connection between SIRT6 and Alzheimer’s.”

Ultimately though, Misholi is keen to stress that SIRTLab is really focused on one key indication: human longevity.

“We strongly believe that the platform we have developed has the potential for delivering the first therapeutic to improve human longevity,” he says. “But, of course, we also need an approved indication from the FDA, so that is why we’ll be going after some specific indications first.”

The company hopes to commence its first human trials in 2024, after it completes toxicity studies this year.