Does gene silencing tech hold the key to cellular rejuvenation?

Junevity founder explains how developments in siRNA therapeutics are enabling new ways to return cells to healthier states.

Earlier this year, we brought you the launch of longevity biotech Junevity, which revealed it was working on “cell reset” therapies designed to extend human healthspan and lifespan. By restoring key transcription factors (genes that regulate cellular damage and health) to their optimal levels using small interfering RNA (siRNA) therapeutics, the company aims to reverse cellular dysfunction and combat diseases linked to aging.

Leveraging advances in gene silencing technology, Junevity aims to “reset” cell health by knocking down the transcription factors regulating diseased and aging pathways. Its founders say the company is on a mission to enable cellular rejuvenation and reverse diseases affecting “billions of people” around the world.

Longevity.Technology: The variety of approaches being taken in the cellular rejuvenation space is fascinating – from the partial reprogramming techniques being adopted by companies including Life Biosciences and NewLimit to the alternative methods employed by the likes of Junevity and Tune Therapeutics. However, while the approaches are different, the ultimate goal remains the same – to find a way to transform diseased or aged cells back to a healthier state. To learn more about what makes Junevity’s approach different, we caught up with Dr Janine Sengstack, the company’s co-founder and Chief Scientific Officer.

Junevity’s technology originated during Sengstack’s PhD work in the lab of UCSF professor Hao Li, an expert in the study of cellular mechanisms of aging.

“Dr Li is one of the leaders in aging and transcription factor biology,” she says. “We teamed up to tackle what we called a ‘high-risk-high-reward’ PhD project to see if we could create a novel computational and experimental platform to identify transcription factors that we could target to take cells from a diseased old state and bring them back to a healthy state.”

Reprogramming beyond Yamanaka

The project was inspired by Professor Shinya Yamanaka’s Nobel Prize winning discovery that an adult cell could be reverted back into an embryonic stem cell using a specific group of protein transcription factors.

“Yamanaka discovered an amazing collection of transcription factors, but they are inherently stem cell related, so if you turn them on too much, they will take your cells from a differentiated state all the way back to a stem cell state, which is amazing, but has potential dangers if you do that in an organism,” says Sengstack. “We wanted to identify new transcription factors that were not stem cell related, so the cell type stays the same the whole time – it just goes back to a healthier version of that cell.”

Treatment of age-related diseases, and indeed aging itself, is a particularly interesting area of development for this kind of technology, due to the highly complex nature of the biology involved.

“As we get older, and in more complex diseases, lots of different changes are happening, which leads to wide scale transcriptional dysregulation,” explains Sengstack. “This basically means genes that used to be tightly regulated, happy, healthy cells, are now all over the place. This leads to more inflammation, less mitochondria, less proteostasis – all these hallmarks of aging can be tied to transcriptional dysregulation.

“What we want to do is identify the right transcription factor that regulates lots of different parts of what’s going wrong, and by targeting that one factor, bring those different aspects back to the healthy state.”

siRNA-enabled reprogramming

The key enabling innovation that Junevity’s founders alighted on was to use emerging siRNA technology to precisely target and down-regulate specific transcription factors. The approach leverages our RNA interference (RNAi) pathway to silence specific genes by targeting their messenger RNA (mRNA).

“Essentially, this provides a way to do highly specific and safe targeting of any gene of your choosing,” says Sengstack, explaining that the company’s platform works by analyzing large-scale human transcriptional data using advanced machine learning tools to identify which transcription factors contribute to cellular aging and disease. Junevity then designs highly specific siRNA molecules designed to reset cellular function in specific tissues.

So how has a small company like Junevity ended up at the forefront of this approach to cellular reprogramming? First of all, explains Sengstack, the technology needed to accomplish an undertaking of this nature simply didn’t exist a few years ago.   

“In the past, this was hard, because the scientific community’s understanding of transcription factors was somewhat limited,” she says. “They are very complicated, they regulate lots of different genes, and until recently, it was relatively hard to know who’s regulating what and in what direction. With advances in modern machine learning and AI tools, we now have a much better understanding of what transcription factor is regulating certain genes. So that’s a big advancement that now allows us to be more confident in targeting transcription factors.”

Another challenge that Junevity had to overcome is that transcription factors are generally hard to drug with a traditional small molecule approach.

“Transcription factors are inherently kind of floppy and not like they don’t have a normal pocket where a drug would just kind of go conveniently,” explains Sengstack. “This is where siRNA comes in, because they target the gene before it becomes a protein, still at the mRNA level. Up till now, they were really challenging to develop, but now there are seven FDA-approved siRNA therapeutics, and about 20 years of many scientists working very hard to figure out how to properly design them and deliver them to people. Today, siRNA has achieved the ideal level of maturity for a company like us to capitalize on the technology.”

“There’s also more large-scale human transcriptional data available now, so that we can actually look at patient data relating to things like ‘disease versus healthy’ and ‘old versus young’,” she adds. “We can use that with our machine learning tools to identify the right transcription factor and then design the right siRNA to make our therapeutic product,”

Rejuvenating the metabolism

As with most other longevity biotechs, while Junevity is committed to creating therapeutics to help people live longer, healthier lives by targeting specific diseases that are closely related to healthspan.

“We’re not going to do a 30-year clinical study on lifespan, so we’re going after very specific and established clinical endpoints,” says Sengstack. “To start with, we have some really exciting data in Type 2 diabetes and in the obesity space, where we have transcription factor targets and siRNA in mice that are looking very promising and we’re moving towards human clinical development. If things continue to go well, we would be aiming to do first clinical trials in 2026. Other indications that we’re very interested in include muscle wasting diseases like cachexia and sarcopenia, and also osteoarthritis, all of which are very related to human longevity and healthspan.”

With a growing body of research suggesting that GLP-1 drugs are already showing their potential to extend healthspan and longevity, Sengstack admits that the company’s strategy of targeting metabolic disease first is no coincidence.

“The GLP-1 drugs have done a lot of phenomenal things, but they also have downsides that we think we could really play into,” she says. “What that class of drug typically lacks, is that if you stop taking it, your weight bounces right back. There can be muscle loss, and body composition sometimes isn’t as healthy after treatment, because you lose both fat and muscle. We have some really exciting mouse data where they lose tons of fat but they don’t lose any muscle.”

Sengstack says that Junevity’s siRNA approach can also potentially address the tolerability and patient compliance issues sometimes associated with GLP-1s.

“It seems that some people don’t enjoy having to take the drugs so frequently, which can lead to people stopping to take them,” she says. “Another benefit of siRNA therapeutics is that they can be dosed very infrequently. Some GLP-1s are taken every week or so, but siRNA can be as long as up to six month dosing, which is just mind boggling.”

While some might question whether developing a new obesity drug can be considered “rejuvenation”, Sengstack has a different view.  

“We consider our approach as a rejuvenation of the metabolism in many ways,” she explains. “In our studies, we do a lot of deep analysis, including RNA sequencing, where we look at liver and fat and muscle in our treated mice, and how they look compared to healthy mice. And we see that so many things go back to a healthy mouse state. We see decreases in things like stress response and inflammation, one of the key hallmarks of aging. We see improvements in mitochondria and fat metabolism as well. All of those pieces together add up to a healthier overall mouse, which I would argue is leading towards a resetting of the metabolism to a younger, healthier state.”

Looking further ahead, Sengstack indicates that the brain could also become an important focus for Junevity in the future.

“Our platform is agnostic to the tissue – as long as we have patient data showing old versus younger, disease versus healthy, then we can create a siRNA for that,” she says. “I think we could tackle CNS-related diseases in the future – there are already very exciting therapeutics being developed right now where people are delivering siRNA to the brain, so we think it might be good timing for that.”

“We don’t think that there’s going to be one magic pill to solve everything relating to aging, so our grand vision is to create novel therapeutics – identifying the right transcription factor per tissue and per disease to bring things back to a healthy level and help you live a longer, healthier life.”

Photographs courtesy of Junevity.