The quest for rejuvenation without reprogramming

Clock.bio founders on how a cocktail of existing drugs may hold the key to restoring all the hallmarks of aging.

Two weeks ago, longevity biotech startup Clock.bio emerged from stealth with $4 million in funding, and setting itself an ambitious goal to be in a Phase 3 trial for a healthspan-extending intervention by the end of the decade. With the clock ticking, the company is already working to map rejuvenation biology across the entire human genome over the next 12 months. Having completed an initial screen of around 1,000 genes, Clock.bio says it has already identified several new potential rejuvenation targets.

Longevity.Technology: Clock.bio’s bold ambitions are based on the company’s work in the lab to “force-age” human stem cells and trigger their self-rejuvenation mechanisms. The company’s approach was developed by University of Cambridge neurosurgeon and bit.bio founder Dr Mark Kotter, who created the ‘aging in a dish’ model, where unbiased CRISPR screens are used to reveal the genes that cause aging and rejuvenation. To learn more about this fascinating company, we caught up with Kotter and Clock.bio’s new CEO Markus Gstöttner.

Clock.bio was built around Kotter’s growing fascination with the aging process. More specifically, to answer the question: What is rejuvenation? One of the foundational ideas that Clock.bio is based on is that youth must be a dynamic state.

Clock.bio launches to decode rejuvenation biology across human genome
Dr Mark Kotter is the founder of Clock.bio.

“Old cells and young cells, all are constantly bombarded with entropy – at every moment in time something goes wrong and needs to be fixed for cells to survive,” says Kotter. “In this framework, youth is when you can efficiently repair the errors that accumulate, but aging is when you don’t repair them as well. Youth is a dynamic state.”

“This raises more questions, such as what processes can drive cells to repair aging-related damage? And does every cell age? Well, we know there are species that don’t age, which begs the question – why do we age, and they don’t?”

Do stem cells hold the key to rejuvenation?

To address this question, Kotter started working with the London Institute for Mathematical Sciences.

“Together, we identified a theoretical framework where it looks like under very constrained conditions, aging is beneficial, and allows a species to outcompete a non-aging species,” he says. “But, of course, there is a type of human cell that doesn’t age – the pluripotent, or embryonic, stem cell.”

This led Kotter to the idea of triggering the self-rejuvenation mechanism of pluripotent stem cells to gain insight into the cellular drivers of aging and rejuvenation. Crucially, Clock.bio has found a way to shortcut the screening process required to identify rejuvenation drivers across the entire human genome.

“We have been able to create a paradigm in the lab, where we override the repair programs, and force-age the stem cells, so that their rejuvenation capabilities kick in again,” says Kotter.

The company uses unbiased CRISPR screens on large samples of stem cells to identify gene candidates that are causally relevant for cell rejuvenation.

“Within 12 months, we will know every gene that’s involved in the restoration of aging hallmarks,” he says, referring to the various types of damage that are known to contribute to aging. “And, if you are able to repair them, then you’ve got a youthful state.”

Rejuvenation and reprogramming

In the longevity circles, cellular reprogramming, the concept of reverting aged cells back to a more youthful state, is a hot topic, and Kotter was involved in the early days of Altos Labs, one of the big players in the field.

“I initially thought maybe my idea of reading out the youth programs of pluripotent stem cells could be part of what Altos was doing,” he says. “But we decided to spin it out as Clock.bio instead.”

Kotter says there are significant differences between the way Clock.bio is looking at cellular rejuvenation and those taking a partial reprogramming approach.

“With partial reprogramming by Yamanaka factors, you see rejuvenation initially, but then a massive change in cell identity, which complicates things greatly,” he says. “In our paradigm, only the age of the cell changes, which allows us to screen with a very flat baseline. We’ve already done our first screen – just 1,000 genes out of the 20,000 – and we’ve found targets.”

Targets already identified

Clock.bio then identified some existing, approved drugs that could potentially be used against the targets identified in the first screen.

“We looked at whether these drugs could beneficially modulate aged neurons – we found that they did, and if we combined them the results got even better,” says Kotter. “So, now we have this end-to-end validation in vitro – from being able to identify rejuvenation genes, which are essentially controlling repair processes, through to activating those repair processes in aged cells. It’s a completely unbiased way to understand every process that’s involved in restoring the aging hallmarks.”  

Based on its compelling initial results, Clock.bio was able to secure its first funding round, and appointed Gstöttner as its new CEO to take things forward.

Clock.bio launches to decode rejuvenation biology across human genome
Markus Gstöttner, Clock.bio’s newly appointed CEO.

“I really had that penny drop moment when I could see through the microscope that cells are damaged and then, within five days, they’re healthy again,” says Gstöttner. “You really want to understand what’s happening in the background at that point – it’s a part of human biology that’s not yet fully understood. So, we’re not here to try and partially reprogram something – we’re here to switch on the light and see what’s happening.”

Make mine… a rejuvenation cocktail?

Gstöttner adds that the company is now “laser focused” on extending what the company has done in 1,000 genes across the full human genome.

“We’re confident that we can go much faster than we’ve gone before,” he says. “In 12 months, we’ll understand all rejuvenation factors, all genes that are activated in the context of rejuvenation.”

Armed with all that information, there will be many different routes and options available to Clock.bio.  

“We’re looking for the right partners to go down these routes,” says Gstöttner. “That means validating them in terms of how they might interact, how they work in somatic cells, how we can continue the drug validation at scale, and, of course, prioritizing them in terms of which disease indications we want to target and which preclinical models we want to get started on.”

Looking to the future, Kotter says he expects that the most likely path to achieving the company’s goal of being in a Phase 3 trial by the end of the decade will be through a “cocktail” of existing drugs.

“I’m pretty bullish – we already found some really good, solid safe drugs, that that had profound effects that are not yet recognized, and these effects were enhanced in combination,” he says.