Extending human health span by several years is the vision of clock.bio, a biotech startup that is investigating the biology of cellular rejuvenation. The company recently raised $5.3 million in seed funding in a round led by Local Globe with participation from BlueYard Capital, Onsight Ventures, and Jonathan Milner, PhD, the founder of Abcam. Those funds have supported efforts to generate its so-called “Atlas of Rejuvenation Factors,” which covers genes linked to human cell rejuvenation. The funds will also support its next steps—validating their findings and prioritizing those that might be modulated with existing drugs.
Located at the Milner Therapeutics Institute at the University of Cambridge, clock.bio has identified more than 100 genes that constitute the atlas using experiments in induced pluripotent stem cells (iPSCs). Specifically, the company’s scientists developed a proprietary aging model that forces stem cells to age and recreate several cellular hallmarks of aging. Their intervention triggered a self-rejuvenation mechanism in the iPSCs enabling them to essentially restart the clock as young, healthy cells. Now clock.bio hopes to validate those hits in somatic cells.
The company has also expanded its team by hiring Markus Gstöttner as CEO and Rodrigo Santos, PhD, an expert in iPSCs as its CTO, both of whom spoke with GEN for this story. Both have experience in the iPSC space. Previously Gstöttner co-founded Meatable, a cultured meat company that used iPSCs and opti-ox technologies. For his part, Santos’ interest in cellular programming began during his time in academia and carried through to his work in industry, where he worked on efforts to control cellular programming by changing gene expression. The team also includes Mark Kotter, MD, PhD, clock.bio’s chairman and co-founder and a stem cell biologist and neurosurgeon at the University of Cambridge.
Giving aging cells new life
As people age, their cells accumulate damaging errors that result in a loss of function, dysregulated genes, and increased risk of disease. A 2013 review paper published in the journal Cell, and an updated version published in 2023, listed twelve hallmarks of aging, nine of which are associated with cellular activity including genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, and cellular senescence. These hallmarks are also linked to disease phenotypes typically associated with older people such as Alzheimer’s disease, various cancers as well as metabolic and cardiovascular disorders
clock.bio believes that cellular reprogramming could be the key to halting and potentially reversing some of these conditions by giving aging, diseased cells a new lease on life. And they hope to learn the secret from the body’s self-renewal resources. “Working with IPCs, we believe that we found a shortcut to addressing several [cellular aging hallmarks] if not all of them at once,” Gstöttner said in an interview. Insight into this shortcut emerged from two key observations. First, it’s possible to force iPSCs to artificially “age” in the lab and faithfully recreate the cellular hallmarks of aging. Second, forcing iPSCs to age triggers mechanisms that result in a spontaneous reversal of the aging process.
This is an important finding because “if the cellular hallmarks of aging are cell phenotypes of age-related conditions, then understanding what is in the cell and [its] DNA [that] allows an iPSC to defend itself against that phenotype [and] against those hallmarks of aging should be of clinical relevance,” he explained.
It takes about three weeks for the iPSCs to rejuvenate after forced aging. Using CRISPR screens and single-cell RNA sequencing, the scientists forced millions of iPSCs to age, triggering their rejuvenation mechanisms. They performed whole-genome screens on almost 20,000 genes during which they alternatively knocked out or activated different genes and looked for observable effects on the rejuvenation efforts. After analyzing results from over three million cells and generating about 20 terabytes of data from single-cell readouts, they identified about 140 genes that potentially regulate cellular rejuvenation in iPSCs. These make up the company’s atlas.
To be clear, their goal is not to “foresee one specific hypothesis,” Gstöttner noted. It is to understand generally “how nature can actually tackle the hallmarks of aging in iPSCs” and to see if that knowledge could translate into clinical applications.
The team is now assessing whether the 140 genes identified in iPSCs work the same way in somatic cells. They are also trying to understand which of these genes are relevant for which specific aging hallmark, the pathways involved, and any associated diseases. These experiments will help them identify the top candidates from the 140 to bring to preclinical development for particular disease indications. Since phenotypes associated with aging cells are observed in multiple conditions, there are a range of diseases that the company could potentially target. They will also work on identifying existing drugs that could be repurposed or find new ones that can target the gene or genes in question.
The company certainly seems to have built the right team needed to bring its vision to life. Besides cellular programming, its hires include experts in bioengineering, bioinformatics, and CRISPR. Importantly, its unbiased approach to target discovery means that it now has “many shots on goal” and opportunities to pivot if one target does not bear fruit, Santos noted. “We really can be nimble and we can partner with multiple companies. The targets that we are identifying are so fundamental to some diseases that it will be easy to carve out potential areas of exclusivity with pharmaceutical partners for co-development.” Furthermore, he pointed out that the company is leveraging scientific discoveries that have been essential in advancing the field including findings from three Nobel prize winners. “That makes this incredibly exciting.”
Gstöttner echoed similar sentiments in his comments citing the potential of iPSCs as well as the value of having a committed team. “We are quite confident that this is a pretty unique and, in this field, unprecedented dataset. We now need to do our homework on prioritizing and validating those targets,” he said. “We have 140 shots on target and we are quite excited to get going on that.”