Leveraging the past to illuminate longevity for the future

Rooted in Amish genetic knowledge, Zoe Biosciences’ novel platform could become the gold standard for delayed human aging.

With an eye fixed firmly on the future, Zoe Biosciences positions itself as developing longevity therapeutics for the 21st century. ‘Zoe’, of course, means ‘life’, and by tackling age-related diseases and aging itself (when the FDA allows), the company, which is helmed by CEO Scott Gies, is hoping to extend both lifespan and healthspan.

Longevity.Technology: However, if you think about the 21st century, cutting edge research and groundbreaking science, then it is unlikely that the Amish community will also leap into your mind – but, by evaluating the genes of people whose traditions are rooted in the past, Zoe Biosciences is spearheading technology for the future.

We sat down with Zoe’s CEO Scott Gies to find out more about the origin of the company and its plans for the future.

Zoe’s platform is built on an ‘Amish mutation’ which is one of the most intriguing backstories we’ve come across. In 2015, Dr Doug Vaughan, a cardiologist and now the company’s CSO, was presented with a young woman from Berne, Indiana, who was suffering from a rare bleeding disorder.

Scott Gies, Zoe Biosciences’ CEO

Together with his colleagues, Vaughan traced the poor clotting ability back to a null mutation in SERPINE1, the gene that codes for the protein, PAI-1, a protein that regulates clotting, stem cell migration and fibrosis [1].

“It turns out this woman was homozygous for the mutation – she had inherited the mutation from both parents – so she had no PAI-1 in circulation,” Scott Gies explains. “Doug set up research facilities in Berne, and after genotyping a large swath of the Swiss Amish community in Berne, the researchers found thousands of heterozygotes (just one copy of the gene, so ~50% PAI-1 levels) for the mutation and about ten homozygotes.”

Those with just one genetic copy – the heterozygotes – do not exhibit any bleeding problems, as they have enough PAI-1 to prevent them. But the significant discovery made by the team was that both homozygotes and heterozygotes are protected from biological aging.

“Not only do the carriers of the mutation live ten years longer on average compared with their unaffected kindred, they live far healthier,” says Gies. “They are protected from cardiovascular, metabolic, and other aging-related diseases.” They also have telomeres that are 10% longer [1].

For Gies and the rest of the Zoe team, the potential upside to human healthspan is not only vast, but already genetically validated in humans, rather than in animal models that attempt to replicate human aging.

Gies describes the Amish research as “a perfect natural experiment”. Because carriers and non-carriers are ‘randomized’ at birth, their genetic make-up is not known until they are genotyped.

“They all live the same lifestyle, driving horse & buggy, eating the same foods, living similar lives, etc,” Gies explains. “This provides an experimental group and a control group with the mutation seemingly being the only variable. It is our job to decipher the downstream effects of the mutation and how we can bring this advantage to a broader patient population.”

The next step is leveraging this knowledge therapeutically. Gies explains that, in a nutshell, humans are walking around with too much PAI-1 for optimal longevity – and that PAI-1 is intimately related to cellular senescence, being both a marker and a mediator [2].

“Importantly, we think this could be a potential gold standard of delayed aging in humans at present,” says Gies. “We can use this example to glean additional insights into human aging and hopefully, redefine what a healthy life looks through novel therapeutic innovations.”

Dr Doug Vaughan, Zoe Biosciences’ CSO

Zoe is attempting to replicate the Berne Amish community’s exceptional longevity with a platform of therapeutics that includes PAI-1 inhibitors across various modalities and disease indications. The biotech has also expanded into other biological targets that are relevant to the Amish’s aging phenotype.

Research is ongoing, and Zoe is actively studying the cutting edge of PAI-1 and aging biology, since the protein appears to have its figurative fingers in several longevity pathways.

As Gies explains, DNAm PAI-1, the DNA methylation correlate of plasma PAI-1 levels, is a critical epigenetic predictor of biological age. “According to Steve Horvath’s aging clock GrimAge, DNAm PAI-1 is the leading predictor of the total number of comorbidities, hypertension, early onset of menopause, type 2 diabetes and fatty liver,” says Gies. “More so, in fact, than GrimAge itself.”

While, understandably, the finer details of the Amish Longevity Platform remain under wraps, Gies did tell us Zoe Biosciences is advancing multiple therapeutic modalities for a number of chronic, aging-related diseases, with partnerships set to play a large role.

“The end goal is to help hundreds of millions of patients live longer, healthier lives. We want to redefine healthspan – total years spent in good health.”

[1] https://www.science.org/doi/10.1126/sciadv.aao1617
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846199/

Photograph: foremankelly/Envato / Northwestern Medicine