LinkGevity founder predicts successfully targeting necrosis will enable multiple age-related diseases to be targeted simultaneously.
Last year we brought you the launch of longevity biotech LinkGevity and its mission to treat aging as a defined, druggable biological process that sits upstream of multiple diseases. The UK-based startup founded by sisters Dr Carina Kern and Serena Kern-Libera, is developing a first-in-class “anti-necrotic” small-molecule therapeutic designed to inhibit necrosis, the uncontrolled death of cells and tissues that is linked to degenerative change across chronic conditions.
While undoubtedly playing a role in the aging process, necrosis has historically been viewed as too chaotic to therapeutically control. So why does the Cambridge-based company believe necrosis has been overlooked as a target, and how is it connecting the biology to a longevity-focused drug development roadmap?
Longevity.Technology: LinkGevity argues that many approaches in longevity have struggled to translate into regulated medicines because they lack clear mechanisms and clinically meaningful indications. By contrast, it positions necrosis as a central driver that can be tied directly to measurable disease outcomes. With a lead candidate in hand and ambitions that extend from kidney injury to a wider range of age-related conditions, LinkGevity is positioning necrosis inhibition as a potential “system-wide” therapeutic strategy. We sat down with Dr Kern to learn more about the company’s approach.
The company’s scientific thesis is grounded in Kern’s Blueprint Theory of Aging, a systems-level framework that aims to map how age-related diseases connect to one another and to identify the key drivers of widespread physiological decline.
LinkGevity co-founder and CEO, Dr Carina Kern.
“The longevity field has quite a few ideas that have been swimming around for decades, and yet we are still to see therapeutic interventions that have really cut at the heart of longevity,” says Kern. “So how do you get to the heart of that? That’s where the Blueprint theory really came in, which is that you need a systems-level solution to a systems-level problem. And the way to do that is to first figure out how these different diseases are connected, and to identify and intervene in key nodes within the system such that you’re having the greatest protective effect across the system as a whole.”
An ‘upstream driver’ of disease
Leveraging an approach akin to factor modeling in finance, Kern started identifying key factors or “nodes” giving rise to the greatest level of degeneration-related change. The theory being that intervening in those nodes would deliver the greatest protective effects.
“When you do that at the macro level, at the physiology level, necrosis is a key node that keeps coming up,” explains Kern. “It comes up across different diseases and the system as a whole.”
Traditionally, necrosis was viewed as the endpoint of injury – death, in effect. But, as Kern’s recent paper in Nature Oncogene points out, necrosis is not just an endpoint – it is also an upstream driver of degenerative change across diseases.
“What happens when you get necrosis is messy cell death,” she says. “Your cell ruptures, it spews out hazardous intracellular contents. And when that happens, it triggers further damage, triggering further necrosis, but also a maladaptive, unwanted wound-healing response, which triggers senescence, cell accumulation, fibrosis, chronic persistent difficult-to-treat inflammation.”
In addition, Kern explains, with necrosis, damage can also happen within the cell, leading to factors such as mitochondrial dysfunction, loss of proteostasis, DNA damage and genomic instability.
“You can now see how necrosis is driving many of the different hallmarks of aging – and is at the heart of chronic, age-related conditions,” she says. “This is why necrosis is such a key node. At a physiology-wide level, if you could intervene in a node like that, you would have what I like to call a Swiss Army Knife therapeutic: a therapeutic that’s not just hitting one age-related disease, but multiple age-related diseases simultaneously.”
‘No benefit’ to necrosis
To support her case, Kern explains that necrosis, arising from cellular damage, is not a genetically controlled process that we have for a reason, such as those our bodies use to get rid of cancerous cells or to enable wound healing or tissue remodeling.
“There’s no benefit to necrosis – it is purely negative,” she says. “The cell is the fundamental building block of all of biology. How your cell lives and dies is going to control your overall health or degenerative status. And necrosis is taking out this vital building block.”
Kern at work in the LinkGevity lab.
Sounds convincing, right? So why, one wonders, aren’t many others looking to explore necrosis as a therapeutic target? Kern explains the short answer is that the status quo is that it is impossible, or near impossible, to intervene in necrosis.
“Many of the individuals we’re working with today have been trying to intervene in necrosis since the 1980s,” she says. “One in particular over at Harvard brings decades of institutional memory on why prior attempts haven’t worked. To intervene in necrosis, you should be able to take cells, stress them to the point where you’re going to see degeneration, and yet with your intervention protect those cells so that they’re still alive and viable. No one to date has been able to do that in the lab.”
No one, that is, until LinkGevity made its key breakthrough, leveraging the same node-based approach it adopted to identify necrosis in the first place.
“We asked ourselves, are there key molecular nodes that one could target such that, even in this chaotic cell death, would provide the greatest protective effect at the cellular and sub-cellular level?” says Kern. “And it turns out that calcium held the answer.”
Calcium overload is key
It is well-known that a key upstream driver of cellular damage is a process known as calcium overload.
“Any form of stress typically damages the cell in many chaotic manners, but your cell repair mechanisms can cope with all of these and repair them,” explains Kern. “What it cannot cope with is calcium flooding the cell, and that happens once your cell is stressed because of membrane instability. That process of calcium overload then switches on multiple signaling pathways in a heightened and destructive manner simultaneously, resulting in the death of the cell from the inside out.”
LinkGevity made its mission to figure out how to prevent calcium overload, which Kern says no one else has been able to do.
“Others have tried to hit different channels in isolation, and there are a multitude of channels, so there’s great complexity,” she says. “But what our AI-enabled platform predicted was that you have to hit two of them in particular, out of all of these different ones, and simultaneously. When we tested that prediction in a lab, it held true.”
Kern describes the results seen in the lab as “remarkable.” When the researchers stressed cells to the point where nearly 100% were dying, they discovered that treating them with the anti-necrotic compound kept 90 to 100% alive. But what does that really mean for its potential in human biology?
“Once necrosis starts in any organ, it propagates further necrosis and senescent cell accumulation, fibrosis, that whole vicious positive feedback loop,” says Kern. “To date, we’ve never been able to break those feedback loops at their source by stopping necrosis itself. The best we’ve been able to do is try to come up with anti-fibrotic medications, anti-inflammatories, senolytics, and so on. Imagine if you could stop it right at the source: that would allow normal cell division and normal cell proliferation to resume, and therefore regeneration. So it’s got potential as a preventative, but also as quite a potent regenerative therapeutic treatment.”
The first drug for aging?
While LinkGevity has not yet published its preclinical findings, citing IP protection, Kern says it has pursued external validation and is prioritizing regulatory-grade evidence as it advances toward first-in-human studies.
“We got our work independently validated by a contract research organization who told us initially it was not going to work- then watched it succeed,” says Kern. “At the end of the day, in science, opinions don’t really amount to much. It is data that speaks volumes. In science, you follow the data – full stop. In our case, you cannot argue with the data.”
For LinkGevity initial clinical pathway is expected to start with kidney-related tissue degeneration, where acute tubular necrosis is widely recognized as the major contributor to injury, and progression toward chronic disease by driving hallmarks of aging like inflammation, senescent cell accumulation, and DNA damage. The kidney, Kern argues, provides an “accelerated aging” model with clinically meaningful endpoints that can be measured on shorter timelines than many other organs, potentially making it a practical first indication for a drug intended to have broader implications for aging biology.
LinkGevity is exploring options in the UK and Europe and is working with NHS Health Innovation East as it navigates the steps required for regulatory approval of a trial using kidney disease as an entry point. But the company has its sights set on loftier goals.
“The way I see it in the future is: this is the Swiss Army Knife therapeutic,” says Kern. “In our case, the ambition is: this could be the first drug approved for kidney injury and its progression to chronic kidney disease, but also to use the kidney as an accelerated aging model to get regulators to approve the first drug for aging.”
Photographs courtesy of LinkGevity.