Nature Oncogene<\/a> points out, necrosis is not just an endpoint \u2013 it is also an upstream driver of degenerative change across diseases.<\/p>\n\u201cWhat happens when you get necrosis is messy cell death,\u201d she says. \u201cYour 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.\u201d<\/p>\n
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.<\/p>\n
\u201cYou can now see how necrosis is driving many of the different hallmarks of aging \u2013 and is at the heart of chronic, age-related conditions,\u201d she says. \u201cThis 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\u2019s not just hitting one age-related disease, but multiple age-related diseases simultaneously.\u201d<\/p>\n
\u2018No benefit\u2019 to necrosis <\/p>\n
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.<\/p>\n
\u201cThere\u2019s no benefit to necrosis \u2013 it is purely negative,\u201d she says. \u201cThe 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.\u201d<\/p>\n
![\"\"](\"data:image\/svg+xml;nitro-empty-id=OTgyOjkwMg==-1;base64,PHN2ZyB2aWV3Qm94PSIwIDAgMTAyNCA2ODMiIHdpZHRoPSIxMDI0IiBoZWlnaHQ9IjY4MyIgeG1sbnM9Imh0dHA6Ly93d3cudzMub3JnLzIwMDAvc3ZnIj48L3N2Zz4=\"\/)
Kern at work in the LinkGevity lab. <\/p>\n
Sounds convincing, right? So why, one wonders, aren\u2019t 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.<\/p>\n
\u201cMany of the individuals we\u2019re working with today have been trying to intervene in necrosis since the 1980s,\u201d she says. \u201cOne in particular over at Harvard brings decades of institutional memory on why prior attempts\u00a0haven\u2019t worked. To intervene in necrosis, you should be able to take cells, stress them to the point where you\u2019re going to see degeneration, and yet with your intervention protect those cells so that they\u2019re still alive and viable. No one to date has been able to do that in the lab.\u201d<\/p>\n
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.<\/p>\n
\u201cWe 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?\u201d says Kern. \u201cAnd it turns out that calcium held the answer.\u201d<\/p>\n
Calcium overload is key <\/p>\n
It is well-known that a key upstream driver of cellular damage is a process known as calcium overload.<\/p>\n
\u201cAny 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,\u201d explains Kern. \u201cWhat 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.\u201d<\/p>\n
LinkGevity made its mission to figure out how to prevent calcium overload, which Kern says no one else has been able to do.<\/p>\n
\u201cOthers have tried to hit different channels in isolation, and there are a multitude of channels, so there\u2019s great complexity,\u201d she says. \u201cBut 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.\u201d<\/p>\n
Kern describes the results seen in the lab as \u201cremarkable.\u201d 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?<\/p>\n
\u201cOnce necrosis starts in any organ, it propagates further necrosis and senescent cell accumulation, fibrosis, that whole vicious positive feedback loop,\u201d says Kern. \u201cTo date, we\u2019ve never been able to break those feedback loops at their source\u00a0by stopping necrosis itself. The best we\u2019ve 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\u2019s got potential as a preventative, but also as quite a potent regenerative therapeutic treatment.\u201d<\/p>\n
The first drug for aging? <\/p>\n
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.<\/p>\n
\u201cWe got our work independently validated by a contract research organization who told us initially it was not going to work- then watched it succeed,\u201d says Kern. \u201cAt the end of the day, in science, opinions don\u2019t really amount to much. It is data that speaks volumes. In science, you follow the data \u2013 full stop. In our case, you cannot argue with the data.\u201d<\/p>\n
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 \u201caccelerated aging\u201d 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.<\/p>\n
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.<\/p>\n
\u201cThe way I see it in the future is: this is the Swiss Army Knife therapeutic,\u201d says Kern. \u201cIn 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.\u201d<\/p>\n
Photographs courtesy of LinkGevity. <\/p>\n","protected":false},"excerpt":{"rendered":"LinkGevity founder predicts successfully targeting necrosis will enable multiple age-related diseases to be targeted simultaneously. Last year we…\n","protected":false},"author":2,"featured_media":19998,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":"","_share_on_mastodon":"0"},"categories":[4],"tags":[13092,5066,3827,13093,4461,13094,13095,1202,41,17],"class_list":["post-19997","post","type-post","status-publish","format-standard","has-post-thumbnail","category-switzerland","tag-carina-kern","tag-exclusive","tag-interview","tag-linkgevity","tag-longevity","tag-longevity-drugs","tag-necrosis","tag-news","tag-swiss","tag-switzerland"],"share_on_mastodon":{"url":"","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/ch\/wp-json\/wp\/v2\/posts\/19997","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/ch\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/ch\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ch\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ch\/wp-json\/wp\/v2\/comments?post=19997"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/ch\/wp-json\/wp\/v2\/posts\/19997\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ch\/wp-json\/wp\/v2\/media\/19998"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/ch\/wp-json\/wp\/v2\/media?parent=19997"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/ch\/wp-json\/wp\/v2\/categories?post=19997"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/ch\/wp-json\/wp\/v2\/tags?post=19997"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}