Could the Future of Longevity Lie in Tackling Necrosis?

LinkGevity is an AI-enabled drug discovery company focused on aging and age-related diseases. Our lead therapeutic is a first-in-class Anti-Necrotic™, designed to block tissue degeneration by preventing cellular necrosis – which refers to non-programmed, or “uncontrolled”, cell death. We are currently preparing to enter late-stage efficacy clinical trials at the end of this year, focused on kidney disease alongside targeting the underlying aging process more broadly.

Our lead therapeutic was selected as one of just 12 global innovations for NASA’s space health program, due to its promise in mitigating accelerated aging and kidney disease in astronauts.

AI is one of the most powerful tools we have today, especially for understanding biology. That said, it also has limitations. In biology, AI works best when you have strong, empirical datasets to draw from – but in many areas, particularly aging and age-related diseases, such datasets are limited. This creates a real challenge. The current drug discovery failure rate for age-related diseases is around 90%, highlighting how difficult the field remains, even with AI.

At LinkGevity, we recognize that while AI is powerful, it’s not enough on its own. That’s why we've developed a novel framework – one that takes a “white box” approach to understanding the causal chains behind disease development. By mapping how interactions across molecular pathways give rise to disease, we can use AI to enable and accelerate drug discovery, rather than rely on it blindly. In short, we are AI-enabled, not AI-dependent.

Traditionally, most aging research – including my early work – has focused on studying distinct features of aging, categorized in different ways, such as the well-known 'hallmarks of aging”. These hallmarks provide a powerful, albeit rough, guide for understanding the visible characteristics of aging.

However, a major challenge has been determining whether these features are primary drivers of aging, secondary effects or merely symptoms. Where exactly do they sit in the causal chain?

Our Blueprint Theory of Aging was developed to address this gap. It aims to map how these features connect causally, piecing them together into a comprehensive framework. A good example is our work on cellular necrosis. Across biology, you see trade-offs and constraints that evolution has optimized for survival across different environments. However, the side effect of these trade-offs is the aging process. Once you understand these interactions, you can identify key intervention points – similar to factor modeling in economics – targeting the nodes that drive the greatest change.

Necrosis represents one such critical node. It often sits at the interface between external stresses (like oxidative stress or microgravity and cosmic radiation in astronauts) and internal biological responses. Multiple upstream stresses converge on necrosis as a common endpoint, leading to tissue degeneration. Following necrosis, a cascade of damaging downstream effects occurs: uncontrolled cell death, harmful inflammation and maladaptive wound healing responses – hallmarks of chronic, age-related diseases like fibrosis, senescent cell accumulation and chronic inflammation. Importantly, necrosis is not limited to a single organ system – it is a widespread feature across biology.

By focusing on these causal drivers rather than symptoms, the Blueprint Theory allows us to approach aging – and age-related disease – from a fundamentally different and more targeted perspective.

The utility of the Blueprint Theory is that it moves us away from viewing age-related diseases in isolation. Medicine has long recognized that biology functions as a system, but until now, there wasn’t a framework that could pinpoint the key nodes – the points that are most catastrophic and drive destruction across multiple diseases. The Blueprint Theory allows us to identify and target these critical nodes. By doing so, instead of tackling single diseases individually – an approach with a 90% failure rate – we can intervene more strategically and address multiple diseases at once.

There are a few important reasons why we’ve focused so heavily on necrosis. Considering the broader context, despite aging likely offering the greatest potential for medical benefit today, no drug has yet been approved to treat it. I believe there are three main reasons for this.

First, the sheer difficulty of developing preventative medicines. Second, there is a lack of clear mechanistic understanding – something regulatory agencies like the US Food and Drug Administration, European Medicines Agency or Medicines and Healthcare products Regulatory Agency require. Third, the exorbitant cost and timelines involved, often spanning decades for clinical trials.

Necrosis offers a strategic advantage because it addresses these barriers. Mechanistically, necrosis is very well understood. In fact, it has been heavily characterized, both systematically in aging as well as in specific areas like kidney disease, as done by our collaborator Dr. Joseph Bonventre, head of the renal division at Harvard University and others. This clear mechanistic insight is critical for regulatory approval.

Moreover, by targeting necrosis, we can intervene, not only post disease onset, but also preventatively. Age-related degeneration involves not just tissue loss from necrosis, but a self-perpetuating cycle of damage, as necrosis promotes further cell death, inflammation, and fibrosis. Cellular damage associated with necrosis also drives core aging processes such as genomic instability, proteostasis loss, telomere shortening, oxidative stress and epigenetic alterations.

Another advantage is that necrosis provides access to excellent models of accelerated aging. While kidney disease commonly develops with natural aging – affecting an estimated half of all individuals by age 75 – it can also be triggered earlier in life when necrosis occurs prematurely. For example, an initial insult like surgery can trigger rapid fibrosis, senescent cell accumulation, and chronic inflammation in the kidney within a much shorter timeframe (we’re talking months), due to positive feedback loops driven by necrosis. After certain surgeries for instance – particularly heart surgeries – there's up to a 40% risk of developing follow-on conditions like kidney disease and accelerated kidney aging, with acute tubular necrosis as the principal driver.

Given that kidney disease is now the ninth leading cause of death globally, according to WHO’s 2024 data, and is anticipated to rise further, targeting necrosis represents a powerful, strategic way to both address a major health burden and advance anti-aging interventions.

While we're starting with the kidney, the vision for our anti-necrotic technology goes far beyond that. This is truly one of the final frontiers in medicine, and we're committed to maximizing its impact. Our goal is to not only develop this technology for chronic diseases but as a preventative measure against aging itself.

Necrosis has also long been a major barrier across multiple scientific fields. In organ preservation, for example, hearts and lungs can currently only be stored for four to six hours before necrosis sets in. In bioengineering and tissue engineering, necrotic cores often form in artificial constructs, limiting progress in growing functional tissues and organs.

We aim to harness the full potential of targeting necrosis – addressing tissue degeneration and aging at its core rather than treating individual indications separately. 

Aging is arguably one of the greatest challenges facing societies today—and one that will only intensify if left unaddressed. For example, kidney disease, an unmet medical need, has become a public health emergency in the UK. Likewise in the US, it costs Medicare around 24% of its annual budget. Aging does not only cause mortality but also morbidity. The devastating aftermath of living with kidney disease is evident: the average life expectancy on dialysis is 5–10 years, with patients enduring around 12 hours of grueling treatment every week. For those who receive a kidney transplant, there is an approximate 40% rejection rate within the first 10 years.

The benefits of extending a healthy lifespan reach beyond individual health; they also impact economic stability. Longer, healthier lives benefit not only patients but also the broader economy. The effects could be very positive: economic growth and productivity are closely linked to the health of the labor force, and even a few extra years of good health could have massive benefits.

However, if financial services firms and policymakers are not prepared for this shift, we could also see challenges emerging.

Longevity is not just a scientific issue – it will influence many aspects of society. I believe solving the so-called productivity puzzle that economists often discuss may hinge, in part, on investing more heavily in longevity research and science.