Although global life expectancy has risen dramatically, these additional years are not necessarily spent in good health; the resulting unmet clinical need is a dark cloud on the horizon.
As early as 1852, Benjamin Gompertz presented his distillation of human mortality to the Royal Society. Death, he argued, arises from two coexisting causes: chance, acting without prior disposition; and deterioration, a gradual loss of the capacity to withstand destruction1.
A century later, the British biologist Peter Medawar refined this definition by separating ageing itself from the physical decline that often comes with it2. In recent decades, this idea has captivated scientists and, more recently, investors, igniting substantial efforts to disconnect getting older from bodily deterioration.
The motivations are clear. There is a strong causal link between age-associated biological deterioration and the prevalence of chronic disease. At the same time, many countries are experiencing significant demographic shifts, with ageing populations who are at greater risk of these diseases.
Despite this trend, certain populations have disproportionately high rates of exceptional longevity. These “Blue Zones” illustrate the complex interplay of genetic and environmental factors that make people more resilient and less prone to chronic disease. Crucially, individuals in these populations do not merely live longer; they retain functional independence for longer. This highlights the difference between extending lifespan and extending healthspan.
In parallel, the identification of the “hallmarks of ageing” has provided a framework for understanding the biological processes that cause age-related decline. Animal studies have yielded compelling evidence that targeting these processes, including cellular fatigue (senescence) or faulty cellular recycling processes, can delay physical deterioration and extend healthy lifespan. Even simple interventions, such as eating fewer calories, have demonstrated clear longevity benefits across many different species.
These findings suggest that many age-related diseases could be treated by targeting their common underlying causes, rather than treating each disease separately. This hypothesis is now entering the clinic, with early-phase trials exploring whether the selective elimination of tired, senescent cells can deliver therapeutic benefits across multiple indications.
The gulf between promise and practice remains vast. Poor clinical translation has long plagued drug discovery, and interventions that show dramatic efficacy in animal models frequently fail in humans due to limited efficacy or unforeseen toxicity. Much of this failure reflects how difficult it is to fully replicate human biology with models. Nowhere is this more apparent than in ageing research.
Simply put, a mouse's lifespan can not be meaningfully compared to a human’s. Even if it could, it would not be practical or ethical to model human ageing over the many decades required. Using accelerated ageing models does not solve this problem. Many of these models purposefully disrupt DNA repair mechanisms, which makes them resemble rare genetic disorders rather than natural human ageing. As a result, they only roughly approximate the ageing process and fail to capture its inherent diversity.
Modelling is especially challenging for anti-ageing treatments because they can have contradictory effects. For example, cellular senescence contributes to tissue dysfunction, inflammation, and tumorigenesis3. Yet senescence isn’t all bad; it stops genetically unstable cells multiplying and, in acute settings, it can recruit immune cells, promote wound healing, and reduce fibrosis. Context is key, and completely blocking these mechanisms could prove catastrophic.
Ultimately, the principal bottleneck in longevity therapeutics may not be identifying pathways to modulate, but rather determining whether they can be modulated safely over time. Anti-ageing therapies differ fundamentally from most modern pharmaceuticals: they target core cellular processes, are intended for chronic or lifelong use, and will likely be administered to asymptomatic individuals. Under these conditions, standard safety limits are inadequate. Toxicities deemed acceptable in certain indications may, over decades, quietly erode healthspan rather than extend it.
This places toxicology at the forefront of longevity drug development, and not as a downstream gatekeeper. The ability to anticipate cumulative toxicity, context-dependent liabilities, and population-specific vulnerabilities is essential if the field is to deliver durable benefit. At Ignota Labs, we are building toxicology models to enable the development of safer medicines. By integrating toxicology with computational modelling from the earliest stages of discovery, we aim not only to identify promising assets, but to rigorously assess whether they can be deployed without unforeseen toxicological liabilities. A deep understanding of toxicology is not a constraint on innovation; it is the condition that makes it possible.
Author: Matthew Mason
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