On this special episode of X10, LifeXtenShow and the Sheekey Science Show collaborate to explain a recent critique of the Hallmarks of Aging, which holds that it lacks explanatory power and has unspoken assumptions.
The hallmarks of aging have played a central role in guiding and contextualizing longevity research since they were first proposed in 2013. But a recent preprint says that despite the usefulness of the hallmarks, they don’t provide a proper explanatory framework for aging. Stick around as we dig into this critique.
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We gave an overview of the hallmarks in an earlier video and have also covered each of them individually, so if you’re not familiar with them, start there and then come back here. To be clear, the new paper isn’t arguing that the hallmarks are bad. Both of the authors recommend the hallmarks to their students and consider them a good overview of the field.
The issue they want to raise is whether the hallmarks of aging actually provide an explanatory framework – whether they merit being considered a paradigm for longevity research. At the root of this criticism is the idea that the hallmarks of aging aimed to do for longevity research what the hallmarks of cancer did for oncology. That is, the hallmarks weren’t envisioned merely as a list of significant factors contributing to aging. Instead, they are supposed to provide a conceptual structure that unites different mechanisms into a single framework that explains aging. The critique claims that they fail to do so. Following the template set by the hallmarks of cancer, the hallmarks of aging take a single primary cause to underlie aging.
This primary cause then leads to several secondary causes, which are the hallmarks themselves, and these underlie the diverse manifestations of aging. In cancer, mutations of tumor suppressors and oncogenes are taken as the primary cause – an idea that’s undisputed by oncologists. But the authors of the critique claim that the hallmarks of aging build on the accumulation of cellular damage as the primary cause.
In other words, they say that the model implicitly takes cellular damage to be the cause behind the different hallmarks, and they argue that this idea was controversial in 2013 and remains controversial now. Building on this, the critique says that the list of hallmarks is relatively arbitrary, failing to provide a good justification for including those factors rather than others. Without such a justification, the hallmarks become a list of topics rather than a unifying framework. The critique goes on to challenge the idea that the hallmarks themselves necessarily result from cellular damage.
The authors say that other factors could be involved. For example, programmatic changes could drive epigenetic changes or the collapse of proteostasis, and factors like biological constraints or trade-offs could be behind some of the other hallmarks.
They also question the division of the hallmarks into primary, secondary/antagonistic and tertiary/integrative groups, saying that there isn’t a strong basis for it. The division relies on a causal chain linking the three groups which the authors describe as tentative, pointing out that, for example, deregulated nutrient sensing or mitochondrial dysfunction could arguably be considered primary rather than secondary hallmarks.
Again, the overall argument isn’t that the hallmarks are bad. They’re clearly relevant and have proven useful in guiding longevity research and helping scientists position themselves in the field. But the argument is that despite this, they don’t provide a unifying explanatory paradigm for aging. The authors don’t stop at critiquing the hallmarks. While they don’t offer an alternative paradigm, they do provide a sketch of what one might look like.
The central idea in their proposal is to build a paradigm that includes multiple primary causes of aging, what they call a ‘multi-cause template’. Instead of a single, implicit primary cause driving various secondary causes, they imagine a paradigm with different classes of primary causes. These various primary causes would combine in different ways to create the various effects of aging. The proposal is that the primary causes would be universal across all animals, but their relative importance – the way they combine – would vary between different species and even different tissues in a single organism.
The authors of the critique claim that a framework built on this template would provide an explanatory paradigm for aging. Such a paradigm would sustain the field of longevity, not only guiding research but also helping with the development of practical applications. To get there, this critique argues that the field needs to move beyond the hallmarks of aging.
How well do you think the hallmarks have held up? Does this critique expect too much of them? Or do you think they do provide an explanatory paradigm? Let us know what you think in the comments. While you’re there, hit subscribe to keep informed about future videos. This video and all of our work at X10 is possible because of funding from the Lifespan Heroes. If you want to be part of making this happen, head to lifespan.io/hero and make a pledge.