Critiquing the Hallmarks of Aging

The biggest problem I see with the Hallmarks of Aging paper is not really the fault of its authors, but rather that a sizable part of the research community now takes that list of aging associated mechanisms as a guide to points of intervention in aging. Unlike the SENS view of aging, a list of mechanisms in aging that preceded the Hallmarks paper by more than a decade, the Hallmarks were not established to be a list of root causes of aging, and were never intended to be taken as such.

In the case of SENS, wherein a great deal of thought has gone into identifying mechanisms that are root causes of aging, one can proceed logically from the mechanisms to building treatments that target those mechanisms. In the case of the Hallmarks, that a specific hallmark exists does not in and of itself justify a strong focus on targeting it; it can be a downstream consequence of the underlying causes of aging, and thus targeting it will not yield meaningful results.

As the main cause of disease and death in the modern world, senescence (i.e. aging; not to be confused with replicative or cellular senescence) is one of the major biological and medical challenges of the 21st century. It would therefore be invaluable to understand the central biological mechanisms of senescence and how they give rise to late-life disease, including cardiovascular disease, many forms of cancer, chronic obstructive pulmonary disease (COPD), dementia, and many other maladies.

With the goal of representing common denominators of aging in different organisms, in 2013 researchers described nine hallmarks of aging. Since then, this representation has become a major reference point for the biogerontology field. The template for the hallmarks of aging account originated from landmark papers defining first six and later ten hallmarks of cancer. Here we assess the strengths and weaknesses of the hallmarks of aging account.

As a checklist of diverse major foci of current aging research, the hallmarks of aging has provided a useful shared overview for biogerontology during a time of transition in the field. It also seems useful in applied biogerontology, to identify interventions (e.g. drugs) that impact multiple symptomatic features of aging. However, while the hallmarks of cancer provide a paradigmatic account of the causes of cancer with profound explanatory power, the hallmarks of aging do not.

A worry is that as a non-paradigm the hallmarks of aging have obscured the urgent need to define a genuine paradigm, one that can provide a useful basis for understanding the mechanistic causes of the diverse aging pathologies. We argue that biogerontology must look and move beyond the hallmarks to understand the process of aging.