The hoverfly and the wasp: A critique of the hallmarks of aging as a paradigm

Abstract

With the goal of representing common denominators of aging in different organisms López-Otín et al. in 2013 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 by Hanahan and Weinberg (2000, 2011) 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, it 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.

Keywords: Aging; Geroscience; Hallmarks; Paradigm; Senescence; Theory.

Figure 1

A very approximate representation of the traditional biogerontological conceptual framework. This framework, we argue, is experiencing a paradigmatic crisis. ROS, reactive oxygen species.

Figure 2

Hallmarks diagrams. A, Hallmarks of cancer (Hanahan & Weinberg 2011). B, Hallmarks of aging (López-Otín et al. 2013).

Figure 3

Formal representation of hallmarks of cancer conceptual structure (upper box). The hallmarks of aging approximate to this structure (lower box) (cf Figure 4).

Figure 4

Conceptual structure from hallmarks of aging; Figure 6 from (López-Otín et al. 2013), in which it is specified that damage here refers to cellular damage.

Figure 5

Seven pillars of aging (Kennedy et al. 2014). The identity of the pillars overlaps only slightly with the hallmarks. The interconnectedness depicted denotes a hopelessness with respect to an effective explanatory paradigm which is in sharp contrast to the hallmarks of cancer. Such interconnectedness is also argued to be present between the hallmarks of aging.

Figure 6

The false distinction between aging and disease; adapted from (Blagosklonny 2007). A, Aging as a process distinct from late-life disease; here disease is incidental to understanding aging. B, Aging as diseases/pathologies caused by wild-type gene action; here disease/pathology is critical to understanding aging.

Figure 7

Alternative paradigm templates. A, the hallmarks template (single primary mechanism). B, multiple primary mechanisms template. Possible primary mechanisms include mechanical senescence, molecular damage, infectious pathogens, and wild-type gene action. According to this model, individual diseases of aging throughout the animal kingdom may be understood in terms of different combinations and extents of primary causes. The overall contribution to senescence varies between taxa. For example, the green box could represent programmatic aging mechanisms specified by wild-type gene action, and the orange box molecular damage (particularly DNA damage). According to this model, development of senescent pathology throughout the animal kingdom, however alien from human diseases, are governed by the same underlying set of principles of senescent pathophysiology. Arrow thickness represents relative pathophysiological contribution.