Conclusions and Perspectives
A global view of the nine candidate hallmarks of aging enumerated in this Review suggests three categories: primary hallmarks, antagonistic hallmarks, and integrative hallmarks (Figure 6). The common characteristic of the primary hallmarks is the fact that they are all unequivocally negative. This is the case with DNA damage, including chromosomal aneuploidies; mitochondrial DNA mutations; and telomere loss, epigenetic drift, and defective proteostasis. In contrast to the primary hallmarks, antagonistic hallmarks have opposite effects depending on their intensity. At low levels, they mediate beneficial effects, but at high levels, they become deleterious. This is the case for senescence, which protects the organism from cancer but which, in excess, can promote aging. Similarly, ROS mediate cell signaling and survival but, at chronic high levels, can produce cellular damage; likewise, optimal nutrient sensing and anabolism are obviously important for survival but, in excess and during time, can become pathological. These hallmarks can be viewed as being designed for protecting the organism from damage or from nutrient scarcity. But when they are exacerbated or chronic, they subvert their purpose and generate further damage. A third category comprises the integrative hallmarks—stem cell exhaustion and altered intercellular communication—that directly affect tissue homeostasis and function. Notwithstanding the interconnectedness between all hallmarks, we propose some degree of hierarchical relation between them (Figure 6). The primary hallmarks could be the initiating triggers whose damaging consequences progressively accumulate with time. The antagonistic hallmarks, being in principle beneficial, become progressively negative in a process that is partly promoted or accelerated by the primary hallmarks. Finally, the integrative hallmarks arise when the accumulated damage caused by the primary and antagonistic hallmarks cannot be compensated by tissue homeostatic mechanisms. Because the hallmarks co-occur during aging and are interconnected, understanding their exact causal network is an exciting challenge for future work.
Defining hallmarks of aging may contribute to (1) building a framework for future studies on the molecular mechanisms of aging and (2) designing interventions to improve human healthspan (Figure 7). However, there are still numerous challenges ahead in relation to understanding this complex biological process (Martin, 2011; Miller, 2012). The rapid development of next-generation sequencing technologies may have a special impact on aging research by facilitating the evaluation of the genetic and epigenetic changes specifically accumulated by individual cells in an aging organism (de Magalhães et al., 2010; Gundry and Vijg, 2012). These techniques are already being used to determine the whole-genome sequence of individuals with exceptional longevity, to perform comparative genomic studies between short-lived and long-lived animal species and strains, and to analyze age-associated epigenetic changes at maximum resolution (Heyn et al., 2012; Kim et al., 2011; Sebastiani et al., 2011). Parallel in vivo studies with gain- or loss-of-function animal models will be necessary for moving beyond correlative analyses and providing causal evidence in favor of the implication of these proposed hallmarks in the aging process. Besides the characterization of individual hallmarks, systems biology approaches will be required to understand the mechanistic links among the processes that accompany and lead to aging (Gems and Partridge, 2013; Kirkwood, 2008). Additionally, molecular analysis of the genome-environment interactions that modulate aging will help to identify drug targets for longevity promotion (de Magalhães et al., 2012). We surmise that ever more sophisticated approaches will eventually resolve many of the pending issues. Hopefully, these combined approaches will allow a detailed understanding of the mechanisms underlying the hallmarks of aging and will facilitate future interventions for improving human healthspan and longevity.
Acknowledgments
We thank all members of our labs for their helpful comments on the manuscript and apologize for omission of relevant works due to space constraints. C.L.-O. is supported by grants from Ministerio de Economía y Competitividad (MINECO) and Instituto de Salud Carlos III (RTICC) and is an Investigator of the Botín Foundation. M.S. is funded by grants from the MINECO, European Union (ERC Advanced Grant), Regional Government of Madrid, Botín Foundation, Ramón Areces Foundation, and AXA Foundation. L.P. is supported by the Max Planck Society, the ERC, and the Wellcome Trust (UK). M.A.B. is funded by ERC Project TEL STEM CELL; FP7 Projects MARK-AGE; and EuroBATS, MINECO, Regional Government of Madrid, AXA Research Fund, Botín Foundation, and Fundación Lilly (Spain). G.K. is supported by the Ligue Nationale contre le Cancer (Equipes labellisée), Agence Nationale pour la Recherche, AXA Foundation Chair for Longevity Research, European Commission (ERC Advanced Grant, ArtForce, ChemoRes), Fondation pour la Recherche Médicale (FRM), Institut National du Cancer (INCa), Fondation de France, Cancéropôle Ile-de-France, Fondation Bettencourt-Schueller, the LabEx Immuno-Oncology, and the Paris Alliance of Cancer Research Institutes. All of the authors contributed equally to conceive and elaborate upon the ideas presented in this Review. All of the authors can be contacted for discussions or clarifications.