Here, we have attempted to identify and categorize the cellular and molecular hallmarks of aging. We propose nine candidate hallmarks that are generally considered to contribute to the aging process and together determine the aging phenotype (Figure 1). Given the complexity of the issue, we have emphasized current understanding of mammalian aging while recognizing pioneer insights from simpler model organisms (Gems and Partridge, 2013; Kenyon, 2010). Each hallmark should ideally fulfill the following criteria: (1) it should manifest during normal aging; (2) its experimental aggravation should accelerate aging; and (3) its experimental amelioration should retard the normal aging process and hence increase healthy lifespan. This set of ideal requisites is met to varying degrees by the proposed hallmarks, an aspect that will be discussed in detail for each of them. The last criterion is the most difficult to achieve, even if restricted to just one aspect of aging. For this reason, not all of the hallmarks are fully supported yet by interventions that succeed in ameliorating aging. This caveat is tempered by the extensive interconnectedness between the aging hallmarks, implying that experimental amelioration of one particular hallmark may impinge on others.

Genomic Instability

One common denominator of aging is the accumulation of genetic damage throughout life (Moskalev et al., 2012) (Figure 2A). Moreover, numerous premature aging diseases, such as Werner syndrome and Bloom syndrome, are the consequence of increased DNA damage accumulation (Burtner and Kennedy, 2010), though the relevance of these and other progeroid syndromes to normal aging remains unresolved due, in part, to the fact that they recapitulate only some aspects of aging. The integrity and stability of DNA are continuously challenged by exogenous physical, chemical, and biological agents, as well as by endogenous threats, including DNA replication errors, spontaneous hydrolytic reactions, and reactive oxygen species (ROS) (Hoeijmakers, 2009). The genetic lesions arising from extrinsic or intrinsic damages are highly diverse and include point mutations, translocations, chromosomal gains and losses, telomere shortening, and gene disruption caused by the integration of viruses or transposons. To minimize these lesions, organisms have evolved a complex network of DNA repair mechanisms that are collectively capable of dealing with most of the damages inflicted to nuclear DNA (Lord and Ashworth, 2012). The genomic stability systems also include specific mechanisms for maintaining the appropriate length and functionality of telomeres (which are the topic of a separate hallmark; see below) and for ensuring the integrity of mitochondrial DNA (mtDNA) (Blackburn et al., 2006; Kazak et al., 2012). In addition to these direct lesions in the DNA, defects in the nuclear architecture, known as laminopathies, can cause genome instability and result in premature aging syndromes (Worman, 2012).