The Hallmarks of Aging


A variety of epigenetic alterations affects all cells and tissues throughout life (Talens et al., 2012) (Figure 2B). Epigenetic changes involve alterations in DNA methylation patterns, post-translational modification of histones, and chromatin remodeling. Increased histone H4K16 acetylation, H4K20 trimethylation or H3K4 trimethylation, as well as decreased H3K9 methylation or H3K27 trimethylation, constitute age-associated epigenetic marks (Fraga and Esteller, 2007; Han and Brunet, 2012). The multiple enzymatic systems assuring the generation and maintenance of epigenetic patterns include DNA methyltransferases, histone acetylases, deacetylases, methylases and demethylases, as well as protein complexes implicated in chromatin remodeling.

Histone methylation meets the criteria for a hallmark of aging in invertebrates. Deletion of components of histone methylation complexes extends longevity in nematodes and flies (Greer et al., 2010; Siebold et al., 2010). Moreover, histone demethylases modulate lifespan by targeting components of key longevity routes such as the insulin/IGF-1 signaling pathway (Jin et al., 2011). It is not clear yet whether manipulations of histone-modifying enzymes can influence aging through purely epigenetic mechanisms, by impinging on DNA repair and genome stability, or through transcriptional alterations affecting metabolic or signaling pathways outside of the nucleus.

The sirtuin family of NAD-dependent protein deacetylases and ADP-ribosyltransferases has been studied extensively as potential anti-aging factors. Interest in this family of proteins in relation to aging stems from a series of studies in yeast, flies and worms reporting that the single sirtuin gene of these organisms, named Sir2, had a remarkable longevity activity (Guarente, 2011). Overexpression of Sir2 was first shown to extend replicative lifespan in Saccharomyces cerevisiae (Kaeberlein et al., 1999), and subsequent reports indicated that enhanced expression of the worm (sir-2.1) and fly (dSir2) orthologs could extend lifespan in both invertebrate model systems (Rogina and Helfand, 2004; Tissenbaum and Guarente, 2001). These findings have recently been called into question, however, with the report that the lifespan extension originally observed in the worm and fly studies was mostly due to confounding genetic background differences and not to the overexpression of sir-2.1 or dSir2, respectively (Burnett et al., 2011). In fact, careful reassessments indicate that overexpression of sir-2.1 only results in modest lifespan extension in C. elegans (Viswanathan and Guarente, 2011).

Regarding mammals, several studies have shown that several of the seven mammalian sirtuins can delay various parameters of aging in mice (Houtkooper et al., 2012; Sebastian et al., 2012). In particular, transgenic overexpression of mammalian SIRT1, which is the closest homologue to invertebrate Sir2, improves aspects of health during aging but does not increase longevity (Herranz et al., 2010). The mechanisms involved in the beneficial effects of SIRT1 are complex and interconnected, including a wide range of cellular actions from improved genomic stability (Oberdoerffer et al., 2008; Wang et al., 2008) to enhanced metabolic efficiency (Nogueiras et al., 2012) (see also Deregulated Nutrient-sensing). More compelling evidence for a sirtuin-mediated pro-longevity role in mammals has been obtained for SIRT6, which regulates genomic stability, NF-κB signaling and glucose homeostasis through histone H3K9 deacetylation (Kanfi et al., 2010; Kawahara et al., 2009; Zhong et al., 2010). Mutant mice deficient in SIRT6 exhibit accelerated aging (Mostoslavsky et al., 2006), whereas male transgenic mice overexpressing Sirt6 have a longer lifespan than control animals, associated with reduced serum IGF-1 and other indicators of IGF-1 signaling (Kanfi et al., 2012). Interestingly, the mitochondria-located SIRT3 has been reported to mediate some of the beneficial effects of dietary restriction (DR) in longevity, although its effects are not due to histone modifications but to the deacetylation of mitochondrial proteins (Someya et al., 2010). Very recently, overexpression of SIRT3 has been reported to reverse the regenerative capacity of aged hematopoietic stem cells (Brown et al., 2013). Therefore, in mammals, at least three members of the sirtuin family, SIRT1, SIRT3 and SIRT6, contribute to healthy aging.

The relationship between DNA methylation and aging is complex. Early studies described an age-associated global hypomethylation, but subsequent analyses revealed that several loci, including those corresponding to various tumor suppressor genes and Polycomb target genes, actually become hypermethylated with age (Maegawa et al., 2010). Cells from patients and mice with progeroid syndromes exhibit DNA methylation patterns and histone modifications that largely recapitulate those found in normal aging (Osorio et al., 2010; Shumaker et al., 2006). All of these epigenetic defects or epimutations accumulated throughout life may specifically affect the behavior and functionality of stem cells (Pollina and Brunet, 2011) (see section on Stem Cell Exhaustion). Nevertheless, thus far there is no direct experimental demonstration that organismal lifespan can be extended by altering patterns of DNA methylation.

DNA- and histone-modifying enzymes act in concert with key chromosomal proteins, such as the heterochromatin protein 1α (HP1α), and chromatin remodeling factors, such as Polycomb group proteins or the NuRD complex, whose levels are diminished in both normally and pathologically aged cells (Pegoraro et al., 2009; Pollina and Brunet, 2011). Alterations in these epigenetic factors together with the above discussed epigenetic modifications in histones and DNA-methylation determine changes in chromatin architecture, such as global heterochromatin loss and redistribution, which constitute characteristic features of aging (Oberdoerffer and Sinclair, 2007; Tsurumi and Li, 2012). The causal relevance of these chromatin alterations in aging is supported by the finding that flies with loss-of-function mutations in HP1α have a shortened lifespan, whereas overexpression of this heterochromatin protein extends longevity in flies and delays the muscular deterioration characteristic of old age (Larson et al., 2012).

Supporting the functional relevance of epigenetically-mediated chromatin alterations in aging, there is a notable connection between heterochromatin formation at repeated DNA domains and chromosomal stability. In particular, heterochromatin assembly at pericentric regions requires trimethylation of histones H3K9 and H4K20, as well as HP1α binding, and is important for chromosomal stability (Schotta et al., 2004). Mammalian telomeric repeats are also enriched for these chromatin modifications, indicating that chromosome ends are assembled into heterochromatin domains (Gonzalo et al., 2006). Subtelomeric regions also show features of constitutive heterochromatin including H3K9 and H4K20 trimethylation, HP1α binding, and DNA hypermethylation. Thus, epigenetic alterations can directly impinge on the regulation of telomere length, one of the hallmarks of aging. Moreover, in response to DNA damage, SIRT1 and other chromatin-modifying proteins relocalize to DNA breaks to promote repair and genomic stability (Oberdoerffer et al., 2008). Beyond its role in chromatin remodeling and DNA repair, SIRT1 also modulates proteostasis, mitochondrial function, nutrient-sensing pathways and inflammation (see below), illustrating the interconnectedness between aging hallmarks.

Aging is associated with an increase in transcriptional noise (Bahar et al., 2006), and an aberrant production and maturation of many mRNAs (Harries et al., 2011; Nicholas et al., 2010). Microarray-based comparisons of young and old tissues from several species have identified age-related transcriptional changes in genes encoding key components of inflammatory, mitochondrial and lysosomal degradation pathways (de Magalhaes et al., 2009). These aging-associated transcriptional signatures also affect non-coding RNAs, including a class of miRNAs (gero-miRs) that is associated with the aging process and influences lifespan by targeting components of longevity networks or by regulating stem cell behavior (Boulias and Horvitz, 2012; Toledano et al., 2012; Ugalde et al., 2011). Gain- and loss-of-function studies have confirmed the capacity of several miRNAs to modulate longevity in Drosophila melanogaster and C. elegans (Liu et al., 2012; Shen et al., 2012; Smith-Vikos and Slack, 2012).

Unlike DNA mutations, epigenetic alterations are – at least theoretically – reversible, hence offering opportunities for the design of novel anti-aging treatments (Freije and Lopez-Otin, 2012; Rando and Chang, 2012). Restoration of physiological H4 acetylation through administration of histone deacetylase inhibitors, avoids the manifestation of age-associated memory impairment in mice (Peleg et al., 2010), indicating that reversion of epigenetic changes may have neuroprotective effects. Inhibitors of histone acetyltransferases also ameliorate the premature aging phenotype and extend longevity of progeroid mice (Krishnan et al., 2011). Moreover, the recent discovery of transgenerational epigenetic inheritance of longevity in C. elegans suggests that manipulation of specific chromatin modifications in parents can induce an epigenetic memory of longevity in their descendants (Greer et al., 2011). Conceptually similar to histone acetyltransferase inhibitors, histone deacetylase activators may conceivably promote longevity. Resveratrol has been extensively studied in relation to aging and among its multiple mechanisms of action is the upregulation of SIRT1 activity, but also other effects associated with energetic deficits (see Mitochondrial Dysfunction).

There are multiple lines of evidence suggesting that aging is accompanied by epigenetic changes, and that epigenetic perturbations can provoke progeroid syndromes in model organisms. Furthermore, SIRT6 exemplifies an epigenetically relevant enzyme whose loss-of-function reduces longevity and whose gain-of-function extends longevity in mice (Kanfi et al., 2012; Mostoslavsky et al., 2006). Collectively, these works suggest that understanding and manipulating the epigenome holds promise for improving age-related pathologies and extending healthy lifespan.

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