A complex interplay between multiple biological effects shapes the aging process. The advent of genome-wide quantitative approaches in the epigenetic field has highlighted the effective impact of epigenetic deregulation, particularly of DNA methylation, on aging. Age-associated alterations in DNA methylation are commonly grouped in the phenomenon known as "epigenetic drift" which is characterized by gradual extensive demethylation of genome and hypermethylation of a number of promoter-associated CpG islands. Surprisingly, specific DNA regions show directional epigenetic changes in aged individuals suggesting the importance of these events for the aging process. However, the epigenetic information obtained until now in aging needs a re-consideration due to the recent discovery of 5-hydroxymethylcytosine, a new DNA epigenetic mark present on genome. A recapitulation of the factors involved in the regulation of DNA methylation and the changes occurring in aging will be described in this review also considering the data available on 5 hmC.

DNA methylation is currently the most promising molecular marker for monitoring aging and predicting life expectancy. However, the mechanisms underlying age-related DNA methylation changes remain mostly undiscovered. Here we discuss the current knowledge of the dynamic nature of DNA epigenome landscape in mammals, and propose putative molecular mechanisms for aging-associated DNA epigenetic changes. Specifically, we describe age-related variations of methylcytosine and its oxidative derivatives in relation to the dynamics of chromatin structure, histone post-translational modifications and their modulators. Finally, we are proposing a conceptual framework that could explain the complex nature of the effects of age on DNA methylation patterns. This combines the accumulation of DNA methylation noise and also all of the predictable, site-specific DNA methylation changes. Gathering information in this area would pave the way for future investigation aimed at establishing a possible causative role of epigenetic mechanisms in aging.

Glutathione (GSH) is the predominant low-molecular-weight antioxidant with a ubiquitous distribution inside the cell. The steady-state level of cellular GSH is dependent on the balance between synthesis, hydrolysis, recycling of glutathione disulphide (GSSG) as well as cellular extrusion of reduced, oxidized, or conjugated-forms. The augmented oxidative stress typical of cancer cells is accompanied by an increase of glutathione levels that confers them growth advantage and resistance to a number of chemotherapeutic agents. Targeting glutathione metabolism has been widely investigated for cancer treatment although GSH depletion as single therapeutic strategy has resulted largely ineffective if compared with combinatorial approaches. In this review, we circumstantiate the role of glutathione in tumour development and progression focusing on how interfering with different steps of glutathione metabolism can be exploited for therapeutic purposes. A dedicated section on synthetic lethal interactions with GSH modulators will highlight the promising option of harnessing glutathione metabolism for patient-directed therapy in cancer.

PARylation [poly(ADP-ribosyl)ation] is involved in the maintenance of genomic methylation patterns through its control of Dnmt1 [DNA (cytosine-5)-methyltransferase 1] activity. Our previous findings indicated that Ctcf (CCCTC-binding factor) may be an important player in key events whereby PARylation controls the unmethylated status of some CpG-rich regions. Ctcf is able to activate Parp1 [poly(ADP-ribose) polymerase 1], which ADP-ribosylates itself and, in turn, inhibits DNA methylation via non-covalent interaction between its ADP-ribose polymers and Dnmt1. By such a mechanism, Ctcf may preserve the epigenetic pattern at promoters of important housekeeping genes. The results of the present study showed Dnmt1 as a new protein partner of Ctcf. Moreover, we show that Ctcf forms a complex with Dnmt1 and PARylated Parp1 at specific Ctcf target sequences and that PARylation is responsible for the maintenance of the unmethylated status of some Ctcf-bound CpGs. We suggest a mechanism by which Parp1, tethered and activated at specific DNA target sites by Ctcf, preserves their methylation-free status.

Epigenetic events include reversible modifications of DNA and histone tails driving chromatin organization and thus transcription. The epigenetic regulation is a highly integrated process underlying the plasticity of the genomic information both in the context of complex physiological and pathological processes. The global regulatory aspects of epigenetic events are largely unknown. PARylation and PARP1 are recently emerging as multi-level regulatory effectors that modulate the topology of chromatin by orchestrating very different processes. This review focuses in particular on the role of PARP1 in epigenetics, trying to build a comprehensive perspective of its involvement in the regulation of epigenetic modifications of histones and DNA, contextualizing it in the global organization of chromatin domains in the nucleus.