Aging by epigenetics—A consequence of chromatin damage?

Abstract

Chromatin structure is not fixed. Instead, chromatin is dynamic and is subject to extensive developmental and age-associated remodeling. In some cases, this remodeling appears to counter the aging and age-associated diseases, such as cancer, and extend organismal lifespan. However, stochastic non-deterministic changes in chromatin structure might, over time, also contribute to the break down of nuclear, cell and tissue function, and consequently aging and age-associated diseases.

Basic concepts of epigenetics

“…150 While HP1α and HP1β are associated with silencing, other forms of HP1, such as HP1-type C, are found in euchromatin interacting with FACT subunit SSRP1, which is responsible for guiding FACT toward active genes to promote nucleosomal instability by H2AX exchange and RNAP activation. [103][104][105]151,152 Macromolecular Chromatin Euchromatin. At the macromolecular level, transcriptionally active euchromatin is housed at the inner nucleoplasm/center of chromosome territories, while silenced heterochromatin is arranged at the outer circular perimeter of the nuclear membrane.…”

“…151 At the nuclear periphery, silenced heterochromatin contains a combination of MBD proteins, repression complexes, H3K9me2, H3K9me3, HP1α, Suv39 h1 and methylated DNA. 152 Within heterochromatin, Suv39 h1 can become a target of the SIRT enzyme, which maintains deacetylation at H4K16, contributing toward the reinforced silencing within heterochromatin. 155 DNA methylation within heterochromatin must be sustained, as its loss could initiate the dismantlement of chromatin, acetylation of histone H4, and H3K4 di-and trimethylation, all events associated with relaxation of nucleosomes.…”

Inflammation, Aging and Cancer: Friend or Foe?

“…Aging process is also associated with minor or major changes in immune response profiles and co-expression and co-existence of mismatched or misdirected inflammatory mediators (e.g., TNF-, IL-6, IFN-,, IFNs, PGE2, etc) features that are characteristics of immunoscenescence involved in a wide range of chronic diseases (Davalos et al 2010, Ginaldi et al, 2005, Chung et al, 2008, Khatami 2008, 2011a, Nagai et al, 2010, Ren et al, 2009, Romanyukha and Yashin 2003, Sansoni et al, 2008, Sedivy et al, 2008, Serbina et al, 2008, Siffrin et al, 2007, Zhang 2010 (Figures 3 and 4). Briefly, low grade (unresolved or subclinical) inflammation and longevity are known as comorbidity and co-mortality risk factors in the genesis and progression of nearly all chronic illnesses.…”

Changes in Chromatin Structure along Aging

“…These regions of heterochromatin accumulate along aging, even in cells with generalized chromatin unpackaging, thus leading to the theory that, instead of increased or decreased chromatin condensation, aging comes followed by heterochromatin redistribution [55].…”

“…Concluding, active or stochastic, several epigenetic events are associated with aging, and can be responsible for age-associated chromatin remodeling [55]. Age-related epigenetic changes have a very strong negative impact on adult stem cell function and proliferative capacity, thus leading to impaired tissue renewal and organismal aging [22,76].…”