Structural Biochemistry/Chromatin and Aging

=Chromatin as a Factor in the Aging Process= In mammals, aging is a complex event that is probably a result of a wide variety of molecular changes interacting with each other. In culture it has been observed that cells undergo an irreversible cell cycle arrest known as replicative senescence which is believed to reflect the aging process at a cellular level. Recent studies have shown that in skin biopsies that these senescent cells accumulate during aging and can represent up to 15% of the total cells. Eukaryotic cells histones and non-histone proteins that form chromatin fiber are closely associated with DNA and the determination of the senescent phenotype has been linked with chromatin involvement.

Introduction
During embryogenesis, chromatin states are what allow for the development of an organism. Evidence shows that it is possible that is that the organization of chromatin deteriorates throughout the lifespan of an organism. New evidence suggests that this chromatin deterioration could have an effect on the way that organisms age.

Chromatin is a mass of genetic material composed of DNA, proteins and RNA complex that is located inside of the nucleus comprised of about 146bp of DNA wrapped around an octamer of histones. There are two divisions of chromatin into heterochromatin and euchrochromatin with heterochromatin being further divided into the two types, constitutive and facultative heterochromatin. For awhile Chromatin has been known to have a correlative relation to just about every process in the mammalian nucleus, but recent advances in technology allowing loss-of-function experiments and genome-wide approaches have given light to the identification of a causal relationship between specific changes in the chromatin structure and the aging phenotype. Aging in this case is the progressive decline in vitality that eventually ends in death and an aging phenotype being some outward sign usually associated with aging such as osteoporosis, sarcopenia, declining immune function, cancer and many others. Chromatin structure is dynamic and goes through extensive developmental and age-associated remodeling that appear to counter the aging and age-associated diseases, such as cancer, and extend the organismal lifespan. However, non-deterministic changes in the chromatin structure might also be a contributing factor to the breakdown of nuclear, cell and tissue function and ultimately causing the very symptoms of aging. Evidence points to the loss of heterochromatin structure, altered patterns of histone modification, loss of key heterochromatin proteins and increased levels of persistent DNA damage to be common signs of both normal and premature aging.

Chromatin as a potential regulator in aging
A characteristic of aging is the loss of homeostatic mechanisms that once acted to offset the macromolecular wear and tear that occurs during an organism’s lifetime. Chromatin, being a macromolecule of the cell, is exposed to stresses that can affect both its structure and function. There is a proposal stating that aging is due to the change from a youthful chromatin configuration to one that helps bring about molecular signatures of aging. One example of this can be found in monozygotic twins, whose chromatin modification patterns diverge increasingly with age. These chromatin changes might be the base to subtle phenotypic variations that become more prominent as twins (as well as closely related individuals) age. This evidence suggests that aging may be the job of chromatin-based epigenetic regulatory mechanisms. The alteration of chromatin structure with regards to aging has been studied in depth; most importantly noted is the reshaping of chromatin during cellular senescence. Cellular senescence is an irreversible state of cell cycle arrest. This arrested state of the cell cycle is hypothesized to reflect aging.

Age-associated deregulation of chromatin modifiers
A common feature of aging is random cell-to-cell variation in gene expression. Also, differences in the expression of chromatin modifiers have been found throughout senescence and aging. This changes the distribution and levels of chromatin modifications throughout the nucleus and at aging-associated loci, leading to the activation of age-promoting physiological responses.

In mammals, there is an age associated decline in genomic DNA methylation at certain DNA sequences which has been theorized to promote the deheterochromatinization of these regions. However there is a tendency for DNA methylation to increase at certain sites as aging progresses which supports the idea that heterochromatin accumulates with tissue aging at these sites. Particularly in locations where the histone chaperone HIRA has been observed. Histone chaperones are histone binding proteins involved in the assembly of histones into nucleosomes and their activity has been used for the determination of chromatin structure and function. In particular HIRA has been linked to to transcription activation and is known to have an evolutionarily conserved role in heterochromatin formation. Experimental data has shown that HIRA either increases in expression or undergoes regulation in aging baboon skin. Given that there has been both an observed overall decline in heterochromatin, but an increase at specific sites it has been suggested that aging is also associated with remodeling the chromatin structure.

SIRT1 and SIRT6 in DNA repair and aging
Silent information regulator 2 (Sir2) has been found to aid in the process of silencing rRNA genes and telomeres. As yeast age (Sir2 are found in yeast), this ability is weakened. This weakened ability results in excision of rDNA arrays from the genome, which creates circular episomal DNAs. If Sir2 continues to function normally, these arrays are inhibited and the lifespan of yeast is extended. Sir2 does not seem to directly affect the lifespan of some organisms, but studies on budding yeast by Karberlein have shown that the silencing protein Sir2 is a limiting component of longevity; deletions of Sir2 shorten life span and an extra copy of the gene increases life span. Some evidence suggests that Sir2 homologs SIRT1 and SIRT6 have very important roles in managing the response to DNA damage and cellular stress. Orthologs of Sir2 have anti-aging functions in many species including nematodes and flies, but the mechanisms do not appear to involve the rDNA circles in these species.

SIRT1 makes changes to chromatin by deacetylation of H1K26, H3K9, and H4K16. Findings from experiments on mice show that SIRT1 binds to repetitive elements. After oxidative DNA damage, SIRT1 performs genome-wide redistribution to damage sites. At damage sites, SIRT1 deacetylates H1, advancing DNA repair. Expression of SIRT1 declines with age and has been correlated with premature aging in mice. SirT1's actual effect on mammalian aging has yet to be established however since it contains many non-chromatin substrates.

SIRT6 also seems to be involved in repairing damaged DNA, further evidenced by the fact that SIRT6-deficient human cells are more affected by DNA damaging agents. SIRT6 helps in homologous recombination by deacetylating the C-terminal binding protein interacting protein. SIRT6 also directs PARP-1, which is one of the first responders to DNA damage. Low levels of SIRT6 annul Werner helicase function, promoting telomere dysfunction.