Heterochromatin theory for aging
The heterochromatin theory of aging postulates that heterochromatin domains, which are set up in early embryogenesis, are gradually lost with age. The loss of heterochromatin results in an aberrant gene expression, which is associated with senescence. Heterochromatin domains are maintained by heterochromatin binding proteins and chromatin-modifying enzymes, like histone trans-acetylase and histone deacetylase. This has the effect that a great majority of genes residing in heterochromatin domains are either silenced or partially suppressed, due to an altered accessibility of transcription factors (Villeponteau, 1997). Animal models show that individuals with decreased heterochromatin levels exhibit substantial reduction of lifespan, whereas increased heterochromatin prolongs lifespan (Larson et al., 2012).
Global heterochromatin loss starts, when there is genomic instability, which destabilizes heterochromatin structure. It is known that heterochromatin is important for chromosomal packaging and segregation (indeed in Drosophila heterochromatin stabilizes repeated DNA sequences, including the rDNA locus) (Larson et al., 2012). This alteration in the genomic stability is done due oxidative stress, thus DNA damage (free-radical theory for aging and nutritional intake models), histone hyperacetylation, and loss of methyl-cytosine. But genomic instability is not the only cause for the heterochromatin loss. Simple thing like the cell division (DNA replication and telomere shortening) also leads to the heterochromatin loss (Villeponteau, 1997).
It has previously been reported that loss of heterochromatin at the rDNA locus disrupts the nucleolar morphology and causes the formation of extrachromosomal circular (ECC) DNA in D. melanogaster. ECC are formed through aberrant recombination at the rDNA locus and have been shown to contribute to aging in yeast. To test if abundance of hetrochromatin affects aging in D. melanogaster by suppressing rDNA locus, Larson et al. (2012) manipulated expression of heterochromatin protein 1 (HP1). They showed that over-expression of HP1 throughout life prolonged lifespan through delaying or even preventing heterochromatin loss, thus keeping ribosomal RNA synthesis repressed. When they reduced the level of HP1, lifespan was shortened. They believe that epigenetic preservation of genome stability and suppression of rDNA transcription may be an evolutionary conserved mechanism for longevity (Larson et al., 2012).
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