Sunday, 13 September 2009

Aging by Epigenetics


ResearchBlogging.orgWe know that organismal longevity and aging is caused by a lot of interacting factors such as nuclear and mitochondrial genome mutations, shortened telomeres, oxidative damage to DNA and other macromolecules, senescence, apoptosis and many more. This review discusses another possible determinant of aging that is 'epigenetics'. We have seen in the earlier post that epigenetics refers to changes in the DNA and histones which are heritable through cell divisions, but do not involve any change in the sequence of the DNA. 

Chromatin is broadly divided into two types, euchromatin and heterochromatin. Euchromatin is decondensed during interphase and is relatively transcriptionally active. Heterochromatin on the other hand remains compact and condensed and is transcriptionally inactive. It is further divided into constitutive and facultative. Constitutive heterochromatin is present in the telomer and centromere and appears to be fixed or irreversible throughout the life time of an organism. Facultative heterochromatin on the other hand, is made as a part of regulated cell differentiation process or other changes in cell phenotype. For example, a single X chromosome is silenced in female mammalian cells for dosage compensation.

However, despite this apparent clear distinction between euchromatin and heterochromatin, it is now being understood that chromatin structure is highly dynamic and stochastic. Essential processes, such as DNA replication, transcription and repair all involve disruption of the very compact structure of DNA. The proteins bound to the chromatin are also not static but exhibit relatively high 'on' and 'off' binding states even in the 'fixed' heterochromatin. It has also been showed that, formation of heterochromatin depends on a degree of transcription, which contributes to heterochromatinization through the RNAi pathway. Thus the telomeric heterochromatin is also shown to be transcribed. Thus heterochromatin is not a static entity.

Is aging associated with epigenetic changes?

The enzymes Histone acetyl teransferases (HATs) and Histone deacetylases (HDACs) respectively determine the steady-state level of histone acetylation. In S.cerevisiae, inactivation of a HDAC, Sir2, decreases replicative lifespan while activation extends it. The anti aging effects of Sir2 in yeast are due to translocation of a Sir2 containing protein complex from telomeres to ribosomal DNA (rDNA) repeats. These repeats are prone to recombination to form extrachromosomal rDNa circles (ERCs), which curtail yeast lifespan. However, Sir2 mediated histone deactylation and heterochromatization, prevents formation of ERCs and thus extends lifespan of yeast. Thus, this epigenetic redistribution counteracts organismal aging. Orthologs of Sir2 have been found in many species like nematodes, flies and even mice. Thus its anti aging role seems to have been conserved throughout evolution.

In mammals, it has been seen that there is a reduction in genomic DNA methylation, with age. It occurs mostly at repetitive DNA sequences, predominantly in regions of constitutive heterochromatin. Since methylation induces silencing of genes, this change will promote deheterochromatinization of these regions. However DNA methylation increases at specific sites called the CpG islands. These are CG rich sequences, some of them present in the promoter regions, which can get methylated. Methylation also increases in the histone 4 on the lysine 20 residue (H4K20) in rat liver and kidney, with age. Like DNA methylation H4K20 methylation is also linked to gene repression, supporting the notion that heterochromatin accumulates in some sites atleast with aging.
One of the histone chaperones, HIRA, shows increased levels of expression in aging baboon skin. This is shown to have a evolutionary conserved role in formation of heterochromatin.
These observations suggest that mammalian aging is associated with chromatin remodelling. In particular, there is a global decrease in DNA methylation, but an increase at specific sites on the genome.

Cellular senescence, is characterized by irreversible proliferation arrest. This may arise due to excessive cell divisions and shortening of the telomere length. Due to this, most human cells have a finite proliferative lifespan. Senescent cells or molecular markers of senescent phenotype increase during aging. Cellular senescence is also well established tumor suppression process, because it can prevent proliferation and neoplastic progression of cells harboring neoplastic lesions. Senescent cells also show chromatin remodeling. Many senescent cells form domains of facultative heterochromatin, called Senescence Associated Heterochromatin Foci (SAHF), which are visibly more condensed that interphase chromatin. These foci have been proposed to silence proliferation promoting genes. Accumulation of SAHF has been associated with aging. Formation of SAHF requires presence of HIRA, which has been shown to be upregulated in aging baboon skin. Also it seems that in cellular senescence too, the constitutive heterochromatin regions are deheterochromatinized. Thus like tissue aging, cellular senescence also is accompanied by redistribution of heterochromatin, from constitutive heterochromatin to other normally euchromatic sites.

Consequences of age-associated epigenetic changes

Studies going back to 1960s indicate that aging is associated with cell aneuploidy. Proper chromosome segregation is dependent on pericentromeric heterochromatin sturcture. Hence cecreased methylation and deheterochromatinization may lead to faulty chromosome segregation and associated aneuploidy. Aneuploidy confers various altered cell phenotypes including a proliferative impairment, which might contribute to decreased tissue renewal capacity with age. It may also give rise to cancer, for which age is the biggest risk factor. Some of the age associated changes in gene expression may also occur due to epigenetics. Methylation of CpG islands is a well described mode of silencing some tumor suppressor genes. A tissue wide age associated methylation of CpG may be an early causative event in the development of neoplasms.

From the discussion it is apparent that chromatin does undergo change with aging in organisms as diverse as yeast and mammals. However with the exception of Sir2 in yeast, the extent to which this impacts the aging process is not yet defined. Some age associated epigenetic alterations in mammals like formation of SAHF, might extend life span by suppressing age associated diseases like cancer. In sum the effects of chromatin on aging are likely to be complex. A pre requisite to properly understanding the contribution of epigenetics to aging is to better understand the specific cell, tissue and system wide malfunctions that are responsible for aging phenotypes like osteoporosis, sarcopenia, cancer and many others. Then it will be feasible to dissect out the contribution to each phenotype of each candidate epigenetic determinant, like global methylation, CpG island methylation and SAHF.

Reference

Sedivy JM, Banumathy G, & Adams PD (2008). Aging by epigenetics--a consequence of chromatin damage? Experimental cell research, 314 (9), 1909-17 PMID: 18423606


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