Chromatin structure as a mediator of aging

Abstract

The aging process is characterized by gradual changes to an organism's macromolecules, which negatively impacts biological processes. The complex macromolecular structure of chromatin regulates all nuclear processes requiring access to the DNA sequence. As such, maintenance of chromatin structure is an integral component to deter premature aging. In this review, we describe current research that links aging to chromatin structure. Histone modifications influence chromatin compaction and gene expression and undergo many changes during aging. Histone protein levels also decline during aging, dramatically affecting chromatin structure. Excitingly, lifespan can be extended by manipulations that reverse the age-dependent changes to chromatin structure, indicating the pivotal role chromatin structure plays during aging.

Figure 1. Alterations to Chromatin Structure During Aging in Eukaryotes

A) Budding yeast undergo changes to histone levels and histone modifications with increased replicative age. Additionally, changes to chromatin modifying proteins and organic molecules that impact chromatin structure occur with increased age. B) Mammalian cells experience changes in histone modifications during successive mitotic divisions in vitro. Levels of histones, histone modifications, and chromatin modifying proteins are altered during the aging process.

Figure 2. Histones Levels Decline During Aging

Young budding yeast cells have high levels of histones that facilitates proper chromatin assembly and histone exchange. With increasing age, histone levels decline, which may cause chromatin to be more open and have reducing histone exchange. This potentially leads to inappropriate access to the DNA, disrupting transcriptional regulation. Increasing the histone supply may allow the formation of tighter chromatin structure, thereby restoring transcriptional regulation and causing lifespan to be extended.

Figure 3. Spermidine Treatment Extends Lifespan via Chromatin Alterations

During aging, yeast experience a decline in polyamine levels that disrupts cellular functions and leads to necrotic death. The addition of spermidine causes a global decrease in H3 N-terminal acetylation and increases the expression of autophagic genes. Autophagic responses reduce the accumulation of damaged molecules and delay the onset of necrosis, extending lifespan.

Figure 4. Persistent DNA Damage Signals From Shortened Telomeres Disrupt Chromatin Structure

Young fibroblast cells have long telomeres and high levels of histones and chromatin modifying proteins. Successive mitotic divisions leads to shortened telomeres that cause persistent DNA damage signals. Asf1 and CAF-1 levels are reduced which disrupts chromatin structure. Reduced SLBP levels reduce the stability of the histone mRNAs during aging. Chromatin structure is likely to be more open in some regions of the genome, resulting in inappropriate access to the DNA and misregulated transcription. Reactivating telomerase extends the telomeres and halts the DNA damage signal, causing protein levels and chromatin structure to be restored.