Epigenetics and aging

Abstract

Over the past decade, a growing number of studies have revealed that progressive changes to epigenetic information accompany aging in both dividing and nondividing cells. Functional studies in model organisms and humans indicate that epigenetic changes have a huge influence on the aging process. These epigenetic changes occur at various levels, including reduced bulk levels of the core histones, altered patterns of histone posttranslational modifications and DNA methylation, replacement of canonical histones with histone variants, and altered noncoding RNA expression, during both organismal aging and replicative senescence. The end result of epigenetic changes during aging is altered local accessibility to the genetic material, leading to aberrant gene expression, reactivation of transposable elements, and genomic instability. Strikingly, certain types of epigenetic information can function in a transgenerational manner to influence the life span of the offspring. Several important conclusions emerge from these studies: rather than being genetically predetermined, our life span is largely epigenetically determined; diet and other environmental influences can influence our life span by changing the epigenetic information; and inhibitors of epigenetic enzymes can influence life span of model organisms. These new findings provide better understanding of the mechanisms involved in aging. Given the reversible nature of epigenetic information, these studies highlight exciting avenues for therapeutic intervention in aging and age-associated diseases, including cancer.

Keywords: Epigenetics; aging; chromatin; histones.

Fig. 1. Overview of epigenetic changes during aging.

In young individuals, the cells within each cell type have a similar pattern of gene expression, determined in large part by each cell having similar epigenetic information. During aging, the epigenetic information changes sporadically in response to exogenous and endogenous factors. The resulting abnormal chromatin state is characterized by different histone variants being incorporated, altered DNA methylation patterns, and altered histone modification patterns, resulting in the recruitment of different chromatin modifiers. The abnormal chromatin state in old cells includes altered transcription patterns and transcriptional drift within the population. The abnormal chromatin state in old cells also leads to new transposable elements being inserted into the genome and genomic instability, including DNA mutations.

Fig. 2. Alterations in chromatin structure during aging leads to activation of retrotransposons.

The schematic at the top depicts the reduction in the level of bulk histone proteins during aging (for example, as seen in budding yeast), leading to a more open chromatin structure and subsequent transcriptional activation of the normally silenced Ty elements. The resulting transcripts from the retrotransposable elements are reverse-transcribed into cDNAs that reinsert elsewhere into the genome of old cells. Overexpression of histones reverses the loss of histones, reduces Ty retrotransposition, and extends replicative life span. The schematic in the middle depicts the heterochromatin reorganization that occurs during aging, as seen, for example, in tissue culture cells during replicative senescence. The normally heterochromatinized retrotransposable elements become euchromatinized, leading to their transcription and transposition elsewhere into the genome. Knockdown of the Alu element transcripts in human adult stem cells leads to escape from senescence and reduced genomic instability. The schematic at the bottom depicts the heterochromatin reorganization that occurs in mouse tissues during aging and is accompanied by activation of retrotransposable elements (RTEs). Calorie restriction reduces the level of retrotransposition in the aged mice genome.

Fig. 3. Summary of DNA methylation changes during aging.

Young mammalian cells are characterized by DNA hypermethylation over the genome, with the exception of CpG islands within the promoters of expressed genes. In particular, DNA repeats, such as LINE, SINE, and long terminal repeat (LTR) transposable elements, are heavily DNA-methylated, helping to maintain them in a constitutive heterochromatin state. During aging, there is general DNA hypomethylation over the genome, which mostly occurs in a stochastic manner within the cell population. Loss of DNA methylation leads to activation of normally silenced DNA sequences like the transposable elements. However, DNA methylation also increases in a nonstochastic manner over the CpG islands of certain genes, correlating with their heterochromatinization and silencing.

Fig. 4. Schematic showing how some external interventions trigger longevity, often at least partly through stimulating autophagy.

The pink writing refers to dietary, chemical, or therapeutic interventions that can extend life span, in at least some organisms (described in the text). Arrows indicate stimulating effects, and blocked lines indicate inhibitory effects. This schematic is not meant to be exhaustive but highlights the pathways that alter the epigenetic information and autophagy.