Abstract
During aging, changes in chromatin state that alter gene transcription have been postulated to result in expression of genes that are normally silenced, leading to deleterious age-related effects on cellular physiology. Despite the prevalence of this hypothesis, it is primarily in yeast that loss of gene silencing with age has been well documented. We use a novel position effect variegation (PEV) reporter in Drosophila melanogaster to show that age-related loss of repressive heterochromatin is associated with loss of gene silencing in metazoans and is affected by Sir2, as it is in yeast. The life span-extending intervention, calorie restriction (CR), delays the age-related loss of gene silencing, indicating that loss of gene silencing is a component of normal aging. Diet switch experiments show that such flies undergo a rapid change in their level of gene silencing, demonstrating the epigenetic plasticity of chromatin during aging and highlighting the potential role of diet and metabolism in chromatin maintenance, Thus, diet and related interventions may be of therapeutic importance for age-related diseases, such as cancer.
Highlights
The phenotypic plasticity of aging highlights the importance of epigenetic factors such as chromatin remodeling in determining longevity
To test the hypothesis that loss of repressive heterochromatin marks with age leads to a loss of gene silencing in regions associated with repressive heterochromatin, we utilized a novel position effect variegation (PEV) reporter containing a heat shock-inducible HS-lacZ gene that allows for visualization of gene expression at the level of single cells, in individual tissues, at any time during the life of the adult fly [27, 28]
The finding of age-associated remodeling of chromatin in repressive constitutive heterochromatin regions in flies and mammals suggests that a loss of gene silencing with age in these regions could play a role in metazoan aging [6, 23]
Summary
The phenotypic plasticity of aging highlights the importance of epigenetic factors such as chromatin remodeling in determining longevity. Changes in chromatin state can alter gene transcription, resulting in expression of genes that are normally silenced, which has been postulated to result in deleterious effects on cellular physiology [1,2,3,4,5,6]. The two major classes of chromatin, euchromatin and heterochromatin, differ in their degree of compaction and their accessibility for essential cellular functions such as gene transcription. In Drosophila, the major constitutive heterochromatin regions are the pericentric regions of 3L, 2L, 2R, and the 4th and Y chromosomes. Nematodes and flies have shown changes in chromatin with age, and most excitingly, have demonstrated that molecular genetic and pharmacological interventions that are predicted to preserve or restore an earlier, more “youthful” chromatin state contribute to extend longevity [2, 3, 719]
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