Organismal aging is influenced by a multitude of intrinsic and extrinsic factors, and heterochromatin loss has been proposed to be one of the causes of aging. However, the role of heterochromatin in animal aging has been controversial. Here we show that heterochromatin formation prolongs lifespan and controls ribosomal RNA synthesis in Drosophila. Animals with decreased heterochromatin levels exhibit a dramatic shortening of lifespan, whereas increasing heterochromatin prolongs lifespan. The changes in lifespan are associated with changes in muscle integrity. Furthermore, we show that heterochromatin levels decrease with normal aging and that heterochromatin formation is essential for silencing rRNA transcription. Loss of epigenetic silencing and loss of stability of the rDNA locus have previously been implicated in aging of yeast. Taken together, these results suggest that epigenetic preservation of genome stability, especially at the rDNA locus, and repression of unnecessary rRNA synthesis, might be an evolutionarily conserved mechanism for prolonging lifespan. Aging is characterized by a progressive decline in vitality and tissue function, leading to the demise of the organism. Many models have been proposed to explain the aging phenomenon. Among the many competing and/or overlapping models is the heterochromatin loss model of aging, which posits that heterochromatin domains (which are set up early in embryogenesis) are gradually lost with aging, resulting in de-repression of silenced genes and aberrant gene expression patterns associated with old age. In this paper, we genetically tested the role of heterochromatin in Drosophila aging. We find that heterochromatin levels indeed affect animal lifespan and that heterochromatin represses, among other things, rRNA transcription. Loss of heterochromatin thus leads to an increase in rRNA transcription, a rate-limiting step in ribosome biogenesis and protein synthesis. We suggest that the biological functions of heterochromatin formation include controlling rRNA transcription, which might play an important role in general protein synthesis and animal longevity.

Reduced protein kinase A (PKA) activity in anterior imaginal disc cells leads to cell-autonomous induction of decapentaplegic (dpp), wingless (wg), and patched (ptc) transcription that is independent of hedgehog (hh) gene activity. The resulting nonautonomous adult wing and leg pattern duplications are largely due to induced dpp and wg expression and resemble phenotypes elicited by ectopic hh expression. Inhibition of PKA in anterior cells close to the posterior compartment can substitute for hh activity to promote growth of imaginal discs, whereas overexpression of PKA can counteract transcriptional induction of ptc by hh in these cells. PKA therefore appears to be an integral component of the mechanism by which hh regulates the expression of key patterning molecules in imaginal discs.

The aging field is replete with theories. Over the past years, many distinct, yet overlapping mechanisms have been proposed to explain organismal aging. These include free radicals, loss of heterochromatin, genetically programmed senescence, telomere shortening, genomic instability, nutritional intake and growth signaling, to name a few. The objective of this Point-of-View is to highlight recent progress on the “loss of heterochromatin” model of aging and to propose that epigenetic changes contributing to global heterochromatin loss may underlie the various cellular processes associated with aging.

The JAK/STAT pathway has pleiotropic roles in animal development, and its aberrant activation is implicated in multiple human cancers^1,2,3. JAK/STAT signaling effects have been attributed largely to direct transcriptional regulation by STAT of specific target genes that promote tumor cell proliferation or survival. We show here in a Drosophila melanogaster hematopoietic tumor model, however, that JAK overactivation globally disrupts heterochromatic gene silencing, an epigenetic tumor suppressive mechanism⁴. This disruption allows derepression of genes that are not direct targets of STAT, as evidenced by suppression of heterochromatin-mediated position effect variegation. Moreover, mutations in the genes encoding heterochromatin components heterochromatin protein 1 (HP1) and Su(var)3-9 enhance tumorigenesis induced by an oncogenic JAK kinase without affecting JAK/STAT signaling. Consistently, JAK loss of function enhances heterochromatic gene silencing, whereas overexpressing HP1 suppresses oncogenic JAK-induced tumors. These results demonstrate that the JAK/STAT pathway regulates cellular epigenetic status and that globally disrupting heterochromatin-mediated tumor suppression is essential for tumorigenesis induced by JAK overactivation.