Scientists at Brown University have found a way to measure the effects of aging by measuring chromatin, a structure along strands of DNA that either silences or permits gene expression. In several newly published experiments they show that gene silencing via chromatin in fruit flies declines with age.
They also demonstrated that administering life span-extending measures to the flies, such as switching them to a lower-calorie diet or increasing expression of the protein Sir2, restores the observed loss of gene silencing due to age.
“For many years it has been suggested that one of the issues that occurs with age, leading to cellular dysfunction, is that some genes that should be silenced lose that silencing,” explained Stephen Helfand, M.D., senior author of the study (“Dietary and genetic effects on age-related loss of gene silencing reveal epigenetic plasticity of chromatin repression during aging”) published online in Aging. “It hasn't been very well demonstrated to take place other than in yeast. So what we were trying to do in flies is see whether genes that are normally repressed lose their repression.”
The answer they report is that the phenomenon is true in flies, too.
To achieve those findings, Dr. Helfand and lead author Nan Jiang exploited a phenomenon called “position effect variegation.” PEV is the variation of a gene’s expression that comes from the gene existing at the border between euchromatin, a loose wrapping of DNA that readily permits gene expression, and heterochromatin, a tight wrapping that keeps it locked down.
The scientists hypothesized that as organisms age, heterochromatin might recede, allowing more genes that had once been silenced to become exposed for expression.
To test whether chromatin gene silencing declines with age, the researchers inserted “reporter” genes right at the border between heterochromatin and euchromatin in two specific parts of the flies’ genomes. The reporter genes have the useful property of showing blue when expressed. If they aren’t being silenced, their expression can be verified simply by applying a brief pulse of heat to the fly. The technique gave the researchers an indicator of chromatin-related gene expression in individual cells, in individual tissues at any time during the life cycle of the fly.
“We use a novel position effect variegation 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,” write the investigators in the journal article. “The life span-extending intervention, calorie restriction, 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.”
That result suggests that while gene silencing appears to erode with age naturally, it can be throttled back and forth with certain interventions.
“This gets at one molecular mechanism by which aging might be put off,” said Dr. Helfand, who teaches in Brown's department of molecular biology, cell biology, and biochemistry.
The fundamental biology he's observed in flies has a good chance of also being at play in humans, according to Dr. Helfand.
Still, humans would not tolerate interventions that work for flies, such as severe calorie restriction. Instead, the research suggests a possible line of research to develop more practical interventions. Finding benign ways to mimic the effects of calorie restriction to restore overall gene silencing, for instance, could ultimately become an alternative to treating the effects of unwanted expression of individual genes in aging patients.