Heterochromatin is the name given to the more tightly packed structural arrangement of chromosomal DNA in the cell nucleus. Changes in the way in which chromosomes are arranged within the cell nucleus are far from simple and, like various epigenetic modifications to DNA, have considerable influence over the pace of production of proteins. Circulating amounts of various proteins are the switches and dials of cellular machinery, changing constantly, determining behavior, and participating in countless feedback loops to further alter the production of other proteins. Every aspect of the cell plays a part in this dance, including the changing structural arrangement of nuclear DNA: it is characteristic of evolved complex systems that any given discrete part of the machine might be involved in a score of different important mechanisms.
It has been suspected for some time that heterochromatin has some influence on aging. Indeed, why shouldn't it? There are any number of ways to increase or shorten life span by altering levels of specific proteins in lower animals ranging from flies to mice. Alterations to the packing structure of DNA are likely to have many further effects, including changing levels of proteins known to alter the workings of longevity-associated processes. When researchers found a way to alter the proportion of DNA packed as heterochromatin in flies, they could dial up and dial down lifespan to a modest degree. There is considerable speculation as to why this works, but no definitive proof of the underlying mechanism as of yet. Sadly there is definitely an upper ceiling on the process: too much heterochromatin and the flies die.
Another interesting line of research links modifications to heterochromatin levels and cellular senescence. Increasing numbers of senescent cells with old age is well known to be a cause of degenerative aging, but here again the nature of the link with changing packaging of nuclear DNA is all very speculative. Much more research is needed to answer even the most basic of questions regarding how and why with any authority.
It is the case that researchers have used the so-called accelerated aging conditions of progeria and Werner syndrome, among others, to explore concepts and mechanisms that might be of relevance to normal aging. I say "so-called" because these conditions only have the superficial appearance of rapid aging: their underlying causes are in fact largely unrelated to ordinary aging. More than a decade after the identification of the critical breakage in cellular metabolism that causes progeria, for example, it is still far from clear whether this mechanism plays any meaningful role in human aging. It shows up to a small degree in old individuals, but is this significant over the present human life span? Perhaps not.
Here researchers investigating Werner syndrome make progress in understanding the disease mechanisms, which appear to involve heterochromatin. The publicity teams putting out the release are greatly overstating the relevance of this work to normal aging, however. Hype in research is a real problem, and sadly many groups who should know better are just as bad as the tabloids these days. So for my two cents, the relevance of this work on the causes of Werner syndrome to normal aging is just as speculative as is the case for work on the causes of progeria. It is likely that both conditions are the result of forms of damage that just don't happen to a meaningful level in a normal metabolism. When you are looking at broken biochemistry there is no guarantee that any of its operational characteristics are of use when understanding normal biochemistry, and breaking things to create a shorter life span usually has little relevance for any attempts to lengthen life span. Or at least that is the case until researchers can turn things around and demonstrate longer-lived animals via a reversal of the mechanism they are studying. Pay attention to longevity demonstrations, not demonstrations of shortened life spans.
Werner syndrome is a genetic disorder that causes people to age more rapidly than normal. People with the disorder suffer age-related diseases early in life, including cataracts, type 2 diabetes, hardening of the arteries, osteoporosis and cancer, and most die in their late 40s or early 50s. The disease is caused by a mutation to the Werner syndrome RecQ helicase-like gene, known as the WRN gene for short, which generates the WRN protein. Previous studies showed that the normal form of the protein is an enzyme that maintains the structure and integrity of a person's DNA. When the protein is mutated in Werner syndrome it disrupts the replication and repair of DNA and the expression of genes, which was thought to cause premature aging. However, it was unclear exactly how the mutated WRN protein disrupted these critical cellular processes.
Scientists sought to determine precisely how the mutated WRN protein causes so much cellular mayhem. To do this, they created a cellular model of Werner syndrome by using a cutting-edge gene-editing technology to delete WRN gene in human stem cells. This stem cell model of the disease gave the scientists the unprecedented ability to study rapidly aging cells in the laboratory. The resulting cells mimicked the genetic mutation seen in actual Werner syndrome patients, so the cells began to age more rapidly than normal. On closer examination, the scientists found that the deletion of the WRN gene also led to disruptions to the structure of heterochromatin, the tightly packed DNA found in a cell's nucleus. This points to an important role for the WRN protein in maintaining heterochromatin. And, indeed, in further experiments, scientists showed that the protein interacts directly with molecular structures known to stabilize heterochromatin - revealing a kind of smoking gun that, for the first time, directly links mutated WRN protein to heterochromatin destabilization.
"Our study connects the dots between Werner syndrome and heterochromatin disorganization, outlining a molecular mechanism by which a genetic mutation leads to a general disruption of cellular processes by disrupting epigenetic regulation. More broadly, it suggests that accumulated alterations in the structure of heterochromatin may be a major underlying cause of cellular aging. This begs the question of whether we can reverse these alterations - like remodeling an old house or car - to prevent, or even reverse, age-related declines and diseases."
Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.