Werner Syndrome versus Natural Aging

In science, a model is a system that is close enough to reality that one can learn something useful from it. It is almost always cost-effective to use models rather than the real thing as a test bed, even if the differences sometimes lead to misleading results. Medical and life science researchers put a great deal of effort into producing animal models of human diseases, a way to explore causes and treatments within available budgets. In some cases this is just a matter of standardization, as a given condition with very similar mechanisms exists in multiple species besides our own. In others, such as Alzheimer's disease, the models must be highly artificial, as none of the relevant mechanisms of the human condition exist naturally in the commonly used laboratory species. Artificial models tend to be far more prone to delivering misleading results, unfortunately.

Aging is an interesting case in modeling, in that the cost concerns are much greater here than in most other conditions. It is expensive in time and funding to generate old animals, and then watch what happens as aging progresses. So researchers have exploited the range of conditions known as DNA repair deficiencies, such as Hutchinson-Gilford progeria syndrome and Werner syndrome, in which cellular dysfunction leads to what appears, superficially, to be accelerated aging. But this is not accelerated aging. Aging is a specific balance of various forms of cellular damage and persistent metabolic waste. DNA repair deficiencies certainly have a surfeit of cellular damage, but it is of types either not seen in normal aging, or not present in any significant degree in normal aging. So some aspects of aging turn out to look somewhat similar, such as cardiovascular disease arising from general tissue dysfunction, but others are far from the same.

At the end of the day, we will need to treat natural aging as a medical condition. This will be accomplished by repairing its specific causative damage, preferably in some order of relative importance. Thus I feel that deeply examining DNA repair deficiencies cannot greatly help here: it is good for patients with these conditions, and thus should be accomplished, but it adds little to efforts to help everyone else. The damage is different in type and priority. The research and development communities will progress more rapidly in the matter of aging by studying aging and its causes, not by studying DNA repair deficiencies that have little in common with aging under the hood.

Today's popular science article on Werner syndrome is interesting for linking this topic with that of the epigenetic clock, the discovery that some epigenetic changes are characteristic of aging. They can be used to measure age, in fact, with a fair degree of accuracy. From the point of view of researchers who see aging as caused by an accumulation of molecular damage, these epigenetic changes are a measure of aging, a reaction to damage. Epigenetic change no doubt causes further downstream changes in tissue function, either good or bad depending on how well they compensate for the presence of damage, but they are not the cause of aging. Yet many in the research community do see epigenetic change as a suitable target for intervention in aging, and arguably they are doing a good job of persuading research groups and raising funds for this strategy. Yet I feel that this sort of approach to the treatment of aging is doomed to a far lesser degree of success than a strategy of targeting the deeper root causes. Force epigenetic changes back to a more youthful configuration, and the underlying damage is still there, still causing all of the other harms it is capable of.

The man who is ageing too fast

Nobuaki Nagashima was in his mid-20s when he began to feel like his body was breaking down. He was based in Hokkaido, the northernmost prefecture of Japan, where for 12 years he had been a member of the military, vigorously practising training drills out in the snow. It happened bit by bit - cataracts at the age of 25, pains in his hips at 28, skin problems on his leg at 30. At 33, he was diagnosed with Werner syndrome, a disease that causes the body to age too fast. Among other things, it shows as wrinkles, weight loss, greying hair, and balding. It's also known to cause hardening of the arteries, heart failure, diabetes, and cancer.

DNA, and the histones that package it up, can acquire chemical marks. These don't change the underlying genes, but they do have the power to silence or to amplify a gene's activity. Steve Horvath, professor of human genetics and biostatistics at the University of California, Los Angeles, has used one type of these, called methylation marks, to create an "epigenetic clock" that, he says, looks beyond the external signs of ageing like wrinkles or grey hair, to more accurately measure how biologically old you are. The marks can be read from blood, urine, organ or skin tissue samples. Horvath's team analysed blood cells from 18 people with Werner syndrome. It was as if the methylation marking was happening on fast-forward: the cells had an epigenetic age notably higher than those from a control group without Werner.

Scientists now understand that WRN is key to how the whole cell, how all our DNA works - in reading, copying, unfolding and repairing. Disruption to WRN leads to widespread instability throughout the genome. "The integrity of the DNA is altered, and you get more mutations... more deletions and aberrations. This is all over the cells. Big pieces are cut out and rearranged." The abnormalities are not just in the DNA but in the epigenetic marks around it too. The million-dollar question is whether these marks are imprints of diseases and ageing or whether the marks cause diseases and ageing - and ultimately death. And if the latter, could editing or removing epigenetic marks prevent or reverse any part of ageing or age-related disease?

Before we can even answer that, the fact is, we know relatively little about the processes through which epigenetic marks are actually added and why. Horvath sees methylation marks as like the face of a clock, not necessarily the underlying mechanism that makes it tick. The nuts and bolts may be indicated by clues like the WRN gene, and other researchers have been getting further glimpses beneath the surface. There's a feverishness around the idea of resetting or reprogramming the epigenetic clock, Horvath tells me. He sees huge potential in all of it, but says it has the feel of a gold rush. "Everybody has a shovel in their hand."


Accelerated epigenetic aging in Werner syndrome
This study shows that Werner syndrome (WS) is associated with an increased epigenetic clock age of blood cells which is independent of changes in blood cell composition.

Approximately 90% of individuals presenting Werner syndrome have any of a range of mutations in the gene, WRN, the only gene currently attributed to cause Werner syndrome. WRN gene and associated protein are important for maintaining genome stability. WRNp is active in unwinding DNA, a step necessary in DNA repair and DNA replication. WRN protein deficiency causes changes in the pattern of gene expression that markedly resemble those of normal old age. However, the loss of helicase activity but no loss of exonuclease function in non-pathogenic human WRN variant does not cause clinical Werner syndrome, suggesting that the intact exonuclease function is sufficient to prevent WRN syndrome (PMC5343477)

Posted by: Dmitry Dzhagarov at May 28th, 2019 2:17 AM

@Dmitry Dzhagarov
Do we have some indication of what are the downsides of non-pathogenic loss
of exonuclease function ? More cancer, for example?

Posted by: Cuberat at May 28th, 2019 4:52 AM
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