3 June 2019

South Africa: Ageing and the Secrets of Our Genes

A rare condition has caused this man's body to age at super speed. Why?

Nobuaki Nagashima was in his 20s when his body began to feel like it breaking down. A member of the military, Nagashima was based in northern Japan where he'd vigorously practised drills out in the snow for 12 years. It happened bit by bit - cataracts at the age of 25 then hip pain at 28.

At 33, he was diagnosed with Werner syndrome, a disease that causes the body to age too fast. Among other things, it shows up as wrinkles, weight loss and balding. It's also known to cause heart failure, diabetes and cancer.

West of Tokyo, Nagashima is waiting under the white light of a Chiba University Hospital room for a doctor. A grey newsboy cap covers his hairless head freckled with liver spots. His eyebrows are thinned to a few wisps. Black-rimmed glasses help with his failing eyesight, his hip joints - replaced with artificial ones after arthritis - ache as he stands to walk across the room. These ailments you might expect to see in an 80-year-old.

Nagashima is just 43.

He's been in and out of hospital ever since his diagnosis. Nagashima's deteriorating health forced him to leave the military -he's lost 15 kilograms since he was diagnosed. He needs a walking stick to do a distance over a few metres.

Nagashima remembers driving home after his diagnosis, crying. When he told his parents, his mother apologised for not birthing a stronger person. But his father told him that if he could endure this disease, he was indeed strong, and maybe scientists would learn from him, gaining knowledge that could help others.

For centuries, humankind searched for fabled fountains of youth. Could a rare group of patients finally hold the key to unravelling the mysteries of life, death and ageing? (Madelene Cronjé, Mail & Guardian)

Apart from the X and Y sex chromosomes, we inherit two copies of every gene in our bodies - one from our mother and one from our father, according to the US National Library of Medicine. Werner syndrome is what's called an autosomal recessive disorder, meaning it only shows when a person inherits a mutated version of a gene called WRN from both parents.

Nagashima's parents are ageing normally. They each have one functional copy of WRN, so their bodies don't show symptoms of the disease. But he was unfortunate to have received two mutated copies of WRN. The family are unaware of any other Werner cases in their history.

WRN was discovered in 1996, and since then there have been few examples of Werner. As of 2008, there were only 1 487 documented cases worldwide, with 1 128 of them in Japan, a 2013 study published in the journal Clinical Interventions in Aging shows.

Lest this seem like a uniquely Japanese condition, George Martin, co-director of the International Registry of Werner Syndrome at the University of Washington, thinks the number of actual cases globally is around seven times higher than the numbers recorded today. He says most cases around the world have not been diagnosed.

The huge imbalance in Japanese cases is partly because of the isolating effect that islands of Japan have had on the population historically - people in more isolated regions in the past were likely to end up having children with someone more similar to them genetically.

Chiba University Hospital holds records of 269 clinically diagnosed patients, 116 of whom are still alive. Only a handful of people with Werner currently attend Chiba. Recently, they started a support group. Nagashima says the meetings often end with the same question: "Why do I have this disease?"

Our experiences shape us, mark us - turns out they also leave their traces our genes and deciphering these witness marks could unlock the secrets of ageing and death. (Utomi Ekpei, AFP)

If you were to unravel the 23 pairs of chromosomes in one of your cells you would end up with about two metres of DNA. That DNA is folded up into a space about a 10 000th of that distance. This compacting happens with help from proteins called histones.

DNA, and the histones that package it, can acquire chemical marks. These don't change the underlying genes, but they can silence or amplify a gene's activity. Where the marks are put or what form they take seems to be influenced by our experiences and environment - in response to smoking or stress, for instance. Some seem to be down to chance, or the result of a mutation, as in cancer. Scientists call this landscape of markings the epigenome. We do not know yet exactly why our cells add these epigenetic marks, but some of them seem to be connected to ageing.

University of California Los Angeles professor Steve Horvath 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 to more accurately measure how biologically old you are. The marks can be read from blood, urine, organ or skin samples.

Horvath's team analysed blood cells from 18 people with Werner syndrome as part of 2013 research profiled in the journal Aging. 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.

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Nagashima's genetic information is part of a Chiba University database. There is also a Japan-wide database of Werner syndrome and the International Registry at the University of Washington. These registries provide researchers with insights into how our genes work and interact with the epigenome, and how that fits with ageing as a whole.

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 million-dollar question is whether 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?

But we know relatively little about the processes through which epigenetic marks are added and why. Horvath sees methylation marks 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 glimpses beneath the surface.

In 2006 and 2007, Japanese researcher Shinya Yamanaka published two studies in the journal Cell that found putting four specific genes - now called Yamanaka factors - into any adult cell could rewind it to an earlier, embryonic state - a stem cell - from which it could then be turned into any other type of cell. This method, which earned Yamanaka the Nobel Prize, has become a mainspring for stem cell studies. But what made this all the more interesting was that it completely reset cells' epigenetic age to a prenatal stage, erasing the epigenetic marks.

Researchers replicated Yamanaka's experiments in mice with a condition called Hutchinson-Gilford progeria syndrome, which has similar symptoms to Werner but only affects children (Werner is sometimes called adult progeria). Remarkably, the mice rejuvenated briefly but died within days. Totally reprogramming the cells also led to cancer and destroyed the cells' ability to function.

Then in 2016, California's SalK Institute engineered a way to partially rewind the cells of mice with progeria using a lower dose of the Yamanaka factors for a shorter period. The premature ageing slowed down in these mice. They not only looked healthier than progeria mice who hadn't had the treatment, but their cells were also found to have fewer epigenetic marks. Moreover, they lived 30% longer than the untreated mice, the 2017 research published in the journal Cell shows.

When the researchers applied this same treatment to normally ageing mice, their pancreases and muscles also rejuvenated.

The big question remains: is the disappearance of the epigenetic marks related to the reversal of cell development - and possibly cell ageing - or an unrelated side-effect? Scientists are still trying to understand how changes in epigenetic marks relate to ageing, and how Yamanaka factors are able to reverse age-related conditions.

Read more: Could this finally solve the Eastern Cape's cancer mystery?

Back in the Chiba hospital room, Nagashima removes one of his sneakers, which he has cushioned with insoles to make walking more bearable.

He says he had wanted to marry his ex-girlfriend. She was understanding after his diagnosis and even took a genetic test to be sure their kids wouldn't inherit the disease. But when her parents discovered his condition, they disapproved and the relationship ended.

He has a new girlfriend now. He wants to make her his life partner, but to do so he must get the courage to ask for her parents' permission.

Nagashima slips down a brown sock, revealing a white bandage wrapped around his swollen foot and ankles. Beneath, his skin is raw, revealing red ulcers caused by his disease. "Itai," he says. It hurts. Then he smiles and says: "Gambatte" - I will endure.

This is an edited version of an article first published by Wellcome on mosaicscience.com and is republished here under a Creative Commons licence.

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