The man who is ageing too fast

When nobuaki Nagashima first felt that his body was deteriorating, he was in his mid-20s. He had been a military member for 12 years, stationed in Hokkaido, Japan's most northern prefecture, where he had been rigorously practicing training maneuvers outside in the snow. It started gradually; he had cataracts at the age of 25, hip discomfort at the age of 28, and skin issues on his leg at the age of 30.

He was 33 when Werner syndrome, a condition that accelerates aging, was discovered in him. It manifests as wrinkles, weight loss, greying hair, and baldness, among other things. Additionally, it has been linked to heart failure, diabetes, cancer, and artery hardening.

About 25 miles west of Tokyo, in a room at Chiba University Hospital, I meet Nagashima. A grey newsboy cap covers his bald skull freckled with liver spots. A few wisps remain of his once thick eyebrows. As he stands to slowly traverse the room wearing black-rimmed glasses to aid with his deteriorating vision, his hip joints, which were replaced with artificial ones due to arthritis, pain. You may anticipate seeing these conditions in an 80-year-old. Nagashima is just 43, though.

He claims that ever since his diagnosis, he has been in and out of the hospital. said he had to quit the service due to his failing health. Nagashima has undergone five or six operations to correct diseases brought on by aging, from his toes to his hips to his eyes. Since his first diagnosis, he has dropped 15 kg. He works a temporary job at the City Hall, coming to the office when his body will let it but working from home when it won't, and needs a walking stick to cover distances of more than a few meters.

He remembers driving home following his diagnosis, weeping to himself. His mother expressed regret for not giving birth to a stronger person when he told his parents. But his father assured him that he was truly strong for having survived the illness, and that perhaps scientists would learn from him and acquire insight that would benefit others.

We receive two copies of every gene in our body, one from each parent, with the exception of the X and Y sex chromosomes. An autosomal recessive disorder, Werner syndrome only manifests when a person inherits a mutated form of the WRN gene from both parents.

Parents of Nagashima are aging regularly. Since they each have one working copy of WRN, their bodies are free of the disease's signs and symptoms. Unfortunately, he acquired two mutant copies of WRN, which was bad. The family is unaware of any other Werner instances in their family history, and his grandparents are still alive and doing about as well as one could anticipate for a pair in their 90s.

Werner was only identified in 1996, and since then, there haven't been many Werner cases. Only 1,487 recorded instances had been found as of 2008, 1,128 of which were in Japan.

In order to dispel any notion that this is a condition that only affects people in Japan, George Martin, co-director of the University of Washington's International Registry of Werner Syndrome, estimates that there are actually seven times more cases of Werner syndrome worldwide than are currently recognized. He claims that the majority of instances in the globe will not have been noticed by any doctors or registries.

He attributes two explanations for the extreme imbalance in Japanese instances. The first is the isolation caused by the mountains and islands of the Japanese terrain and the population throughout history. Historically, individuals in more remote areas were more likely to have children who were genetically similar to them. The Italian island of Sardinia, which likewise has a concentration of Werner cases, has a comparable impact. Second, the Japanese medical system is more attentive than most when Werner syndrome manifests due to the condition's shocking character and the increased frequency with which it occurs in Japan (affecting an estimated one in a million persons globally but one in 100,000 in Japan).

There are 269 clinically diagnosed patients with records at Chiba University Hospital, 116 of whom are still living. Sachi Suga is one of them; she can only move around in a wheelchair. It is challenging for her to maintain the Japanese custom of ofuro, which involves unwinding each night in a deep tub of scalding hot water. Her muscles are so weak that she can no longer get in and out of the bath. She used to frequently prepare breakfast for herself and her husband, but now days she can't stand for more than a few minutes at a stove. He consumes the quicker-to-make miso soup she makes the night before before leaving for work at 5.30 a.m.

Suga is a waif-like woman with glass-like little wrists who is wearing a short black wig. She speaks to me in a throaty, raspy voice. She tells me about the home health aide who comes to help bandage her ulcer-covered legs three times a week. She is in excruciating leg and back agony. "I wanted to have my legs amputated because it ached so bad." On the plus side, the 64-year-old has lived significantly longer than the 55-year-old median life expectancy for Werner syndrome sufferers.

There are now very few Werner students at Chiba. They just established a support group. Suga claims that as soon as our chat began, she immediately forgot about the discomfort. The sessions, according to Nagashima, frequently finish with the same query: "Why do I have this disease?"

"His mother apologised for not giving birth to a stronger person. But his father assured him that he was truly strong if he could survive the illness."

You would have around two meters of DNA if you unraveled the 23 pairs of chromosomes in one of your cells. That DNA is packed far more tightly than even the most compact origami design, into a space that is 10,000 times smaller than that. Histone proteins play a key role in this compacting process.

Chemical alterations to DNA and the histones that encase it are possible. These have the ability to mute or increase the activity of a gene but do not alter the underlying genes. Our experiences and environment seem to have an impact on where the marks are placed or what form they take, such as in response to stress or smoking. Some appear to be the consequence of chance or a mutation, as in the case of cancer. This pattern of marks is known as the epigenome. Although the specific reason why our cells accumulate these epigenetic markers is yet unknown, several of them appear to be related to aging.

A type of these, known as methylation marks, have been used by Steve Horvath, professor of human genetics and biostatistics at the University of California, Los Angeles, to develop a "epigenetic clock" that, according to Horvath, looks beyond the external signs of aging like wrinkles or grey hair to more accurately measure how biologically old you are. Samples of skin tissue, blood, urine, or organs can all be used to interpret the markings.

18 Werner syndrome patients' blood cells were examined by Horvath's team. The methylation marking appeared to be occurring in rapid succession because the cells' epigenetic ages were noticeably older than those of cells from a control group without Werner.

"Whether these signs are the result of diseases and aging or if they actually cause diseases, aging, and eventually death is the million dollar issue."

The genetic data of Nagashima and Suga is stored in a database owned by Chiba University. Additionally, the University of Washington's International Registry and a Werner syndrome database that spans all of Japan are available. Researchers are learning more about how our genes function, how they interact with the epigenome, and how all of this relates to aging thanks to these registries.

Scientists now recognize that WRN plays a crucial role in how the entire cell and our DNA read, copy, unfold, and repair. Widespread genome-wide instability results from WRN disruption. "When the DNA's integrity is compromised, additional mutations, deletions, and aberrations occur. The cells are covered with this, claims George Martin. The arrangement of large components is changed. The epigenetic markings around the DNA as well as the DNA itself exhibit anomalies.

Whether these signs are the result of diseases and aging or if they actually cause diseases, aging, and eventually death is the million dollar issue. If the latter, can any aspect of aging or age-related illness be prevented or reversed by editing or erasing epigenetic marks?

Before we can even respond to that, it's important to note that we still don't fully understand how and why epigenetic markers are added. According to Horvath, methylation marks are more like the face of a clock than the actual mechanism that keeps it ticking. Other researchers have been gaining more peeks below the surface, and indicators like the WRN gene may reveal the nuts and bolts.

Shinya Yamanaka, a Japanese researcher, released two experiments in 2006 and 2007 in which he discovered that inserting four particular genes, now referred to as Yamanaka factors, into any adult cell could change it into a stem cell, which could subsequently be transformed into any other type of cell. This approach, which won Yamanaka the Nobel Prize, has emerged as the backbone of stem cell research. But what made this even more intriguing was that it entirely erased the epigenetic markings and reset the epigenetic age of the cells to a prenatal stage.

Researchers repeated Yamanaka's findings in mice with Hutchinson-Gilford progeria syndrome, a disease that exclusively affects youngsters but has symptoms with Werner (Werner is sometimes called adult progeria). Remarkably, the mice revived momentarily, but they perished after a few of days. Completely altering the cells has also resulted in cancer and a loss of function.

Then, in 2016, researchers at the Salk Institute in California developed a technique to use a lower dose of the Yamanaka factors for a shorter period of time to partly rewind the cells of mice with progeria. In these mice, premature aging slowed down. In addition to having healthier and more vibrant appearances than progeria mice who had not received the therapy, it was also discovered that their cells had less epigenetic alterations. Additionally, they had a 30% longer lifespan than the untreated mice. The muscles and pancreases of mice that were naturally aging underwent the same therapy showed rejuvenation, according to the researchers.

Separately, the same researchers are modifying additional epigenetic markers on mice using gene editing techniques to see what occurs. In an effort to change the function of genes, they are also attempting to manipulate the histone proteins. In mice, several of these methods have already been successful in correcting muscular dystrophy, diabetes, and renal disease. The group is currently testing identical procedures on rats to determine whether they might lessen the signs and symptoms of Parkinson's disease and arthritis.

The crucial question is whether the loss of the epigenetic markers is a consequence of the reversal of cell growth, which may result in cell aging, or if it is only a side effect. Scientists are currently working to understand how Yamanaka variables can correct age-related illnesses as well as how alterations in epigenetic marks relate to aging.

According to Horvath, there are obvious similarities in how the body ages in many different body parts from an epigenetic perspective. Epigenetic aging in the brain exhibits patterns of methylation marks that are comparable to those in the liver or kidney. According to him, "ageing is actually pretty clear, because it's extremely repeatable in different organs," when seen in terms of these signs.

According to Horvath, there is a feverishness surrounding the concept of resetting or reprograming the epigenetic clock. All of it has enormous potential, but he claims it has the air of a gold rush. There are shovels in the hands of everyone.

Jamie Hackett, a molecular scientist at the European Molecular Biology Laboratory in Rome, says the enthusiasm stems from the thought that you may have an effect over your genes. There used to be a fatalistic attitude that said you had to accept what you got and had no control over it.

"The idea that you can affect your DNA is what causes the enthusiasm."

Nagashima takes off one of his high-top sneakers that he padded with insoles to make walking more tolerable once they are back in the Chiba hospital room.

He talks to me about a prior love interest. They had desired to wed. She was sympathetic following his diagnosis and even had a DNA test to ensure they wouldn't pass the illness on to their offspring. However, when her parents learned about his condition, they didn't like it. The romance was over.

He currently has a new girlfriend. He tells me that he wants to take her into his life as his partner, but that he first has to have the guts to obtain her parents' consent.

Nagashima removes a brown sock to show a white bandage covering his swelling foot and ankles. His skin is bare below, exposing red sores brought on by his illness. Itai," he replies. It aches. He then grinned. "Gambatte," he says, meaning "I'll take it.