Drugs to slow the ageing process a step closer thanks to decoding of complex enzyme
Study of telomerase disease mutations could open the door for new anti-ageing and cancer treatments; also in health research news, antidepressant use linked to dementia, and why PMS may make women drink more alcohol
Scientists have celebrated the completion of a 20-year quest to map the complex enzyme telomerase, which is thought to avert ageing by repairing the tips of chromosomes in plants and animals, including humans.
Decoding the enzyme’s architecture could lead to drugs that slow or block the ageing process, along with new cancer treatments, they reported in the journal Nature.
“It has been a long time coming,” lead investigator Kathleen Collins, a molecular biologist at the University of California, Berkeley, said.
“Our findings provide a structural framework for understanding human telomerase disease mutations, and represent an important step towards telomerase-related clinical therapeutics.”
Part protein and part RNA – genetic material that relays instructions for building proteins – telomerase acts on microscopic sheaths, known as telomeres, that cover the tips of the chromosomes found inside all cells.
In humans, each cell contains 23 pairs of chromosomes, including one pair of sex chromosomes – the “X” and “Y” – that differ between males and females.
Australian-American biologist Elizabeth Blackburn, who shared the 2009 Nobel Prize in Medicine for discovering telomeres and their protective function in the 1970s, likened them to the tiny plastic caps that keep shoelaces from fraying.
Eventually, however, shoelace tips and telomeres do break down: every time a cell divides the telomeres get worn a little bit more, until the cell stops dividing and dies. This, biologists agree, is probably central to the natural ageing process.
But there is a twist. In 1985 Blackburn discovered telomerase, and its remarkable capacity to extend a cell’s lifespan by essentially rebuilding telomeres with extra bits of DNA, much in the same way that retreading a tyre can make it nearly as good as new.
Telomerase, in other words, was revealed to be a key agent in longevity. It can also be linked to disease.
“Inherited genetic mutations that compromise telomerase function cause disorders,” said Michael Stone, a professor at the Centre for Molecular Biology or RNA at the University of California, Santa Cruz.
A deficiency of the enzyme could accelerate cell death. At the other extreme, too much telomerase “supports unbridled cell growth in most human cancers”, he wrote in a commentary, also in Nature.
Early efforts to develop drugs that could control the enzyme’s expression – essentially switching it on or off – “were hampered by an incomplete understanding of the structure and organisation of the telomerase complex”, Stone added.
To crack the telomerase code, Collins and her team used a state-of-the-art cryoelectron microscope (Cryo-EM) to see the enzyme in action at unprecedented resolutions of seven or eight angstroms. An angstrom is one ten-billionth of a metre long. Cryo-EM can decipher the molecular structures of compounds that cannot be crystallised and imaged with X-rays. Its developers won the 2017 Nobel Prize in Chemistry.
“When I got to the point where I could see all the subunits – we had 11 proteins in total – it was a moment of ‘Wow! Wow! This is how they all fit together’,” said lead author Thi Hoang Duong Nguyen, a postdoctoral student at UC Berkeley’s Miller Institute for Basic Research in Science.
A 2010 study showed that ageing could be reversed in mice that were treated with telomerase. In 2011, scientists found a way to transform age-worn cells from people over 90 into rejuvenated stem cells indistinguishable from those found in embryos.
In lab experiments, several critical markers of ageing in cells were “reset”, including the size of telomeres.
Does PMS drive women to drink?
Researchers have reported a link between pre-period discomforts and drinking alcohol, but could not conclude whether premenstrual suffering causes women to hit the bottle, or the other way round.
An analysis of data from 19 studies in eight countries found a “moderate association” between premenstrual syndrome (PMS) symptoms such as cramps, breast tenderness, fatigue, moodiness, and depression on the one hand, and a tipple on the other. The link was “more pronounced” with heavy drinking – equivalent to one average-sized drink per day or more – the researchers said.
This suggested drinking may be the cause, rather than the consequence, of some PMS cases, they said. But the data “cannot strictly rule out that PMS causes women to drink in order to mitigate their symptoms”, study co-author Bahi Takkouche of the University of Santiago de Compostela in Spain said.
Either way, the findings “are important given that the worldwide prevalence of alcohol drinking among women is not negligible”, the team wrote in the online journal BMJ Open.
The data used was taken from studies conducted in the United States, Britain, Poland, Switzerland, Turkey, South Korea, Taiwan and Australia.
PMS symptoms, which vary from woman to woman, usually last one to a few days before menstruation. According to the UK’s National Health Service, about one in 20 women suffer symptoms so severe they interrupt their lives or work.
In the US, previous research has found, the economic cost can reach US$5,000 (HK$39,240) per PMS case per year due to women staying away from work, and seeking medical pain relief.
Most cases are never recorded, however, as many women simply carry on as best they can.
Worldwide, the proportion of women who drink alcohol is about 29 per cent, the research team said. “Heavy” drinkers made up about six per cent of the female population.
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In Europe and America, these figures are “much higher”– about 60 per cent of women drink in Europe, and 13 per cent heavily. Based on these figures and the study findings, the team estimated that about one in 10 PMS cases may be associated with drinking worldwide, and one in five in Europe.
In a comment on the study, gynaecologist Nick Panay of the Queen Charlotte’s and Chelsea Hospital in London said the “potential causal association” between alcohol use and PMS was “interesting”.
It was, however, “not surprising given the impact of alcohol on hormones and neurotransmitters” – the body’s chemical messengers, he said.
Antidepressant use may be linked to dementia
Long-term use of certain antidepressants has been linked to dementia in a large British study, researchers said, though they could not definitively conclude that the drugs were the cause. The study in more than 300,000 people in Britain found that those diagnosed with dementia were almost a third more likely to have been prescribed so-called anticholinergic medicines to treat depression and certain bladder conditions between four and 20 years earlier.
“What we don’t know for sure is whether the medication is the cause of the dementia,” said George Savva from the University of East Anglia’s School of Health Science. He is co-author of the study in the BMJ medical journal. “It could be that these medications are being prescribed for very early symptoms indicating the onset of dementia.”
Anticholinergic drugs block certain nerve impulses to reduce spasms of the bladder muscles, for example, and to ease depression symptoms or Parkinson’s disease.
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Anticholinergic antidepressants include amitriptyline, dosulepin, and paroxetine, said the researchers, who compared the medical records of 40,770 dementia patients over 65 to those of 283,933 people without dementia.
“More than 50 million people worldwide are affected by dementia and this number is estimated to be 132 million by 2050,” said Savva. “Developing strategies to prevent dementia is therefore a global priority.”
The study results suggested a “potential preventative approach” that demands further investigation. The team urged people taking anticholinergic medicines not to stop until they have consulted their doctor or pharmacist.