Getting older slower
The holy grail in medicine has always been to find a way to slow, if not reverse, the human ageing process. Dr Zhongjun Zhou’s work in understanding how a mutant protein responsible for Hutchinson-Gilford Progeria Syndrome (HGPS) may contribute to the normal ageing process comes closest to attaining that goal.
Getting old slower
Despite medical breakthroughs, people who live longer are not necessarily healthier. The longer average lifespans of people is, in fact, increasing the prevalence of ageing associated diseases like Alzheimer’s, Parkinson’s, or cancer.
Zhou makes a distinction between health-span and lifespan. In Hong Kong, the average life expectancy is 83 years, but the health-span might be significantly shorter when a person is healthy, not just alive. Extending a person’s health-span reduces the number of years a person is exposed to diseases.
“Wouldn’t we all like to be happy and healthy until 79, and then die suddenly at 80? That would be fantastic for everyone, we wouldn’t suffer,” Zhou explains. “We’re not looking at only extending lifespan but also maximising disease-free healthspan. That is the goal in the study of ageing.”
Zhou moved to Hong Kong after his PhD in Medical Biochemistry in the Karolinska Institutet in Sweden. He then started research on premature ageing, and for the first time demonstrated that a mutant form of Lamin A protein jeopardises the genome maintenance in HGPS, the most severe early ageing disease in human.
Study of aging
The cells in the human body are subject to various damages. Many of these damages can be efficiently repaired. For those cells whose damages cannot be repaired, they either undergo senescence and cell death if the damage is severe and vital, or continue to proliferate in the presence of such damage without significantly affecting cellular functions until the accumulation of damages becomes vital. During our early years of development, functions of senescent/dead cells can be replaced by stem cells. However, when stem cells are depleted, senescent cells will no longer be replaced. The accumulation of senescent cells leads to tissue dysfunction. This is when we start to age. Although cellular senescence doesn’t necessarily always lead to ageing in an organism, there is a correlation.
The ageing process can be hastened by environmental factors like over-exposure to sunlight, which intensifies tissue damage. It can also be a result of damage to the telomere (the structure at two ends of a chromosome), which can inadvertently cause ageing.
“Damage is very important in triggering the ageing process,” says Dr. Zhou. “If you enhance the repair machinery, it will slow down the damage.”
Hutchinson-Gilford Progeria Syndrome
Hutchinson-Gilford Progeria Syndrome (HGPS) is a very rare disorder that occurs when a specific mutation spontaneously appears on the sperm or oocyte that will then develop into the embryo after fertilisation. There is no known treatment and most patients hardly survive past their teens. The prevalence of HGPS is one in 8 million people. This raises the question of why it is important to study HGPS if the chance of getting HGPS is so low, and the answer lies in the clues it provides to the normal human ageing process.
Human genes are composed of exons and introns which are found in continuous sequence in a genomic DNA. They are then transcribed to RNA. For them to be mature messenger-RNA (mRNA) they have to undergo a process called RNA splicing wherein introns are snipped as an intervening sequence, and the remaining exons are combined together. These are then translated into a protein.
However, when cells become old, this mechanism malfunctions and the splicing accuracy decreases. This defect in splicing can result in a similar splicing event that occurs in HGPS patients, leading to the production of an abnormal Lamin A protein (Lamin A is a component of the nuclear envelope in a cell) in the body known as progerin.
But unlike in the normal ageing process where there is a minimum production of mutant Lamin A protein, HGPS patients express progerin in their early embryonic stage with high quantities.
The finding of progerin accumulation in normal ageing was a major leap forward in the study of biology of ageing.
“There is evidence that normal ageing processes share paralleled mechanisms with this premature ageing disease,” says Zhou. “We can’t exclude the possibility that progerin may play some role in the normal ageing process. One could understand more about the normal ageing processes through investigating HGPS. That’s why the study of this disease is significant.”
To find the link, Zhou and his team genetically modified mice so that they can recapitulate features of HGPS. Their lifespan is only 5-6 months. By manipulating DNA repair and protecting stem cells, his team is able to extend the lifespan of these prematurely ageing mice by 25 to 30 percent.
At his lab in the Li Ka Shing Faculty of Medicine at the University of Hong Kong, Dr Zhou cannot hide his excitement with the implication: “If we can achieve similar extension in normal humans it would be huge, in human years, it would be 16 additional years if the average lifespan is 80.”
Recently Zhou’s team was also able to extend the lifespan of other prematurely aged mice 12-fold. Mice lacking a longevity gene, SIRT6 normally survive only 4 weeks. Through reducing cellular senescence, they have made these short-lived mice successfully survive up to 12 months.
So far, researchers have not been able to extend the health-span of animals because of the difficulty in distinguishing between health-span and lifespan in mice. But breakthroughs in genomic science and stem cells have helped scientists to understand more and more about the fate of cells during ageing. Dr Zhou is optimistic that these findings could help to extend health-span in humans. In collaboration with clinicians in Xi’an, his group initiated clinical trials on HGPS patients starting from last year based on Zhou’s research findings. It may take a few years before results of any kind can be observed.
Despite the importance of finding ways to slow down ageing, Zhou laments the fact that there is very little funding for research in Hong Kong, a place with a burning need due to its ageing population.
Another issue that worries Zhou is that although Hong Kong enjoys one of the highest life expectancy rates in the world, the territory doesn’t yet have any long-term vision in the battle against ageing associated diseases as a whole. As ageing is the biggest single risk factor for all major diseases today like osteoporosis, Alzheimer’s, Parkinson’s, cancer, cardiovascular diseases, etc, Zhou advocates a holistic approach so that society is better prepared for dealing with a burst of age-associated diseases. The Hong Kong government should take the problem seriously and allocate a sizable budget for ageing research with highest priority to develop strategies for intervention, otherwise we may be left with a great burden due to the ever increasing number of patients with major age-associated diseases.
The general public’s perception of medicine and health is another hurdle in promoting healthy ageing, most people don’t seek medical attention until it is too late.
“It isn’t serious enough unless it’s urgent, it keeps running until it’s worn out and becomes difficult and expensive to be fixed. That is our mentality,” says Zhou, “and ageing is anything but urgent. People will tell you as such: it’s normal. Or they may ask why we should extend our lifespans even further if ageing is a problem. The key point is the health-span not just lifespan."
“We’re never going to win this battle if we wait until people get sick. We should prevent diseases from developing.” Zhou explains.
Metformin, a drug developed in the 1930s to treat diabetes, was recently found to have anti-ageing properties and has since been widely promoted as the first drug that can delay the ageing process. Zhou’s group is also investigating if Metformin regulates epigenetics, genome alterations without changes in DNA sequence. Research in these fields will hold the key in extending the health-span of the population.
Although largely known for his work in the field of ageing, Dr. Zhou has also made major contributions in cell development, cell signaling regulation, and tumor development. In addition to work on regulation of chromatin organisation and ageing, he is also investigating how a cell surface proteinase controls neural development.
Dr Zhou was awarded the Young Investigator Award by the International Society for Fibrinolysis and Proteolysis in 2000, and the Young Oversea Chinese Scientist Award in 2005 by Natural Science Foundation of China. In 2006 he received the Faculty Outstanding Research Output Award from Li Ka Shing Faculty of Medicine, and was honored with State Science and Technology Award from the State Council of China in 2011, followed by Outstanding Research Award by the University of Hong Kong in 2014. Zhou graduated from Xiamen University with BSc. in Biochemistry. He obtained a masters degree in Biochemistry and Ph.D. in Pathophysiology from Peking Union Medical College. He also obtained Ph.D. in Medical Biochemistry from Karolinska Institutet in Sweden. He joined HKU as Research Assistant Professor in 2002, and later became an Associate professor in 2005. In 2011 he co-founded Asian Society of Aging Research. He is currently a professor of Biochemistry at the Li Ka Shing Faculty of Medicine, the University of Hong Kong. He was a Croucher Senior Fellowship Award recipient in 2015.
To view Dr Zhou’s personal Croucher profile, please click here.