The key to sun-induced skin aging: Granzyme-B
David Granville has a ray of hope for those who want a deep, dark tan without the long-term consequence of wrinkles. And his discovery has potential for treating problems far below the skin, and much more serious.
His team of scientists at UBC and Providence Health Care discovered the key to that aging process – a destructive enzyme called Granzyme-B. Block that enzyme, and skin stays smooth, even after repeated exposure to ultraviolet (UV) light.
The findings, published in Aging Cell, points the way for a drug that would block the activity of Granzyme-B in certain places, preventing the aging and deterioration of tissues that depend on the structural protein collagen – not just skin, but blood vessels and lung passages.
A principal investigator in the Centre for Heart Lung Innovation of UBC and St. Paul’s Hospital, Dr. Granville was investigating the role of Granzyme B in atherosclerosis, aneurysms and heart attacks. Immune cells use Granzyme-B to destroy harmful pathogens, but Dr. Granville also suspected it of contributing to the hardening and narrowing of blood vessels. He and his team bred mice without Granzyme-B, intending to examine their vasculature. Before they could that far, they couldn’t help but notice the mice’s youthful-looking skin.
So he and postdoctoral fellow Leigh Parkinson put the mice in a custom-built carousel that slowly turned under UV lamps to mimic natural sunlight, exposing them for three to four minutes, three times a week – enough to cause redness, but not to burn.
After 20 weeks, the skin of mice lacking Granzyme-B had aged much less, and their collagen was more intact, compared to a control group.
viDA Therapeutics, a company co-founded by Dr. Granville, is currently developing a Granzyme-B inhibitor based on technology licensed from UBC. The company plans to test a topically applied drug on people with discoid lupus erythematosus, an autoimmune disease worsened by sunlight that can lead to disfiguring facial scarring. (The musician Seal has such a condition.)
If the drug proves effective in preventing lupus-related skin lesions, it has potential for preventing the normal, gradual aging of the skin, which is mostly caused by sun exposure. But the drug might also be used for life-threatening conditions, such as aneurysms and chronic obstructive pulmonary disease, caused by the breakdown of collagen and other proteins that provide structure to blood vessels and lung passages.
Diesel exhaust causes changes “deep under the hood”
Just two hours of exposure to diesel exhaust fumes can switch some genes on, while switching others off.
That discovery, by Chris Carlsten, an Associate Professor in the Division of Respiratory Medicine, resulted from an experiment involving an unusual contraption: a booth — about the size of a standard bathroom — in which volunteers spend time breathing diluted and aged diesel exhaust.
Dr. Carlsten and his collaborators examined how exhaust affects the chemical “coating” that attaches to many parts of a person’s DNA. That carbon-hydrogen coating, called methylation, can silence or dampen a gene, preventing it from producing a protein – sometimes to a person’s benefit, sometimes not. Methylation is one of several mechanisms for controlling gene expression, known as epigenetics.
The study, published in Particle and Fibre Toxicology, found that breathing diesel-tainted air (similar to conditions along a Beijing highway) caused methylation changes at about 2,800 different points on people’s DNA, affecting about 400 genes. In some places on the genome, it led to more methylation; in more places, it decreased methylation.
Finding out how these changes in gene expression translate to health is the next step for researchers. But this study showed how vulnerable our genetic machinery can be to air pollution, and that changes are taking place even if there are no obvious symptoms.
“Usually when we look at the effects of air pollution, we measure things that are clinically obvious – air flow, blood pressure, heart rhythm,” Dr. Carlsten says. “But asthma, higher blood pressure or arrhythmia might just be the gradual accumulation of epigenetic changes. So we’ve revealed a window into how these long-term problems arise. We’re looking at changes ‘deep under the hood.’ ”
The fact that DNA methylation was affected after only two hours of exposure has positive implications, says Dr. Carlsten, the Canada Research Chair and AstraZeneca Chair in Occupational and Environmental Lung Disease, and an investigator with the Vancouver Coastal Health Research Institute.
“Any time you can show something happens that quickly,” he says, “it means you can probably reverse it” – either through a therapy, a change in environment, or even diet.
A physician does an about-face, based on her own research
Throughout her medical career, Laura Magee has taken a restrained approach to using blood pressure medication in her pregnant patients. Then she up-ended her own beliefs.
Her research, published in the New England Journal of Medicine, showed that treating a woman’s elevated blood pressure during pregnancy is safer for her, and safe for her baby. As a result of these findings, Dr. Magee and her collaborators recommend normalizing blood pressure in pregnant women.
The study addressed an age-old belief that reducing elevated blood pressure during pregnancy – which occurs in 10 per cent of pregnancies – might lead to reduced growth in the womb and worse health at birth.
But normalizing a pregnant women’s elevated blood pressure did not result in poorer outcomes for babies before or after birth. At the same time, allowing the mother’s blood pressure to be mildly to moderately elevated in pregnancy led to more episodes of dangerously elevated blood pressure that increase the risk of stroke and death for the mother during pregnancy.
“Before this study, I was a ‘less tight’ controller,” says Dr. Magee, a Clinical Professor in the Department of Medicine and the Department of Obstetrics & Gynaecology. “I was hoping that this approach would be better for the baby, without increasing risks for the mother. However, I was wrong. As a responsible maternity care provider, I can no longer justify a ‘less tight’ approach to blood pressure control.”
The study involved nearly 1,000 pregnant women in 15 countries, half of whom were assigned a lower blood pressure target than the other half. The number of babies who died or were admitted for prolonged newborn intensive care was similar between the two blood pressure control groups, while fetal growth was also similar.
“Our trial showed that you should treat a mother’s high blood pressure in pregnancy,” says Dr. Magee, a physician at BC Women’s Hospital and Health Centre and a scientist at the Child & Family Research Institute. “This reduces her risk without increasing the risks for her baby.”