Discovery reverses aging of mouse hearts—could it work in humans, too?

Posted May 13, 2013, 12:19 pm

Every living thing is constantly aging. It seems universal and inevitable—a law of nature. Just look in the mirror, or check out your family and friends.

Yet in the past decade, a remarkable series of experiments from laboratories all over the world has begun to challenge that “law.” In both simple animals like worms and in more complicated animals like mice, scientists are discovering what causes aging—and how to slow it. The life spans of several simple animals have been extended greatly by simple biological manipulations. More important, during that extra time alive, the animals remain quite strong and fertile.

The latest example of such aging research was just reported in the prestigious scientific journal Cell by two of my Harvard Medical School colleagues. Cardiologist Richard T. Lee (co-editor in chief of the Harvard Heart Letter) and stem cell biologist Amy Wagers and their teams have found a substance that rejuvenates aging hearts in mice. (You can see a video of the researchers discussing their work below.) The discovery could someday lead to a treatment that prevents or reverses the most common kind of heart failure in humans: age-related diastolic dysfunction. There is currently no specific treatment that prevents or reverses this condition.

In diastolic dysfunction, the heart muscle becomes thicker and stiffer. As a result, when blood enters the heart, its muscular walls can’t stretch enough to accept all the blood flowing into it. That means the heart pumps less blood with each beat, making it difficult to circulate blood to every cell in the body. Blood backs up into the lungs, causing difficulty breathing. It also backs up into the rest of the body, causing fatigue and swelling, particularly in the legs and feet. That’s heart failure.

Mice have a similar condition. It develops as the animals get older, just like it does in humans. The team led by Lee and Wagers wondered if something was present in the blood of young mice that kept the heart young. To pursue that possibility, they joined the circulation of an old mouse to that of a young mouse. As a result, the two animals shared the same blood. After 4 weeks, the thickened and stiff heart muscle of the old mouse became dramatically thinner and more flexible.

In other words, it looked like Lee and Wagers’ hunch was right: some substance was present in the blood of young mice that rejuvenates the heart muscle of old mice. Most likely, that substance had been in the blood of the old mice when they were younger, but had decreased as the mice aged.

The team then identified a substance called growth differentiation factor 11 (GDF11) as a good candidate to be the “anti-aging” substance: it was at high levels in the blood of young mice but not old mice. To prove its role, Lee and Wagers gave old mice enough GDF11 so they had the same blood levels of it as young mice. Again, the thickened, stiff heart muscle of the old mice became rejuvenated. So at least in mice, a common kind of aging of the heart could be reversed by a particular anti-aging substance.

Will this discovery in mice offer any help to humans with heart failure? It will take a lot more research to know. It may not work in humans the way it works in mice. It may work in humans, but cause unacceptable side effects. Any beneficial effects might not last.

On the other hand, it also is possible that this substance has anti-aging effects in more organs than just the heart—and not only in mice, but maybe also in humans. So the discovery could have even greater potential than it now appears.

For me, what is important about this study is not whether it will help human health: we just can’t know if it will until much more research is performed.

What I find important is that the work by Lee and Wagers, like a number of studies before it, reveals a remarkable new truth: there are substances naturally present in all living things that cause aging and that retard it. In other words, aging is not a mystical process. Aging is chemistry. By understanding that chemistry, we may someday be able to slow aging.

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Exposure to light at night may cause depression, learning issues, mouse study suggests

Nov. 14, 2012 — For most of history, humans rose with the sun and slept when it set. Enter Thomas Edison and colleagues, and with a flick of a switch, night became day, enabling us to work, play and post cat and kid photos on Facebook into the wee hours.

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According to a new study of mice led by a Johns Hopkins biologist, however, this typical 21st-century scenario may come at a serious cost: When people routinely burn the midnight oil, they risk suffering depression and learning issues, and not only because of lack of sleep. The culprit could also be exposure to bright light at night from lamps, computers and even iPads.

"Basically, what we found is that chronic exposure to bright light -- even the kind of light you experience in your own living room at home or in the workplace at night if you are a shift worker -- elevates levels of a certain stress hormone in the body, which results in depression and lowers cognitive function," said Samer Hattar, a biology professor in the Johns Hopkins University's Krieger School of Arts and Sciences.

Published in the Nov. 14 advance online publication of the journal Nature, the mice study demonstrates how special cells in the eye (called intrinsically photosensitive retinal ganglion cells, or ipRGCs) are activated by bright light, affecting the brain's center for mood, memory and learning.

But the study involved mice, so why are we talking about humans? Hattar offers some insight: "Mice and humans are actually very much alike in many ways, and one is that they have these ipRGCs in their eyes, which affect them the same way," he said. "In addition, in this study, we make reference to previous studies on humans, which show that light does, indeed, impact the human brain's limbic system. And the same pathways are in place in mice."

The scientists knew that shorter days in the winter cause some people to develop a form of depression known as "seasonal affective disorder" and that some patients with this mood disorder benefit from "light therapy," which is simple, regular exposure to bright light.

Hattar's team, led by graduate students Tara LeGates and Cara Altimus, posited that mice would react the same way, and tested their theory by exposing laboratory rodents to a cycle consisting of 3.5 hours of light and then 3.5 hours of darkness. Previous studies using this cycle showed that it did not disrupt the mice's sleep cycles, but Hattar's team found that it did cause the animals to develop depression-like behaviors.

"Of course, you can't ask mice how they feel, but we did see an increase in depression-like behaviors, including a lack of interest in sugar or pleasure seeking, and the study mice moved around far less during some of the tests we did," he said. "They also clearly did not learn as quickly or remember tasks as well. They were not as interested in novel objects as were mice on a regular light-darkness cycle schedule."

The animals also had increased levels of cortisol, a stress hormone that has been linked in numerous previous studies with learning issues. Treatment with Prozac, a commonly prescribed anti-depressant, mitigated the symptoms, restoring the mice to their previous healthy moods and levels of learning, and bolstering the evidence that their learning issues were caused by depression.

According to Hattar, the results indicate that humans should be wary of the kind of prolonged, regular exposure to bright light at night that is routine in our lives, because it may be having a negative effect on our mood and ability to learn.

"I'm not saying we have to sit in complete darkness at night, but I do recommend that we should switch on fewer lamps, and stick to less-intense light bulbs: Basically, only use what you need to see. That won't likely be enough to activate those ipRGCs that affect mood," he advises.

This study was supported by a grant from the David and Lucile Packard Foundation.

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