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Aging, Disease & Mitochondria

There exists a connection between this tiny but powerful organelle...and life as we know and understand it.

The mitochondria have long been understood to be the "powerhouse of the cell" but the relationship between mitochondrial function and aging, and diseases of aging, is beginning to be uncovered.

The evidence is convincing, as profiled by three leaders in the field of mitochondrial medicine.

Dr. Christoph Westphal, CEO and co-founder of Sirtris Pharma, discusses the relationship between mitochondrial disease and more common diseases, such as diabetes, Parkinson's, Alzheimer's, and cancer.

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Vamsi Mootha, MD, PhD of Harvard University & the Broad Institute (Boston) studies the relationship between mitochondria and disease, discussed at a MitoAction awareness event

 


From the Boston Globe, September 15th, 2008:

Power outage

'You think, "My daughter is 4 - she shouldn't have these problems." But if you were 94, you'd say, "That's part of aging." '

By Carolyn Y. Johnson, Globe Staff  |  September 15, 2008

HINGHAM - Eva Balcells giggles happily as she plays on the floor, but the 4-year-old moves with the deliberate caution of a frail elderly person, her arm trembling as she reaches in slow motion to grasp a toy car.

Eva has a rare genetic flaw in her mitochondria - the tiny, pill-shaped structures that power her cells - that leaves her weak, ravages her brain, and will eventually take her life.

Most people would see Eva's incurable illness as an impossibly sad story, an unfortunate throw of the DNA dice that affects an estimated 1 in 40,000 children. But a growing body of scientific evidence says that in her steady gaze they should see themselves.

The same type of power plant failure that causes Eva's body to go awry is now being implicated in some of the most common ailments of old age, and the possibility that mitochondria play a central role in aging is drawing a surge of public and private investment - into everything from understanding the basic science, to crafting antiaging elixirs targeted to them.

"All these diseases - diabetes, cancer, atherosclerosis - the major diseases of mankind, appear to have major mitochondrial components," said Dr. Alan M. Krensky, a deputy director of the National Institutes of Health, which has designated mitochondria research as one of six priority areas for $375 million in new funding over the next five years.

Mitochondria churn out energy for everything from neurons to muscle cells. The obscure organelles have been hard to figure out because their function depends on both their own swath of DNA and genes that lie in chromosomes in the cell's nucleus. The mitochondrial genome was sequenced in 1981, and since then dozens of rare genetic disorders that cause mitochondrial dysfunction like Eva's, called Leigh's disease, have been identified.

Such diseases were so devastating that it was easy to pin them to mitochondrial dysfunction. But researchers began to wonder whether mitochondria might be involved in more common diseases that share some of the same symptoms and have defied attempts to find a clear cause. Perhaps the dementia, strokes, or heart disease of old age were connected to mitochondrial disease.

They had reasons to think mitochondria might be affected by aging. Mitochondrial function declines over time - a fact that may seem obvious to anyone who realizes at 80 they don't have the energy they did when they were 20. Mitochondria are also prone to mutations in genetic material, because as they make energy, they also spew out free radicals, reactive molecules that can cause mutations.

Then, study after study showed that common diseases were correlated with mitochondrial dysfunction. Boston-area researchers in 2003 found that the genes involved in mitochondrial function are less active in patients with Type 2 diabetes. Scientists who bred "couch potato" rats with little capacity for aerobic exercise found evidence that impaired mitochondria function might be linked to metabolic problems, ranging from obesity to high blood pressure. Other studies have found that impaired mitochondria appear in diseases such as cancer, Parkinson's, and Alzheimer's.

No study has proven that malfunctioning mitochondria cause the common diseases of aging, but the idea got a huge vote of confidence early this summer, when pharmaceutical giant GlaxoSmithKline bought Cambridge's Sirtris Pharmaceuticals for $720 million. The company is working to create drugs that can increase the number of mitochondria and boost their function, including a compound based on resveratrol, a substance in red wine believed to have antiaging properties.

"We entered this field looking at all the diseases of aging - and it just so happened that all diseases of aging seemed to have as an issue the mitochondrial activity or metabolism of the cell," said Dr. Christoph Westphal, chief executive of Sirtris. "All these illnesses that look so different - they really have one unifying theme."

The company is testing drugs that have been demonstrated to boost mitochondrial number and function in patients with Type 2 diabetes and, at the other end of the spectrum, patients with a genetic mitochondrial disease called MELAS, which causes seizures and headaches, strokes, and dementia.

Dr. Vamsi Mootha, an associate member of the Broad Institute at Harvard and MIT who this summer published an encyclopedia of 1,100 proteins that are at work in mitochondria, thinks that the rare mitochondrial disorders may have the potential to shift the way people think about common diseases. He cites the story of cholesterol.

Researchers who uncovered the mechanism behind a rare genetic disorder that causes people to get heart attacks at an early age illuminated the role that LDL cholesterol played in heart disease.

"What those rare cases pointed to is the idea that the cholesterol pathway could influence heart disease," Mootha said. "With mitochondrial disease, the reason it's exciting is it helps identify pathways in the same way."

Researchers have yet to prove that mitochondria play a causal role in all these diseases; there's always the possibility that the low-functioning mitochondria are just a symptom of the havoc the disease wreaks on the body.

Bradley Wise, program director in the division of neuroscience at the National Institute on Aging, cautioned that no study has shown that mitochondria are the linchpin that cause diseases of aging. Still, he pointed out that improving mitochondrial function might be protective, eliminating one risk factor for a disease.

The flood of publicity and interest into the field has given hope to patients and families dealing with genetic mitochondrial disorders who have long had to fight for recognition of their disease. They welcome the broader attention to mitochondria, which reflects something they see on a daily basis.

"Eva has tremors, she has weakness," said Cristy Balcells, Eva's mother. "You think, 'My daughter is 4 - she shouldn't have these problems.' But if you were 94, you'd say, 'That's part of aging - stuff stops working.' "

The Mitochondrial Disease Action Committee will hold a fund-raising and awareness walk on Sept. 21 in Cambridge to increase awareness of mitochondrial disease. For more information, visit mitoaction.org/walk.