Finding Genes That Slow Down Brain Aging

What if, at 80 years old, you could choose to restore your brain to its 20-year-old level of functioning? You could have your optimal ability to remember facts, learn information, react, and balance, and be in no danger of Alzheimer’s disease. This sounds fantastical but it may be possible. This possibility is what piqued my interest in studying human brain aging and is the long-term goal of my research project.

People are living longer because of advances in medicine for common diseases such as cancer and heart disease, among other factors. But this longevity is leaving an increasing proportion of people suffering from late life neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. In fact, by the time individuals in the U.S. reach 95 years of age, they have a 50/50 chance of having Alzheimer’s disease. Treatment options for Alzheimer’s disease are poor, at most delaying decline by a few months. This leads many people to wonder why they would want to live to very old age if it means that they have a good chance of suffering from a devastating incurable disease, will lack the balance to avoid falling and breaking bones, or will lack the cognition to do the things that they enjoy. 
 
We study aging of the human brain because if we can understand what happens within aging neurons, then we can create drugs that specifically slow down or reverse brain aging. We believe that this is possible due to the work of many laboratories that have shown that lifespan-extending genetic and environmental interventions in animals can also extend health span, that is, years of disease-free living. Scientists have now created worms that live up to six times longer and mice that live up to 50% longer, and many of these animals also suffer from diseases of aging – including Alzheimer’s – later and at a slower rate. This research tells us that lifespan-extending interventions in people should also extend health span and improve quality of life. 
 
Our approach is to directly study the genetics and molecular processes in human brains across the lifespan. Specifically, people donate their brains to science and we study tissue samples from them. What we have begun to understand is that the molecular state of the brain is a surprisingly accurate clock. Just as we can fairly accurately tell how old a person is by looking at them, we can also tell how old a person’s brain is by looking at its molecular signature (Figure i; see photo gallery). But just as some people look older or younger than their chronological age, some people’s brains look older or younger than their chronological age. We think that this may be in part because they have genetic factors that result in their brains aging faster or slower than the average person’s. If we can identify what those genetic factors are, then we can figure out how they work and ultimately design drugs to target those pathways. In practice, a lot of what we do is computational: We create computer programs that sift through and model vast amounts of data on the genetic differences and molecular states of brain cells. This allows us to predict which genes are the key master regulators governing the rate of brain aging.
 
We have begun to have success with these computations. Figure ii contains preliminary data showing an example of a gene we have identified that has a slightly different sequence between people whose brains age quickly and those whose brains age slowly. These results have been replicated in two separate studies. This gene’s function is to repair environmental damage that neurons undergo over time. People with slower brain aging have a version of this gene that is more abundant, so having more of this gene appears to cascade down to slow overall brain aging.
 
This is one example of an anti-brain-aging drug target. Perhaps one day we could create a drug that would increase the levels of this gene in elderly people who have the inferior version of it. We still have a long way to go in narrowing down the best anti-aging drug targets and proving that they do what we think they do experimentally, but we believe that we may get there soon. I think that the future of treating neurodegenerative disease will be in slowing down and reversing brain aging itself, which will have the wonderful side effect of restoring our thinking and moving abilities to their youthful peak. We are optimistic that this may be a reality within our lifetimes.
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Elizabeth Chadis

Assistant Dean for Development
t: 617-253-8903
e: ECHADIS@MIT.EDU
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