Age-induced metabolic changes in protein acetylation and their role in cognitive loss

Everyone knows you’re not supposed to shoot the messenger. Yet, to extend our healthy years further into old age, decreasing delivery of certain cellular messages might be exactly what we need to do. As cells go about their business, carrying out all the chemical reactions of life (collectively known as metabolism), some of the molecular byproducts (metabolites) transmit messages that affect how our genes are expressed. Some of these metabolites make changes to the packets of DNA and proteins that form our chromosomes. Such “remodeling” alters the way our DNA is read—without changing the genetic sequence itself—by tacking on specific chemical groups. This type of modification belongs to the realm of epigenetics. Some epigenetic remodeling, spurred on by the products of metabolism, increases as organisms enter midlife, the period when early symptoms of aging appear. Now, the work of Dr. Shahaf Peleg has shown that reducing that activity by disrupting communication between metabolism and our epigenome might hold the secret to living longer and healthier lives.
Unexpectedly, he found that metabolism in fruit flies increases at midlife. The trouble is increased metabolism means cells generate more of one product that also directs epigenetic changes associated with aging. Since metabolism can’t just be turned down like the volume on a stereo, Dr. Peleg took aim instead at the connection between it and epigenetic remodeling. Using genetic techniques to reduce levels of the molecules acting as messengers, he was able to scramble this cellular communication. The result was healthier flies living longer, with less age-associated changes to their gene expression through epigenetic modification: the aging process had slowed down.
“It’s not just about reducing metabolism,” Dr. Peleg explains. “It’s all about the connectivity,” a phenomenon with a role in many different conditions whose shadow looms over us as we age: cancer, neurodegenerative disease, inflammation… The good news is that this communication between metabolism and gene expression is similar across species, meaning that Dr. Peleg’s results in flies could apply to humans. The next step will be to test it in mice, with the hope of, one day, developing drugs for people. Such a treatment would be taken around age 35 to 45, when aging is only just beginning. The goal is not to reverse age-related decline, but rather to extend one’s healthy years before it even sets in. “The idea is to live longer and healthier,” Dr. Peleg says. The potential impact of that—for individuals, for health systems, for the economy and society—can hardly be overstated.

Scientific title: Age-induced metabolic changes in protein acetylation and their role in cognitive loss

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