Thanks to advances in medical science over the past century, humans have never lived longer than we do right now. But longer doesn't necessarily mean healthier, and those who reach the ripe old age of 100 might spend almost half their life battling age-related chronic disease. Now, a Harvard team has discovered a link between aging and a core biological process known as RNA splicing, which may be manipulated to not only increase our lifespan, but help us stay healthier for longer.

Proteins are the essential building blocks of cells, making up the structure of different parts of the body as well as carrying out and regulating the functions of organs and tissues. Our genes provide the blueprints for producing the required proteins, and one of the main parts of that process is RNA splicing, where RNA molecules are cut and reconnected to allow for more varied proteins to be expressed.

The effects that genes and proteins have on aging is well documented, and previous studies have found ways to use genes like AMPK and Nanog to delay or even reverse the effects of aging. But, the researchers point out, the splicing process remains relatively unexplored.

"Although we know that specific splicing defects can lead to disease, we were really intrigued about de-regulation of RNA splicing as a driver of the aging process itself, because practically nothing is known about that," says William Mair, senior author of the study. "Put simply, splicing is a way for organisms to generate complexity from a relatively limited number of genes."

Keeping the entire process of gene expression running smoothly is key to maintaining youthful health, and the researchers wanted to study the broad effects that might ripple out from the natural, age-related disturbances to the splicing process.

"What kills neurons in Alzheimer's is certainly different from what causes cardiovascular disease, but the shared underlying risk factor for these illnesses is really age itself," says Mair. "So one of the big questions is: Is there a unifying theme that unfolds molecularly within various organ systems and allows these diseases to take hold?"

In old C. elegans specimens, those treated with dietary restrictions (right) showed more youthful gene splicing patterns than naturally-aged animals (left)(Credit: Caroline Heintz)

To study how splicing might affect aging, the researchers looked to Caenorhabditis elegans, a species of roundworm that's often used as a precursor to human tests in biological research, thanks to it having a genome very similar to ours. C. elegans has a storied history, being the first animal to have its genome sequenced and all the neurons in its brain mapped, and it may be the first creature sent to Mars to study the physiological effects of long-distance space travel.

"C. elegans is a great tool to study aging in because the worms only live for about three weeks, yet during that time they can show clear signs of age," says Caroline Heintz, first author of the study. "For example, they lose muscle mass and experience declines in fertility as well as immune function. Their skin even wrinkles, too."

Since the worms' cells are transparent, the team tagged the gene splicing with fluorescent proteins to help them visualize the process as the worms aged. Over five days, the researchers were able to see natural variability in the worm population, with some specimens keeping a healthy pattern of splicing for longer than others. Based on that, the team could predict the lifespans of specific worms.

"This is a really interesting result, and suggests that we might someday be able to use splicing as a kind of biomarker or early signature of aging," says Heintz.

Next, the team used the process of dietary restriction, which has been shown to increase the lifespan of organisms like C. elegans, and observed that the worms' splicing patterns stayed youthful throughout the creatures' lives. What's more, the benefit was seen across several different genes, suggesting that splicing has a fairly broad role in aging.

Further research focused on one particular part of the process called splicing factor 1 (SFA-1), and found that increasing the levels of this component extended the lifespan of the worms. The good news? SFA-1 is also found in humans.

"These are fascinating results, and suggest that variability in RNA splicing might be one of the smoking guns of the aging process," says Mair. "Of course, we have much more to learn, but this study opens up an entirely new avenue of investigation that could help us understand how to not only live longer, but also healthier."

The research was published in the journal Nature.

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