A study of C. elegans found that the balance of mRNA in cells affects lifespan

Why do some people live longer than others? The genes in our DNA sequence are important, helping to prevent disease or maintain overall health, but differences in our genome sequence alone explain less than 30% of the natural variance in human life expectancy.

Investigating how aging is affected at the molecular level could shed light on lifespan variation, but generating data at the speed, scale and quality necessary to study it in humans is not feasible. Instead, researchers are turning to worms (Caenorhabditis elegans). Humans share a lot of biology with these little creatures, who also have great natural differences in lifespan.

Scientists at the Center for Genomic Regulation (CRG) observed thousands of genetically identical worms living in a controlled environment. Although diet, temperature, and exposure to predators and pathogens are the same for all worms, many individuals continue to live longer or shorter than average.

The study traced the primary source of this variation to changes in mRNA content in germ cells (those involved in reproduction) and somatic cells (cells that make up the body). The mRNA balance between these two cell types becomes disrupted, or “disconnected,” over time, causing some individuals to age more quickly than others. The findings are published today in the journal Cell.

The study also found that the size and speed of the separation process is influenced by a group of at least 40 different genes. These genes play many different roles in the body, from metabolism to the neuroendocrine system. But the study is the first to show that they all interact to make some individuals live longer than others.

Knocking down some genes extended the worm’s lifespan, while knocking out others shortened it. The findings suggest a surprising possibility: the natural differences seen in aging worms may reflect randomness in the activity of many different genes, making it appear as if individuals are subject to knockdowns of many different genes.

“Whether a worm lives to day 8 or day 20 is due to seemingly random differences in the activity of these genes. It seems that some worms are just lucky to have the right combination of genes activated at the right time,” says Dr. Matthias Eder, first author of the article and researcher at the Center for Genomic Regulation.

Knocking down three genes—aexr-1, nlp-28, and mak-1—had a particularly dramatic effect on lifespan variation, reducing the range from about 8 days to just 4. Rather than extending the lives of all individuals uniformly, removing any one of these of genes drastically increased the life expectancy of worms at the lower end of the spectrum, while the life expectancy of the longest-lived worms remained more or less unchanged.

The researchers observed the same effects on health span, the period of life spent healthy, rather than simply how long an individual is physically alive. The researchers measured this by studying how long the worms maintained vigorous movement. Knocking down just one of the genes was enough to disproportionately improve healthy aging in worms at the low end of the health spectrum.

“It’s not about creating immortal worms, but rather about making aging a fairer process than it currently is—a fairer game for everyone. In a way, we were doing what doctors do, which is taking worms that die sooner.” than their peers and make them healthier, helping them live closer to their maximum potential life expectancy, but doing so by targeting the underlying biological mechanisms of aging, not just treating sick individuals. Basically, it makes the population more homogeneous and longer to boot,” says Dr. Nick Stroustrup, lead author of the study and group leader at the Center for Genomic Regulation.

The study does not address why knocking out the genes does not seem to negatively affect the worm’s health.

“Several genes could interact after a certain age to provide built-in redundancy. It may also be that the genes are not needed for individuals living in the benign, safe conditions where worms are kept in the laboratory. In the harsh environment of the wild, these genes may be more important for survival. These are just some of the working theories,” says Dr. Eder.

The researchers made their findings by developing a method that measures RNA molecules in different cells and tissues, in combination with the “Lifespan Machine,” a device that tracks the lifetimes of thousands of nematodes at once. Worms live in a Petri dish located inside the machine under the watchful eye of a scanner.

The device scans the nematodes once an hour and collects a lot of data about their behavior. Scientists plan to build a similar machine to study the molecular causes of aging in mice, whose biology is more similar to humans.