Research on C. elegans shows that the mRNA balance in cells influences lifespan

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

Investigating how aging is affected at the molecular level could shed light on variation in lifespan, but generating data at the speed, scale and quality needed to study this in humans is unfeasible. Instead, researchers turn to worms (Caenorhabditis elegans). Humans share a lot of biology with these little creatures, which also have a wide, natural variation in lifespan.

Researchers from the Center for Genomic Regulation (CRG) observed thousands of genetically identical worms living in a controlled environment. Even if 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 levels in germline cells (those involved in reproduction) and somatic cells (the cells that make up the body). The mRNA balance between the two types of cells is disrupted, or ‘uncoupled’, over time, causing aging to progress more rapidly in some individuals than in others. The findings are published today in the journal Cell.

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

Knocking down some genes extended a worm’s lifespan, while knocking down others shortened its lifespan. 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 have been exposed to the silencing of many different genes.

“Whether a worm makes it to day 8 or day 20 depends on seemingly random differences in the activity of these genes. Some worms just seem to get lucky because they have activated the right mix of genes at the right time,” says Dr. Matthias Eder, first author of the article and researcher at the Center for Genomic Regulation.

Knocking out three genes – aexr-1, nlp-28 and mak-1 – had a particularly dramatic effect on the variation in lifespan, reducing the range from about eight days to just four. one of these genes dramatically increased the life expectancy of worms at the low end of the spectrum, while leaving the life expectancy of the longest-lived worms more or less unchanged.

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

“This isn’t about creating immortal worms, but rather about making aging a fairer process than it currently is – a fairer game for everyone. In a sense, we’ve done what doctors do, which is take worms that would sooner die than their peers and make them healthier, allowing them to live closer to their maximum potential life expectancy. But we do this by targeting the fundamental biological mechanisms of aging, and not just by treating sick individuals,” says Dr . Nick Stroustrup, senior author of the study and group leader at the Center for Genomic Regulation.

The study does not address the question of why switching off the genes does not appear to have a negative impact on the worm’s health.

“Several genes could interact to provide built-in redundancy after a certain age. It may also be that the genes are not needed for individuals living in benign, safe conditions where the worms are kept in the laboratory. In the harsh environment of the wild, these genes could be crucial 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 monitors the entire life of thousands of nematodes at the same time. The worms live in a petri dish in the machine, under the watchful eye of a scanner.

The device takes an image of nematodes once an hour and collects a lot of data about their behavior. The researchers plan to build a similar machine to study the molecular causes of aging in mice, which have biology more similar to humans.