C. elegans study reveals mRNA balance in cells influences lifespan

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

Exploring how aging is influenced at the molecular level could shed light on variation in lifespan, but it is impossible to generate data at the speed, scale and quality needed to study this in humans. ‘man. Researchers are instead turning to worms (Caenorhabditis elegans). Humans share a lot of biology with these little creatures, whose lifespans also vary naturally.

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

The study traced the main source of this variation to changes in the mRNA content of germ cells (those involved in reproduction) and somatic cells (the cells forming the body). The mRNA balance between the two cell types becomes disrupted, or “uncouples,” over time, leading to faster aging in some individuals than others. The results 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 to allow some individuals to live longer than others.

Deleting some genes extended a worm’s lifespan, while deleting others shortened it. The results suggest a surprising possibility: that the natural differences observed in worm aging could reflect the randomness of the activity of many different genes, making it appear that individuals were exposed to inactivations of many different genes.

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

Deleting three genes – aexr-1, nlp-28 and mak-1 – had a particularly dramatic effect on the variance in lifespan, reducing the range from about 8 days to just 4. Rather than extending the lifespan of all individuals uniformly, deleting any one of these genes significantly increased the lifespan of worms at the lower end of the spectrum, while the lifespan of the longest worms is remained more or less unchanged.

Researchers observed the same effects on lifespan, the period of life spent in good health, rather than simply on the length of time an individual is physically alive. The researchers measured this by studying how long the worms maintain vigorous movement. Knocking out just one of the genes was enough to disproportionately improve healthy aging in worms at the lower 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 all. In a way, we’ve done what what doctors do, that is, take worms that would die earlier than their peers and make them healthier, thereby helping them live closer to their maximum potential life expectancy. fundamental biological mechanisms of aging, and not just by treating sick individuals. It’s basically about making a population more homogeneous and living longer to boot,” says Dr. Nick Stroustrup, lead author of the study and. group leader at the Center for Genomic Regulator.

The study does not explain why gene destruction does not appear to negatively affect the worm’s health.

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

The researchers made their discoveries by developing a method that measures RNA molecules in different cells and tissues, combining it with the “Lifespan Machine”, a device that simultaneously tracks the entire lives of thousands of nematodes. The worms live in a petri dish housed inside the machine under the watchful eye of a scanner.

The device images the nematodes once an hour, collecting lots of data on their behavior. The researchers plan to build a similar machine to study the molecular causes of aging in mice, whose biology more closely resembles that of humans.