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Why do some people live longer than others? The genes in our DNA sequence are important, helping to avoid disease or maintain general health, but differences in our genomic sequence alone explain less than 30% of the natural variation in human lifespan.

Studying how aging is affected at the molecular level can shed light on variation in lifespan, but generating data at the speed, scale and quality needed to study this in humans is impossible. Instead, the researchers turned to worms (Caenorhabditis elegans). Humans share much of their biology with these tiny creatures, which also have a large, natural variation in lifespan.

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 for longer or shorter periods of time than average.

The study traced the main source of this variation to changes in the mRNA content of germline cells (those involved in reproduction) and somatic cells (the cells that make up the body). The mRNA balance between the two cell types becomes disturbed, or “disconnected,” over time, causing aging to occur 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 shedding 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 make some individuals live longer than others.

Knocking out some of the genes extends the worm’s life, while knocking out others shortens 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 were exposed to knockdowns of many different genes.

“Whether a worm lives to day 8 or day 20 comes down to seemingly random differences in the activity of these genes. Some worms seem to be just lucky because they have the right combination of genes activated at the right time,” says Dr. Matthias Eder, first author of the paper and a researcher at the Center for Genome Regulation.

Knocking out 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. Instead of extending the lifespan of all individuals equally, removing all one of these genes dramatically increased the lifespan of worms at the lower end of the spectrum, while the lifespan of the longest-lived worms remained more or less unchanged.

The researchers observed the same effects on health span, the period of life spent in a healthy state, not just how long a person is physically alive. The researchers measured this by studying how long the worms maintained vigorous movement. Knocking out just one of the genes was enough to disproportionately improve healthy aging in worms at the lower end of the healthiness spectrum.

“This is not 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’re doing what doctors do, which is taking worms that would die earlier than their peers and making them healthier, helping them live closer to their maximum potential lifespan to boot.” , says Dr. Nick Stroustrup, senior author of the study and group leader at the Center for Genome Regulation.

The study did not address why the gene knockdown did not appear to negatively affect the worm’s health.

“Several genes could interact to provide built-in redundancy after a certain age. It is also possible that the genes are not needed in individuals living in benign, safe conditions where worms are kept in the laboratory. In the harsh environment of the wild, these genes may be more critical 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, combining it with the “Lifespan Machine,” a device that tracks the lifetimes of thousands of nematodes at once. The worms live in a petri dish placed inside the machine under the watchful eye of a scanner.

The device images nematodes once an hour, collecting a lot of data about their behavior. The researchers have plans to build a similar machine to study the molecular causes of aging in mice, which have biology that more closely resembles that of humans.