Researchers have identified a new key mechanism governing the aging process in worms. By genetically manipulating this mechanism, they have successfully extended the lifespan and health-span of worms without changing their diet, environment, or other external factors. This allows them to trade weak, frail old age for robust golden years.
Why do some individuals live longer than others? While genetics play a significant role in avoiding disease and maintaining overall health, they only explain less than 30% of the variability in human life expectancy.
Studying how aging works at a molecular level could offer insights into lifespan differences, but collecting the necessary data in humans is impractical. That’s why researchers turn to worms (Caenorhabditis elegans) as they share many biological similarities with humans and exhibit a wide range of lifespans.
Scientists at the Centre for Genomic Regulation (CRG) observed thousands of genetically identical worms in a controlled setting. Despite identical diets, temperatures, and exposure to predators or pathogens, some worms lived longer or shorter lives than the average.
The study found that variations in the mRNA content of germline cells (related to reproduction) and somatic cells (body cells) were the primary source of this variability. Over time, the mRNA balance between these cell types becomes disrupted, accelerating aging in some worms. These findings are published in the journal Cell.
Additionally, the research identified a group of at least 40 genes that influence the speed and extent of this decoupling process. These genes serve various functions in the body, from metabolism to the neuroendocrine system, and collectively affect individual lifespan.
Manipulating some of these genes extended worm lifespan, while altering others shortened it. This suggests that the natural aging differences observed in worms may result from random gene activity variations.
“The lifespan of a worm, whether it lives to day 8 or day 20, is determined by random gene activity. Some worms seem lucky as they possess the right gene mix activated at the right time,” explains Dr. Matthias Eder, lead author of the study at the Centre for Genomic Regulation.
By targeting three genes – aexr-1, nlp-28, and mak-1 – the research significantly reduced the lifespan variability from around 8 days to just 4. Removing any of these genes notably increased the lifespan of short-lived worms while having minimal impact on longer-lived worms.
The researchers also observed improvements in healthspan, the duration of healthy life, in worms by maintaining vigorous movement. Knocking down a single gene notably enhanced healthy aging in worms with shorter healthspans.
“Our aim is not to create immortal worms but to make aging a more equitable process – a fairer game for everyone. We’re essentially enhancing the health of worms that would typically have shorter lives, allowing them to get closer to their maximum potential lifespan by targeting fundamental aging mechanisms,” says Dr. Nick Stroustrup, senior author of the study at the Centre for Genomic Regulation.
The study does not explore why knocking down these genes does not appear to harm worm health. Dr. Eder suggests that multiple genes may provide redundancy as worms age or that these genes are unnecessary in safe lab conditions but crucial in the wild. These are some of the proposed theories.
To make these discoveries, researchers developed a method to measure RNA molecules in various cells and tissues, coupled with the use of the ‘Lifespan Machine’ which tracks the entire lives of numerous nematodes simultaneously. The nematodes are observed in a petri dish inside the machine, continuously scanned for behavioral data. Future plans involve creating a similar machine to study aging causes in mice, species anatomically closer to humans.
