Specific small sequence changes in the DNA have long been shown to increase health- and lifespan in various species. The research group headed by CECAD member Martin Denzel at the Max Planck Institute for Biology of Ageing has now globally investigated gene mutations in the small roundworm Caenorhabditis elegans to find genetic pathways that control the aging process.
Some mutations improve the lifespan of worms
The tiny worm C. elegans is a perfect organism to study genetics and aging. First, the worms are hermaphrodites. Because they reproduce by self-fertilization, the offspring of one worm is genetically identical with their parent. Second, the standard lifespan of C. elegans is only 21 days, which makes it easy to study their whole life cycle. Since the aging process is a conserved feature during the evolution of animals, researchers hope to draw parallels between worm, mouse, and human aging.
To realize their goal of identifying genes that modulate the aging process, Denzel and his team treated worms with a chemical agent that causes small mutations in the worm’s DNA. “We searched for mutant worms that live longer than worms without any mutations. In total, we found over 100 worm strains that outlive controls by more than 18%. Some strains even lived 50% longer. This was the fundamental groundwork of our study”, explains Dr. Maxime Derisbourg, one of the lead authors of the study.
Blocking a stress response makes worms live longer and healthier
While finding worms that significantly live longer was a first success, the novelty in this process was the identification of specific new DNA mutations that caused the observed lifespan extensions. “We were excited to find that we could connect mutations in genes that control the process of mRNA translation with the longevity of the mutant worms," says Laura Wester, the second lead author of the study. mRNA translation is an important step in protein production in every cell of any living organism. To build proteins and enzymes, DNA is transcribed to messenger RNA (mRNA), which is then translated into a protein. The researchers identified long-lived worms with mutations in four different genes that act together on the first step of this protein production process. In addition to enabling protein production, the same genes are implicated in a process that shuts down protein production when the organism is stressed, for example when not enough food is available. This so-called integrated stress response acts like a “time-out” and prevents the production of faulty proteins under stress conditions.
Surprisingly, the researchers could show that some of their long-lived worm strains have a lower activity of this stress response. Also, if they deliberately and fully shut down this stress response genetically or pharmacologically by using specific drugs, worms out-lived the standard lifespan of 21 days and showed a lifespan extension of over 20%. Based on these and other findings, the researchers propose that fine-tuning the integrated stress response and the early protein production process can lead to an improved health- and lifespan. Denzel and the lead authors are looking forward to investigate whether these observations hold true in higher organisms such as mice or eventually even humans: “Our results let us hypothesize that specifically modulating the integrated stress response and fine-tuning the early steps of protein production in healthy organisms can extend lifespan not only in worms, but potentially also in higher organisms such as mice or even humans. This intriguing possibility is yet to be discovered.”
Original publication:
Maxime J. Derisbourg *, Laura E. Wester *, Ruth Baddi, Martin S. Denzel.
Mutagenesis screen uncovers lifespan extension through integrated stress response inhibition without reduced mRNA translation.
Nature Communications, 2021
Published online: 15.03.2021, DOI: 10.1038/s41467-021-21743-x
* Equal first authors
Original announcement: