Latest German Study: Calorie Restriction Reverses Fast and Clumsy DNA Reading During Aging

Key Points

Aging affects numerous cellular processes, including the quality and concentration of proteins within cells. DNA transcription constitutes one of the essential steps in protein production from DNA sequences; however, it’s currently unknown to what extent transcription contributes to or is affected by aging.

Published in Nature, Beyer and colleagues from the University of Cologne in Germany show that DNA transcription speed accelerates with age in species ranging from worms to flies, mice, rats, and humans and that a calorie-restricted diet slows DNA transcription. Manipulating genes to reduce DNA transcription speed in aged worms and flies increases their lifespans. Furthermore, increasing the abundance of proteins that DNA wraps around for organizational packing — histones — increases fly lifespan. These findings suggest that DNA becomes less organized around depleted histones during aging, which can increase the rate of transcription and facilitate clumsy, error-prone protein production. Antiaging interventions like calorie restriction can reverse this effect, slowing DNA transcription rates, which may theoretically result in protein production with fewer errors.

“Our results uncover fundamental molecular mechanisms underlying animal ageing and interventions to extend lifespan, providing clues as to how we might contribute to healthy ageing in the future,” says Dr. Andreas Beyer, professor at the Institute for Genetics of the Faculty of Mathematics and Natural Sciences at the University of Cologne and principal investigator of the study, in a press release. “The fact that interventions, such as a reduced calorie intake, also have a positive effect on a healthy ageing process on the molecular level via improving the quality of gene transcription is something which we have now been able to prove quite clearly with our study.”

Calorie Restriction Reverses Age-Related DNA Transcription Acceleration

To find whether transcription features like speed change during aging, Beyer and colleagues measured the number of RNA sequences that don’t contribute to protein production (introns) removed during transcription, an indicator of overall transcription speed. Lesser RNA introns suggests increased transcription speeds. Beyer and colleagues used animals ranging from worms to flies, mice, rats, and humans and included tissue analyses from these animals’ brain, liver, kidney, and blood. In their transcription speed analyses, they discovered that across species and tissue types, DNA transcribed to RNA accelerates with age and that the antiaging intervention of calorie restriction, where calories are cut from the diet, slows transcription in mice. Faster transcription can result in more RNA errors, leading to RNA degradation and protein sequence errors, both factors that can contribute to the production of lower quality proteins and cellular and tissue dysfunction during aging. Reversing accelerated transcription during aging with calorie restriction may improve the quality of proteins and enhance health during aging.

To find whether slowing transcription affects health and lifespan, Beyer and colleagues used worms and flies. The researchers genetically inhibited the function of the transcribing enzyme RNA polymerase II, rendering the enzyme slower. By slowing the rate of DNA transcription, the researchers increased the median worm lifespan by ~20% and the median fly lifespan by ~10%. These findings support that slowing DNA transcription increases lifespan in worms and flies and likely health during aging since health is required for longer lifespans.

Because the organization of DNA around histones depends on histone availability and histone levels decline during aging, Beyer and colleagues genetically increased histone levels in flies. They tested whether increasing histone abundance could slow transcription and increase lifespan. Interestingly, they found that genetically increasing histone levels slowed DNA transcription and increased lifespan, suggesting that DNA transcription accelerates during aging due to lower abundance of histones for DNA organization and structure.

Calorie Restriction Can Especially Benefit Overweight or Obese Adults

The study’s findings suggest that accelerated DNA transcription, which has been linked to clumsy and error-prone protein production, may drive aging. Along those lines, slowing DNA transcription by genetically manipulating the transcribing enzyme RNA polymerase II increased worm and fly lifespan.

Moreover, accelerated DNA transcription likely results from less organized and more loosely-compacted DNA that develops with age due to less histone abundance. In that regard, Beyer and colleagues showed that mutant flies with increased histone protein levels for DNA organization and compaction exhibited longer lifespans. The study also ties the antiaging intervention of calorie restrictions to better transcription, possibly through increasing the abundance of histone proteins for DNA organization and compaction.

Essentially, calorie restrictions reverse DNA transcription acceleration during aging in multiple tissues from multiple species. The question remains whether calorie restrictions increase lifespan in humans. Studies using nonhuman primates suggest that calorie restricted diets don’t exactly increase lifespan in normal weight or lean people but that overweight or obese people may benefit to some degree. Calorie restricted diets may improve the number of years people live without disease (healthspan), though, by potentially slowing DNA transcription.