The lifespans of flies and worms are prolonged by inhibiting the activity of RNA polymerase III, an enzyme common to all animals, finds a new study published in the December 14 issue of the journal Nature.
Filer et al find that inhibition of Pol III extends organismal lifespan in flies and worms. Image credit: Sven Lachmann.
The study found that the lifespans of flies and worms, and the survival of yeast cells were extended by an average of 10% following a modest reduction in the activity of RNA polymerase III (Pol III).
“We uncovered a fundamental role for Pol III in adult flies and worms: its activity negatively impacts stem cell function, gut health and the animal’s survival,” said study first author Danny Filer, from the Institute of Healthy Ageing at University College London, UK.
“When we inhibit its activity, we can improve all these.”
Pol III is present in most cells across all animal species, including humans. While it is known to be essential for making proteins and for cell growth, its involvement in aging was unexplored until now.
“As Pol III has the same structure and function across species, we think its role in mammals, and humans, warrants investigation as it may lead to important therapies,” Filer said.
The effects of inhibiting Pol III were found to be comparable to the action of the immune-suppressing drug rapamycin, which has previously been shown to extend the lifespans of mice and many other animals.
This discovery will help scientists understand the mechanism of action of drugs, such as rapamycin, that show promise for extending the lifespans of mammals.
“Understandably, there’s a lot of hype around drugs that extend lifespan and promote healthy aging but very little is known about how they work, which is fundamental knowledge,” said co-lead author Dr. Nazif Alic, also from the UCL Institute of Healthy Ageing.
“We now think that Pol III promotes growth and accelerates aging in response to a signal inhibited by rapamycin, and that inhibiting Pol III is sufficient to result in flies living longer as if they were given rapamycin.”
“If we can investigate this mechanism further and across a wider range of species, we can develop targeted antiaging therapies.”
The researchers used a range of genetic methods, including insertional mutagenesis and RNA mediated interference, to inhibit Pol III in adults and observe the extension of lifespan.
Yeast, flies and worms were used as model organisms as they are not closely related but all contain Pol III.
Inhibiting Pol III in the guts of flies and worms, was sufficient to extend lifespan, and when Pol III was inhibited in flies’ intestinal stem cells alone, they also lived longer.
“It is amazing that we can make one genetic adjustment and positively impact on lifespan and intestinal health, understanding more about the underlying molecules at work here promises new strategies for anti-aging therapies,” said co-lead author Dr. Jennifer Tullet, from the University of Kent, UK.
_____
Danny Filer et al. 2017. RNA polymerase III limits longevity downstream of TORC1. Nature 552: 263-267; doi: 10.1038/nature25007
