Caenorhabditis elegans (C. elegans), a transparent roundworm, is a popular inhabitant of many labs. These worms show several repetitive behaviors, including defecation, where the worm undergoes a cycle of muscle constrictions to expel faeces every 45 seconds. In 2005, scientists discovered that by removing a single gene made the worms defecate with a faster frequency − this gene was called flr-4.
More than a decade later, this gene has made a comeback, but in a very different story.
In a recent study, scientists led by Arnab Mukhopadhyay at the National Institute of Immunology (NII) found that when they knocked down flr-4, worms had 40−60% longer lifespan.
The survival of an organism depends on how widely it can adapt their diet. For example, giant pandas, whose main diet is bamboo shoot, are on the verge of extinction due to diminishing bamboo covers. However, different diets lead to different metabolic rates, which in turn affect the lifespan of an individual (higher metabolic rates are associated with shorter lifespan and vice versa). How do animals balance between adapting to consume different kinds of diet and maintaining their lifespans?
This is where genes which maintain consistent lifespans in response to different diets come in. These are called ‘gene-diet’ pairs, where specific genes regulate the organism’s lifespan upon consuming specific diets. “There are only a few gene-diet pairs known to us that regulate longevity. Gene-diet pairs are interesting to study as they imply that in wild-type animals, the effect of the diet on life span is suppressed to maintain homeostasis. Only when the gene is mutated, you observe the effect,” said Mukhopadhyay.
The protein coded by flr-4, a kinase, preferentially phosphorylates two amino acid groups in proteins. To understand the effect of this gene on lifespan, the researchers made a mutant where they abolished this phosphorylation activity. These mutant worms were then fed two different diets− one was the standard diet of C. elegans, B strain of E.coli bacteria, while the second diet was the H strain of E.coli. B strain has lower carbohydrate content and promotes higher fat storage. The researchers found that mutant worms lived much longer when fed on H strain of E.coli compared to the B strain, while wild-type worms maintained equal lifespans on the two bacterial diets.
To understand how this gene regulates homeostasis on different diets, the researchers investigated which genes and pathways get altered when they inactivated flr-4. They found that when worms with no flr-4 activity are fed with the H strain of E.coli, they have increased levels of a set of genes that are known to protect cells against harmful agents. This could possibly explain the increased lifespan of mutant worms fed with H strain. Mukhopadhyay and his team propose that flr-4phosphorylates a yet-unknown substrate and this activity is required to maintain lifespan equilibrium when consuming different kinds of diets.
Intriguingly, flr-4 is expressed in both neurons and intestine, and reducing the expression of this gene in either tissue extends lifespan. Although the role of gut in regulating the response to different diets may be intuitive, what is the role of neurons? “It is possible that the neuronal circuit is required for smell/taste while the intestinal network identifies nutrients that the food releases,” said Mukhopadhyay. But the exact role of neurons in extending lifespan and which component of food interacts with flr-4 gene are questions which the team is now beginning to probe.
“The fact that multiple tissues of an organism, including neurons, muscles as well as intestine participate in life span regulation shows how a complex signalling network is required to maintain normal physiology within an organism to ensure optimal life span,” said Kavita Babu, Assistant Professor at the Indian Institute of Science Education and Research (IISER), Mohali, who was not involved in this study.
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