Buck Institute researchers demonstrated for the first time a link between dietary restriction (DR), circadian rhythms, eye health and lifespan in fruit fly Drosophila melanogaster. The study results also unexpectedly indicated that processes in the fly’s eye are actually driving the aging process.
Previous studies have shown an association between eye disorders and poor health in humans. “Our study argues that it’s more than just correlation – eye dysfunction can actually cause problems in other tissues,” said senior author and Buck Institute professor Pankaj Kapahi, PhD, whose lab has shown for years that fasting and calorie restriction can improve many body functions. “We are now showing that not only does fasting improve vision, but that the eye actually plays a role in influencing lifespan.”
“The discovery that the eye itself, at least in the fruit fly, can directly regulate lifespan came as a surprise to us,” said lead author Brian Hodge, PhD, who has done his post-study. doctorate in the laboratory of Kapahi. The explanation for this connection, Hodge said, lies in the circadian “clocks,” the molecular machinery within every cell of every organism, which has evolved to adapt to everyday stresses, such as changes in light and temperature caused by rising and setting of the sun.
Kapahi, Hodge and colleagues reported their findings in Nature communicationsin a paper titled “Food restriction and transcription factor clock delay eye aging to extend lifespan in Drosophila melanogaster“, in which they concluded,” Our findings establish the eye as a regulator of diet-sensitive lifespan. “
Circadian rhythms are 24-hour oscillations that influence complex animal behaviors, such as predator-prey interactions and sleep / wake cycles, up to the fine-tuning of the temporal regulation of molecular functions of gene transcription and protein translation. “Circadian rhythms are generated by endogenous clocks that detect temporal signals (eg, light and food) to govern the rhythmic oscillations of gene transcription programs, synchronizing cellular physiology with everyday environmental stressors,” the authors write. “In addition to keeping time, the molecular clock regulates the temporal expression of downstream genes, known as clock-controlled genes, to promote tissue-specific rhythms in physiology.”
The Drosophila The molecular clock includes transcriptional-translational feedback loops, the authors explained, in which the transcription factors Clock (CLK) and Cycle (CYC) rhythmically activate their repressors. It is interesting to note that “Drosophila and mammalian photoreceptors possess a cellular molecular clock mechanism that temporally regulates many physiological processes, including sensitivity to light, metabolism, pigment production, and susceptibility to light-mediated damage.
Previous research has shown that food or calorie restriction delays disease and prolongs life span. “Food restriction is one of the most robust therapies for extending lifespan and amplifying circadian rhythms with age,” the team continued. In 2016, Kapahi’s lab published a study in Cell metabolism showing that fruit flies on a restricted diet had significant changes in their circadian rhythms as well as prolonged lifespan. Hodge, who joined the lab in the same year, wanted to dig deeper to understand which processes that improve circadian function were altered by dietary changes and whether circadian processes were needed for the longer lifespan observed with dietary restrictions.
“The fruit fly has such a short lifespan, which makes it a really beautiful model that allows us to screen many things at once,” said Hodge, who is currently a scientist at Fountain Therapeutics in southern San Francisco. The study began with an extensive investigation to see which genes fluctuate circadian when flies on an unlimited diet were compared to those fed only 10% of the protein from the unlimited diet.
Immediately, Hodge noticed numerous genes that were both diet responsive and also exhibited highs and lows at different times, or “rhythms.” She then found that the rhythmic genes that activated the most with dietary restrictions all seemed to come from the eye, particularly photoreceptors, the specialized neurons in the eye’s retina that respond to light. “We found that circadian processes within the eye are very high in expression in flies raised on DR,” the researchers noted in their paper. In particular, DR improved the rhythmic expression of genes that code for proteins involved in light adaptation (ie, calcium manipulation and deactivation of rhodopsin-mediated signaling). “
This discovery led to a series of experiments designed to understand how ocular function fits into the story of how food restriction can extend lifespan. For example, they started experiments showing that keeping flies in constant darkness extended their life. “It seemed very strange to us,” Hodge said. “We thought flies needed light signals to be rhythmic or circadian.” The authors noted: “Diet restricted flies are protected from the lifespan shortening effects of photoreceptor activation. In contrast, photoreceptor inactivation, achieved through rhodopsin mutation or housing of flies in the ‘constant darkness, mainly extends the lifespan of flies raised on a nutrient-rich diet. “
The researchers then used bioinformatics to ask, “Do genes in the eye that are also rhythmic and responsive to dietary restrictions affect lifespan?” The answer was that yes, they do. “We always think of the eye as something we need, to provide sight. We don’t think of it as something that needs to be protected to protect the whole organism, ”said Kapahi, who is also an associate professor of urology at the University of California, San Francisco.
The team also reported that among the most interesting and unexpected results of their study was the observation that the Drosophila eye affects systemic immune responses. Because the eyes are exposed to the outside world, Kapahi explained, the immune defenses are critically active, which can lead to inflammation that, if present for long periods of time, can cause or worsen a number of common chronic diseases. Also, light by itself can cause photoreceptor degeneration which can cause inflammation.
The authors concluded: “Ours fiThe findings establish the eye as a diet-sensitive lifespan regulator. DR‘The neuroprotective role of s in photoreceptors appears to be mediated by the transcription factor CLK, which promotes the rhythmic oscillation of genes involved in the suppression of phototoxic cellular stress.
Kapahi noted: “Staring at computer screens and phones and being exposed to light pollution late into the night are very disturbing conditions for circadian clocks. It messes with eye protection and this could have consequences beyond just sight, damaging the eye. rest of the body and the brain “.
There is still a lot to understand about the role the eye plays in an organism’s overall health and lifespan, including: how does the eye regulate lifespan and does the same effect apply to other organisms? “… we cannot conclude whether neuronal or eye-mediated increases in systemic inflammation are causing aging in other tissues,” the scientists acknowledged. “Furthermore, the mechanisms through which the Drosophila eye and, more specifically, photoreceptors influence systemic immune responses are not clear ”.
The biggest question raised by this work as it might apply to humans is, simply, do photoreceptors in mammals affect longevity? Probably not as much as in fruit flies, Hodge said, noting that most of the energy in a fruit fly is devoted to the eye. But since photoreceptors are just specialized neurons, he said, “the strongest link I would say is the role circadian function plays in neurons in general, especially with dietary restrictions, and how these can be harnessed to maintain neuronal function during aging “.
Once researchers understand how these processes work, they can begin targeting the molecular clock to decelerate aging, Hodge said, adding that it could be that humans can help maintain vision by activating clocks at all. inside of our eyes. “It could be through diet, medications, lifestyle changes … We have a lot of really interesting research ahead of us,” she said.