Visual Vitality: Study Finds Dietary Restriction Delays Circadian Eye Aging to Extend Lifespan

The changes to our vision can happen so gradually that you might barely notice it at first. But after age 40, the visual system slowly deteriorates, causing you to hold books farther and farther away, reach for your glasses more often than before, or start to have trouble driving in the dark.   

Apart from the frustrating annoyances of losing vision with age, researchers now suggest that visual aging can directly regulate lifespan—and that our eyes may also be the link between caloric restriction and lengthened longevity. In a recent study published in Nature Communications, Buck Institute researchers demonstrate for the first time a direct link between dietary restriction, circadian rhythm, eye health, and lifespan in fruit flies.

The Aging Eye 

Aging is associated with a progressive decline in visual function and eye disorders—and this can begin in mid-life, much earlier in life than many think. 

Researchers believe that changes to circadian rhythms—our internal 24-hour body clocks—are a causal determinant of how quickly or slowly our eyes age. This is seen in animal studies, in which mice with mutations to circadian clock genes display premature eye aging. 

Progressive declines in circadian rhythm function are a common hallmark of aging. (If you used to sleep in until 9 A.M. but now find yourself waking with the roosters, this is a prime example of age-induced circadian changes.) However, alterations to our internal clocks may not merely be a biomarker of aging, but rather, circadian rhythm dysfunction might play a causal role in aging.

Not only that, but visual aging is also linked to disorders in other organs and tissues, including poor metabolic, cardiovascular, and cognitive health. Senior author of this study and Buck Institute Professor Pankaj Kapahi, Ph.D., states, “Our study argues that it is more than correlation: dysfunction of the eye can actually drive problems in other tissues.”

But, the molecular mechanisms behind why the circadian clock influences eye aging have not been well understood—until now, with this research by Hodge and colleagues. 

How What We See Changes How Long We Live

Dietary (or caloric) restriction—the reduction of total calories or nutrients consumed daily—is known to delay disease and extend lifespan. The mechanisms driving these benefits may be tightly linked with our inner clocks, as dietary restriction enhances and preserves circadian function with age.

Hodge and colleagues looked to specialized neurons in the eye that detect light—photoreceptor cells—to uncover more of the mysteries of these mechanisms. The research team speculates that fruit fly (Drosophila melanogaster) photoreceptor cells can serve as a powerful model for visual and retinal degeneration—although we certainly aren’t flies, they are a commonly used model in biological research. As lead author Brian Hodge, Ph.D., explains, “The fruit fly has such a short lifespan, making it a really beautiful model that allows us to screen a lot of things at once.”

Photoreceptors—in both flies and mammals like us—have intrinsic molecular clocks that temporally regulate many physiological processes, including metabolism, light sensitivity, and pigment production. 

A previous study from the same team found that fruit flies on a calorie-restricted diet had significant changes in their circadian rhythms and extended lifespans. For decades, researchers have verified the link between caloric restriction and lifespan extension in apes, rodents, and lesser species. Conversely, mice on unhealthy high-fat diets exhibit circadian rhythm disruption in a way that accelerates aging. 

Although the circadian clock was suspected as one of the main players in this connection, it was unexpected to find that the eye directly regulated lifespan in this study with fruit flies. As Kapahi says, “We are now showing that not only does fasting improve eyesight, but the eye actually plays a role in influencing lifespan.”

Tick, Tock, CLOCK

In this study, Hodge and colleagues first surveyed gene activity in fruit flies to see which ones fluctuated on a time-dependent basis, finding many genes that were both diet-responsive and temporal-based, or “rhythmic.” The flies were either fed an unrestricted diet or one with just 10% of the standard protein amount—the dietary restriction group.

The rhythmic genes that were activated with dietary restriction all appeared to be coming from the flies’ photoreceptors, leading the Buck Institute team to wonder how eye function related to dietary restrictions’ impact on longevity. From there, they set up various experiments to test these theories, like one showing that flies living in constant darkness had significantly extended lifespans. (This may be why naked mole rats—who have evolved to be virtually blind—are the longest-lived rodents.) 

The team also found that manipulating the circadian genes—the primary one is aptly named CLOCK—inside photoreceptors influenced visual aging. Fruit flies without an active CLOCK gene displayed accelerated declines of visual senescence—the irreversible growth arrest of cells—and reductions in behavioral and electrical responses to light in their photoreceptors. Dietary restriction slowed down the typical age-related visual declines in flies with normal circadian genes. But flies without CLOCK had only minimal protection against these declines, indicating that dietary restriction’s ability to improve visual markers is reliant on healthy CLOCK function. 

Hodge and colleagues then wondered if the rhythmic photoreceptor genes activated by dietary restriction also influenced lifespan—and it turned out they did. Flies without the CLOCK gene displayed significantly shorter lives, even on a restricted diet.

On the flip side, flies with increased CLOCK activity in their photoreceptors had longer lives. The researchers concluded that greater CLOCK was required for the full lifespan extension mediated by dietary restriction. 

“The finding that the eye itself, at least in the fruit fly, can directly regulate lifespan was a surprise to us,” said lead author Brian Hodge, Ph.D.

Looking Forward

Overall, the disruption of photoreceptor CLOCK function accelerates visual decline and shortens lifespan. Conversely,  increasing CLOCK activity protects against visual decline and photoreceptor dysfunction. When combined with dietary restriction, fruit flies exhibited significantly longer lives and optimal survival. 

As the authors state, “​​Our findings establish the eye as a diet-sensitive regulator of lifespan.” But, do we know if these results will translate to humans? When asked if mammalian photoreceptors will also influence longevity, Hodge reflects, “Probably not as much as in fruit flies. But since photoreceptors are just specialized neurons, the stronger link I would argue is the role that circadian function plays in neurons in general, especially with dietary restrictions, and how these can be harnessed to maintain neuronal function throughout aging.”

Future research should target our circadian clocks to slow down aging and better understand the links between our eyes and longevity. As for now, we’ll have to wait and see.

References: 

Hodge BA, Meyerhof GT, Katewa SD, et al. Dietary restriction and the transcription factor clock delay eye aging to extend lifespan in Drosophila Melanogaster. Nat Commun. 2022;13(1):3156. Published 2022 Jun 7. doi:10.1038/s41467-022-30975-4

Katewa SD, Akagi K, Bose N, et al. Peripheral Circadian Clocks Mediate Dietary Restriction-Dependent Changes in Lifespan and Fat Metabolism in Drosophila. Cell Metab. 2016;23(1):143-154. doi:10.1016/j.cmet.2015.10.014