Apple for My Eye

Chronobiologist Brian Hodge is predominantly focused on developing drugs for aging and age-related disease at Fountain Therapeutics in California, US. Here, Hodge talks to our Associate Editor Oscelle Boye about his team’s explorations into the links between lifestyle and eye health in fruit flies, which were showcased in a Nature Communications paper in June 2022 (1).

What’s your elevator pitch for the study?
 

Our study examines how the anti-aging and lifespan extending benefits of dietary restriction are mediated in part by amplifying circadian homeostatic processes within the eye that protect it from light and age-associated damage. Surprisingly, we found that the photoreceptor itself plays a role in organismal aging; forcing photoreceptor degeneration or simply altering circadian clock function within the photoreceptor was sufficient to shorten lifespan.

What prompted you to undertake this research?
 

In graduate school, I was working on understanding the role that circadian molecular clocks play in adult tissue physiology and function, paying particular attention to circadian rhythms in mouse skeletal muscle. By examining clock mutant animals, our group and others began to find that disrupting circadian rhythms resulted in accelerated aging. I became fascinated with understanding how circadian clocks may mediate the beneficial effects of anti-aging diets. As I was finishing up my graduate school projects, I read a fascinating story from Pankaj Kapahi’s group, which showed how the well-established lifespan-extending dietary paradigm – dietary restriction (DR) – robustly amplified circadian rhythms in fruit flies. Not long after, other groups demonstrated similar findings with calorie restriction (CR) amplifying circadian rhythms in aged mice. Although I never worked with the fruit fly, I was aware of its utility because many of the top circadian biologists were “fly people” – the 2017 Nobel prize was awarded to three fly biologists for the discovery of the core molecular clock mechanism in Drosophila. So, I did something that most early career scientists don’t do – I decided to stop working with mice and shifted to working with the fruit fly for my post-doctoral studies. I wanted to know: Do lifespan extending dietary paradigms (DR/CR) slow aging by activating the clocks within our cells? And if so, which tissues are the clocks working through to improve survival? It was apparent to me that if I wanted to perturb the clocks in an array of tissues and examine how they influenced DR’s ability to extend lifespan, I would have to do so in a short-lived animal like the fly; such a problem would take decades to solve if I was looking at multiple mouse lifespans.

Why do ophthalmologists need to know about this study?
 

Simply put, I think it is important that ophthalmologists are aware that circadian rhythms play a pivotal role in eye health. Our findings build on earlier observations that circadian disruption accelerates eye aging because we demonstrate how diet influences clock function within the eye. Furthermore, this study provides a more mechanistic understanding of the genes/processes under circadian control in the eye and how they influence eye aging.

Why are circadian rhythms important for the eye?
 

Circadian rhythms evolved to allow cells to anticipate and cope with daily environmental stressors by aligning cellular physiology to that of the solar day. UV light not only acts as one of our strongest time-cues for entraining our rhythms, but is also very damaging to our cells (phototoxicity, DNA damage, and so on). Throughout the day there is a ~100-million-fold difference in light intensity (Lux) when the sun is at its brightest to the middle of the night. As a protective measure against phototoxicity, the clocks within our photoreceptors temporally regulate their excitability inversely with the sun’s brightness. By analyzing gene expression changes over a 24-hour period we found that many of the processes that regulate light sensing and adaptation to light are circadian and temporally segregated. During the light phase, we found an enrichment for genes associated with the suppression of phototransduction (negative regulation of rhodopsin signaling, rhodopsin endocytosis, calcium sequestration/exocytosis), while processes associated with light sensitivity peaked in the middle of the night (dark) phase (expression of rhodopsins and the TRP channels responsible for calcium-mediated action potentials). Interestingly, the amplitude (the difference between the peak and trough) of the gene expression rhythms was more robust in animals on DR. When we genetically knocked out the clock function within the photoreceptors, we saw that DR’s ability to delay aging was lost. Inversely, we found that when animals were reared on a high-nutrient diet their circadian rhythms were dampened and their photoreceptors degenerated quicker with age. When we over-expressed or activated the clocks within photoreceptors, we were able to markedly delay visual senescence even in animals on a high-nutrient diet.

Humans are not fruit flies – so how well can the results be extrapolated?
 

The mechanisms of phototransduction (the process of converting light signals to action potentials) differs from Drosophila photoreceptors and the rods/cones found in our eyes, but are more similar to the intrinsically photosensitive retinal ganglion cells (ipRGCs). Unlike the rods and cones, human ipRGCs are not involved in visual perception (shapes, color, and so on), but function to sense and communicate lighting information to the central clocks (suprachiasmatic nucleus) within our brains to entrain our behavior with that of the solar day. The amount of light that reaches our retinas declines quite significantly with age due to a progressive thickening and yellowing of our corneas. Losses in the fraction transmitted blue light coupled with age-related degeneration of ipRGCs results in an overall loss in our ability to entrain to light with age; for example, most older people take much longer to entrain to new light cycles when they change time zones. Interestingly, circadian behavioral decline is one of the earliest and debilitating symptoms of neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). These individuals suffer from sleep fragmentation that is thought to further exacerbate neurodegeneration. A number of groups have begun to observe positive results when performing blue-light therapy with AD and PD patients: strong lighting cues, provided at the right time of day, appear to help entrain their weakened clocks.

Our findings show that the eye is highly sensitive to one’s dietary intake, and therefore fasting and or fasting mimetics that promote strong circadian rhythms in the eye may help to slow eye aging and promote stronger circadian behavioral rhythms in the aged and in individuals suffering from neurological disorders. Additionally, with the advent of the light-bulb and computer screens, modern humans are constantly bombarded with light pollution that can adversely affect the eye and accelerate retinal degeneration. Therefore, understanding how diet and other therapies that protect the eye from light and age-associated damage should be of high priority.

Where do we go from here?
 

I think an obvious next steps would be to i) examine how diet influences circadian rhythms within the mammalian eye, and ii) determine if the molecular clocks within our eyes can be therapeutically targeted. There are a number of academic labs and a few early biotech startups actively developing clock-enhancing small molecules that have beneficial and anti-aging effects on mice. I would really like to see if and how these compounds may be used to treat eye disorders and fight age-related visual declines.

Visual perception is tightly linked with one’s general well-being and quality of life, but our findings demonstrate for the first time that the eye itself can actually influence the aging process and modulate an organism’s longevity. So, I think it’s time that we begin to look at the eye in a new light and try to understand the mechanisms by which the eye can influence aging in other tissues.