The biological clock is ticking: circadian rhythms and aging

introduction

I decided to create this text because ever since working as a nurse aide in memory care facility over the summer, routine and age have stayed somewhat in the back of my mind. I figured, if everyday we live, and everyday we age, the two must be connected in some meaningful way. At first, the research was more so about my own curiosity between the aging and circadian rhythms. Reading the articles, however, I started to notice a trend among the abstracts where they’d report statistics about the growing graying population, as well as the growing incidence of age-related diseases. I began to think about the implications of this, if healthcare systems today could support these rates. Even if they could, would that really be the best solution? There were plenty of grim statistics regarding caregiving from both non-professional and professional perspectives.

Consequently, I refocused my question because it wasn’t about living to a hundred, it was about thriving at a hundred. Growing old shouldn’t mean losing the ability to do things you once could do— senescence is a possible reality and something to strive for. More than ever, there should be an emphasis on preventive healthcare, and even if it only raised awareness, so if you decide to read this, thank you!

A short disclaimer: what we know about health is constantly changing, so while I believe circadian rhythms play some important role in our health, I can’t say how exactly or to what extent. This is just the general consensus from the articles I read—the way I like to think about it is that I’m one brain trying to make sense of all the information of thousands of brains, many of which belong to experts who know way more in terms of the different pathways and all the players involved. I don’t intend to spread misinformation about health, so if something here strikes you, I recommend conducting your own research (of course being mindful of biases and sourcing. Again, thank you!

circadian rhythms

We’re asleep during the night, and we’re up during the day. We don’t follow this pattern everyday because we’re told to... this routine is sort of just built into our physiology. This is just one example of a circadian rhythm, the scientific way of saying there are tiny clocks in our body that regulate when we sleep, eat, produce hormones, and much more. Circadian rhythms are regulated by specific time cues, and in this case of the sleepwake cycle, that time cue is light.

bidirectional relationship

A bidirectional relationship exists between aging and circadian rhythms, meaning signs of aging either "affects the circadian clock function" or are "regulated by" the circadian clock (1).

On one hand, aging affects circadian rhythm: 1. The elderly experience more frequent sleep disruptions, get fewer hours of REM sleep, secrete less melatonin (a hormone regulated by the circadian system known to signal sleep and have antioxidant properties), and begin to prefer mornings (1). 2. The elderly in general experience "reduction in amplitude of melatonin, body temperature, sleep-wake cycle, loss of sensitivity to time cues (like light), and a change in period," meaning their circadian rhythms largely deviate from the typical 24 hours (2). 3. The master clock or pacemaker of circadian rhythms in the brain, the suprachiasmatic nuclei (SCN) ages. Their cellular properties, neuron connectivity and gene expression decline (3).

On the other hand, circadian rhythms affect aging: 1. In a transplant experiment where an older animal received fetal SCN tissue in their brain, their dampened rhythms of drinking, temperature, hormone release, and locomotor activity were restored. Additionally, some of the older animals showed an increased lifespan, suggesting the SCN might play a role in longevity (1). 2. Mutations of a clock gene called Bmal1 led to accelerated aging in fruit flies and mice. Their cognitive function slowed; tissue deteriorated more quickly; there was “progressive development” of significant muscle atrophy and bone loss, cataracts, and a 70% reduced lifespan in comparison to wild counterparts (1).

Today, circadian rhythms are important from an aging perspective because they're the first signs of something gone awry. As mentioned previously, the circadian period is likely to deviate from the normal 24 hours in the elderly. Because disruptions in the circadian rhythm is a sign of increased disease risk, detecting these deviances early makes it so "healthy rhythmic patterns can be restored" (4). Such deviations might manifest as decreases in sleep or greater day-to-day blood pressure variability. Overall, offsets of the clock gene system increase risk for obesity, diabetes, and cardiovascular diseases. Supporting evidence comes from a study where adults ate and slept on a 28 hour day schedule, as opposed to 24 hours. Ten days of this circadian misalignment resulted in prediabetes and hypertension in the subjects (5). Today, modern lifestyle factors that disrupt circadian rhythms include shift work, too much artificial light at night, and erratic eating patterns (3, 4).

sources

1. Hood S, Amir S. 2017. The aging clock: circadian rhythms and later life. The Journal of Clinical Investigation. 27(2):437-446. 2. Pandi-Perumal S, Seils L, Kayumov L, Ralph M, Lowe A, Moller H, Swaab D. 2002. Senescence, sleep, and circadian rhythms. Ageing Research Reviews. 1(3): 559-604 3. Banks G, Nolan P, Peirson S. 2016. Reciprocal interactions between circadian clocks and aging. Mammalian Genome. 27:332-340. 4. Cornelissen G, Otsuka K. 2017. Chronobiology of Aging: A Mini-Review. Gerontology. 63(2):118–128. 5. Kagawa Y. 2012. From clock genes to telomeres in the regulation of the healthspan, Nutrition Reviews. 80(8):459-471. Graphic adapted from Fig. 1 of "Chronobiology of Aging: A Mini-Review (4)

the importance of lifestyle habits it’s not just genes:

A common belief is that how one ages is largely attributed to genetics. However, results from a genome-wide association study of a million humans show that lifestyle factors might be more of an important component than expected. The study showed that older adults have approximately the same number of disease alleles as younger participants (1). Thus, centenarians don’t reach 100 solely due to their genes: Their longer lifespan is likely the result of lifestyle habits that potentially prevented the expression of those disease risk alleles (1). The most studied lifestyle factors contributing to longevity seem to be “caloric restriction, regular daily rhythm, and physical activity” (1).

sources

1. Kagawa Y. 2012. From clock genes to telomeres in the regulation of the healthspan, Nutrition Reviews. 80(8):459-471.

Eating predictably

Erratic eating patterns may shorten healthspan as it’s associated with “higher energy intake, higher fasting total, bad cholesterol, and smaller postprandial thermogenesis,” which is the increase in your metabolism after a meal (1) In a similar vein, time-restricted eating (eating only during a specific time window, e.g. from 11 am to 7 pm) or intermittent fasting (alternating eating days) “reportedly forestalled and even reversed diseased processes” of neurodegenerative disorders, cardiovascular conditions, diabetes, and several cancers (1). The potential explanation is that certain circadian systems peak depending on the timing of food availability. In other words, the body predicts when there would be food accessible, so it knows it’ll have the energy to optimally carry out its functions (1). Defined eating patterns can "sustain a robust circadian clock," and this is supported by epidemiological studies that show erratic eating increasing the risk of disease. On the other hand, defined eating patterns, such as sustained feed-fasting cycles or prolonged overnight fasting, is associated with protection from breast cancer (2).

Eating less

In multiple animal models, caloric restriction (CR) by about 75% has consistently been shown to promote longevity. In rats, this increased lifespan is also accompanied by fewer age-associated diseases, such as diabetes, obesity, stroke, heart disease, etc. In general, CR and physical exercise are known to reduce body mass index, blood pressure, and glucose levels (1) In relation to circadian rhythms, both CR and physical exercise are known to "strengthen and maintain synchrony" of the circadian rhythm (1). The aforementioned dampened circadian amplitudes are characteristic of aging. In contrast, restricted feeding is associated with larger circadian amplitudes of body core temperature (1).

Eating breakfast

In a study where humans were fed one meal per day, greater weight loss was shown when those meals were consumed in the morning (breakfast) versus the evening (dinner). These findings are in "accordance with circadian variation in diet-induced thermogenesis, which is higher in the morning than in the evening in healthy people" (1).

sources

1. Cornelissen G, Otsuka K. 2017. Chronobiology of Aging: A Mini-Review. Gerontology. 63(2):118–128. 2. Manoogian E, Panda S. 2017. Circadian rhythms, time-restricted feeding, and healthy aging. Aging Research Reviews. 39: 59-67.

more info: 1. “Chrononutrition: Why Meal Timing, Calorie Distribution & Feeding Windows Really Do Matter” article by Danny Lennon in Stronger By Science. Published 11/18/19

sleep

Circadian rhythms greatly impact the timing and duration of REM sleep specifically, so "proper alignment between timing of sleep and the circadian phase of sleep" is critical for sleep duration and quality (1). Research on 1.1 million men and women from age 30 to 102 showed that "optimal survival" is found those who sleep around seven hours a night (2). On the other hand, sleeping more than 8.5 or less than 4.5 hours had a 15% greater risk of early death, which was predominantly caused by cardiovascular diseases—42% and 33% of deaths among men and women respectively (2). Overall, individuals sleeping seven hours had lower BMIs on average, and lacking sleep or sleeping excessively was associated with obesity, and obesity is known to accelerate aging (2).

More info: Matthew Walker’s TED Talk on sleep

light

Light tells us when to wake up and when to sleep. Because of technology, we receive more light during the night from TVs and our phones, and we might receive not enough light during the day under the roof of houses, schools, offices, etc. Although exposure to light at night is associated with depression in rodents, not getting enough light during the day is associated with seasonal-affective disorder (SAD). Additionally, exposure to light at night has been hypothesized "with an elevated risk of cancer "Kloog et al. 2011) and obesity (Wyse et al. 2011)" (3). In some studies, light therapy has been shown to improve mood-related symptoms in those with Alzheimer's disease or dementia, more on that later (4).

summarized lifestyle factors,

However, there's caveat: you shouldn’t just stop eating because “higher levels of dietary restraint,” are also associated with shorter telomere length (2). It seems by far the greatest emphasis is moderation and regularity. In "From clock genes to telomeres in the regulation of the healthspan" by Yasuo Kagawa, the juxtaposition between “hedonic” lifestyles with “moderate” lifestyles (2) highlights this importance. According to Kagawa, hedonistic lifestyles accelerate aging. A characteristic of a “hedonic” lifestyle is eating irregularly or sleeping too much or too little. Both are associated with obesity, which is known to accelerate aging (2). Overall, offsets of the clock gene system increase risk for obesity, diabetes, and cardiovascular diseases, and supporting evidence comes from a study where adults ate and slept on a 28 hour day schedule, as opposed to 24 hours. 10 days of this circadian misalignment resulted in prediabetes and hypertension in the subjects (2).

sources

1. Duffy J, Zitting K, Chinoy E. 2015. Aging and Circadian Rhythms. Sleep Medicine Clinics. 10(4):423-434. 2. Kagawa Y. 2012. From clock genes to telomeres in the regulation of the healthspan, Nutrition Reviews. 80(8):459-471. 3. Banks G, Nolan P, Peirson S. 2016. Reciprocal interactions between circadian clocks and aging. Mammalian Genome. 27:332-340. 4. Hood S, Amir S. 2017. Neurodegeneration and the Circadian Clock. Frontiers in Aging Neuroscience. 9:170. 5.

geroprotectors

Because many circadian system pathways overlap with aging pathways, circadian rhythms are being studied to develop drugs that are meant to delay the aging process. These drugs, called geroprotectors, target certain circadian modulations and are meant to prevent onset of age-related diseases (1, 2). So far, the clinical investigations conducted support a drug named everolimus slowing the natural, aging-related decline of the immune system (1). Additionally, the antidiabetic drug metformin better decreased cardiovascular disease risk, cancer incidence, and overall mortality in comparison to other antidiabetic medication (1). From a broader perspective, in "Geroprotectors: A role in the treatment of frailty" there's a table of many drugs being clinically tested to "delay, halt, or reverse" frailty, and these geroprotectors specifically aim to treat different aging-related diseases like diabetes, chronic kidney disease, muscle fatigue, muscle atrophy, as well as aim to improve memory, decrease inflammation (3).

sources

1. Cornelissen G, Otsuka K. 2017. Chronobiology of Aging: A Mini-Review. Gerontology. 63(2):118–128. 2. Hood S, Amir S. 2017. Neurodegeneration and the Circadian Clock. Frontiers in Aging Neuroscience. 9:170 3. Trendelenburg A, Scheuren A, Potter P, Muller R, Bellantuono I. 2019. Geroprotectors: A role in the treatment of frailty. Mechanisms of Aging and Development. 180:11-20.

cancer, chronotherapy

Both pharmacological and lifestylerelated treatments for aging can be further enhanced by timing. Specifically in regards to cancer, delivering an anti-cancer drug at a particular time improves the outcome of that treatment in comparison to random application (1). This makes sense because both human physiology and the environment where a tumor resides are highly rhythmic (1). The goal for chemotherapy is to kill as many malignant cancer cells as possible without causing damage to surrounding healthy tissue. Let's say there's a clinician who wants to administer a drug that inhibits DNA replication. It makes the most sense, then to administer that drug when in healthy cells, DNA replication is at its lowest levels. Ultimately, the optimal times for administering a drug takes into account the circadian phase of the cell cycle for both healthy cells and malignant cells (1). However, this process, called chronotherapy, is not exactly straightforward because there's a ton of factors to consider, like the type of drug, the gender of the patient, etc. Nonetheless, chronotherapy has been shown to improve prognosis in cancer patients, as well as alleviate some of the side effects of chemotherapy.

Chronotherapy led to faster tumor regression rates in patients with oral cavity cancer and doubled two-year-disease-free survival rates. It was done by applying radiotherapy when tumor temperature was at its peak, which was found by analyzing circadian rhythms (2).

In metastatic colorectal cancer, timing the application versus constant infusion "had a dramatic impact on the level of side effects" experienced by the patient (1). Inflammation in the digestive tract was reduced by 5x, the number of patients who experienced drug toxicity issues decreased by 3x. They felt better and are "much more likely to stick with the prescribed chemotherapeutic regime" (1).

neurodegenerative disorders

According to Circadian Medicine, neurodegenerative disorders are associated with disrupted timing and quality of sleep. Because these disruptions typically occur years before an official disease diagnosis, measuring these disruptions could serve as early warning signs (2). Circadian and sleep disruptions increase oxidative stress and inflammation in the body. As oxidative stress is a “causal factor” of neuronal damage, cell death, and mitochondrial dysfunction observed in AD, PD, and HD, accumulation of oxidative stress can initiate or accelerate pathology throughout the nervous system (3, 4). Thus, by fixing circadian function, it may be possible to delay neurodegenerative diseases by means of improving their symptoms of disease, such as the buildup of oxidative stress (3). Additionally, There may be a more direct role between circadian rhythms and neurodegenerative disorders. For instance, single mutations of clock genes Bmal1 and Per1 are associated with increased risk of Parkinson’s (4). Certain clock genes also regulate the expression of genes causing Alzheimer’s (4).

Firstly, a common age-related disease is cataracts and maculopathy, which make it more difficult for light to pass through. Additionally, as one ages, the lens yellows and thickens naturally, allowing less light absorption (4). As many circadian rhythms in the body respond to light as a time cue, the lack of light leads to circadian disruptions. The retina and optic nerve show "degenerative changes in AD," and this makes it harder to provide light input to the SCN (5). Because the SCN is the master pacemaker in the body, diminished ability to receive light cues results in circadian disruptions throughout the body. Consequently, light therapy has been shown to alleviate some of the behavioral disorders of AD, such as sundowning, wandering, agitation, delirium. In several studies, light therapy had caused some of these behaviors to disappear, as well as improve sleep-wake rhythm disorders in AD patients (5).

sources

1. Tamai K, Whitmore D, Colwell C. 2015. Circadian Clock Control of the Cell Cycle and Links to Cancer. In: Colwell C. Circadian Medicine. John Wiley & Sons. Los Angeles, CA. p. 169-180. 2. Cornelissen G, Otsuka K. 2017. Chronobiology of Aging: A Mini-Review. Gerontology. 63(2):118–128. 3. Schroeder A, Colwell C. 2015. Can we Fix a Broken Clock? In: Colwell C. Circadian Medicine. John Wiley & Sons. Los Angeles, CA. p. 337-349. 4. Hood S, Amir S. 2017. Neurodegeneration and the Circadian Clock. Frontiers in Aging Neuroscience. 9:170. 5. Pandi-Perumal S, Seils L, Kayumov L, Ralph M, Lowe A, Moller H, Swaab D. 2002. Senescence, sleep, and circadian rhythms. Ageing Research Reviews. 1(3): 559-604.

conclusion

When I started this research process, I was not expecting to feel a sense of gravity in this topic. In learning how the population of older adults is increasing, how circadian rhythm deregulations are the first sign of something going wrong, and how certain measures can be taken in response, I’ve learned the significance of circadian rhythms and aging, and how understanding their relationship can help us take control of our health. A librarian told me leaving with even more questions is inherent in the research process. I’ve learned that our systems today aren't necessarily broken, but there are problems. How do we get rid of "graveyard" shift work? Can we solve these issues with the technology we have today? What other mechanisms can geroprotectors be built from? How much of aging is simply genetics? How much is too much in regards to caring about our health? Among the circadian rhythm changes, which are clearly detrimental to healthy aging but also responsive to treatment? There’s still many unknowns and confounding variables surrounding aging and circadian rhythms, but knowing the research being done and clinical trials being tested, the future feels more hopeful.

Despite these questions, I’ve learned a lot. Cornelissen put it succinctly: It’s about ‘adding life to years’ and not just ‘years to life.’" I think about growing old, and how it’d affect more than just me. If possible, I want to delay the conversation of being told “we can’t take care of you anymore” because that’s a crushing conversation for everyone involved. When there’s so already so much uncertainty surrounding the future—resources, personal funds, genetic predispositions—if how you grow old is a raffle full of senescence tickets or senility tickets, why not increase your odds of aging healthily?