The biological clock is ticking: circadian rhythms and aging

The biological clock is ticking circadian rhythms & aging

Illustrated booklet by Carolina Gokingco

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.

circadian rhythms W

e’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.

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

sources 1.

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,

2.

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!

1

3.

4.

5.

Hood S, Amir S. 2017. The aging clock: circadian rhythms and later life. The Journal of Clinical Investigation. 27(2):437-446.

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 Banks G, Nolan P, Peirson S. 2016. Reciprocal interactions between circadian clocks and aging.

Mammalian Genome. 27:332-340.

Cornelissen G, Otsuka K. 2017. Chronobiology of Aging: A Mini-Review. Gerontology. 63(2):118– 128.

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)

bidirectional relationship A

bidirectional relationship exists between aging and circadian

Overall, offsets of the clock gene system increase risk for obesity,

rhythms, meaning signs of aging either "affects the circadian clock

diabetes, and cardiovascular diseases. Supporting evidence comes from a

function" or are "regulated by" the circadian clock (1).

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

On one hand, aging affects circadian rhythm:

and hypertension in the subjects (5). Today, modern lifestyle factors that

1.

The elderly experience more frequent sleep disruptions, get fewer

disrupt circadian rhythms include shift work, too much artificial light at

hours of REM sleep, secrete less melatonin (a hormone regulated

night, and erratic eating patterns (3, 4).

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.

2

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

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).

3

sources 1.

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

Eating predictably

E

rratic 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

Eating less

I

n 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

Eating breakfast

I

n 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).

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).

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

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).

sources 1.

2.

Cornelissen G, Otsuka K. 2017. Chronobiology of Aging: A Mini-Review. Gerontology.

63(2):118–128.

Manoogian E, Panda S. 2017. Circadian rhythms, time-restricted feeding, and healthy aging. Aging Research Reviews. 39: 59-67.

4

sleep

C

ircadian rhythms greatly impact the timing and duration of REM sleep

light

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

L

ight tells us when to wake up and when to sleep. Because of technology, we receive

more light during the night from TVs and

4.5 hours had a 15% greater risk of early

our phones, and we might receive not enough

death, which was predominantly caused by

light during the day under the roof of houses,

cardiovascular diseases—42% and 33% of

schools, offices, etc. Although exposure to

deaths among men and women respectively

light at night is associated with depression

(2). Overall, individuals sleeping seven hours

in rodents, not getting enough light during

had lower BMIs on average, and lacking sleep

the day is associated with seasonal-affective

or sleeping excessively was associated with

disorder (SAD). Additionally, exposure to

obesity, and obesity is known to accelerate

light at night has been hypothesized "with

aging (2).

an elevated risk of cancer "Kloog et al. 2011)

summarized H

and obesity (Wyse et al. 2011)" (3). In some

shorter telomere length (2). It seems by far

More info: Matthew Walker’s TED Talk on sleep

studies, light therapy has been shown to improve mood-related symptoms in those with Alzheimer's disease or dementia, more on that later (4).

sources 1.

2.

3.

4.

5.

5

Duffy J, Zitting K, Chinoy E. 2015.

Aging and Circadian Rhythms. Sleep Medicine Clinics. 10(4):423-434.

Kagawa Y. 2012. From clock genes to telomeres in the regulation of the healthspan, Nutrition Reviews.

80(8):459-471.

Banks G, Nolan P, Peirson S. 2016.

Reciprocal interactions between circadian clocks and aging. Mammalian Genome. 27:332-340.

Hood S, Amir S. 2017.

Neurodegeneration and the Circadian Clock. Frontiers in Aging Neuroscience. 9:170.

lifestyle factors,

owever, there's caveat: you shouldn’t just stop eating because “higher levels

of dietary restraint,” are also associated with 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).

geroprotectors B

ecause many circadian system pathways

comparison to other antidiabetic medication

overlap with aging pathways, circadian

(1).

From

a

broader

perspective,

in

rhythms are being studied to develop drugs

"Geroprotectors: A role in the treatment of

that are meant to delay the aging process.

frailty" there's a table of many drugs being

These drugs, called geroprotectors, target

clinically tested to "delay, halt, or reverse"

certain circadian modulations and are meant

frailty, and these geroprotectors specifically

to prevent onset of age-related diseases

aim to treat different aging-related diseases

(1, 2). So far, the clinical investigations

like diabetes, chronic kidney disease, muscle

conducted support a drug named everolimus

fatigue, muscle atrophy, as well as aim to

slowing the natural, aging-related decline

improve memory, decrease inflammation (3).

of the immune system (1). Additionally, the antidiabetic drug metformin better decreased cardiovascular disease risk, cancer incidence, and overall mortality in

sources 1.

2.

3.

Cornelissen G, Otsuka K. 2017. Chronobiology of Aging: A Mini-Review. Gerontology. 63(2):118–128.

Hood S, Amir S. 2017. Neurodegeneration and the Circadian Clock. Frontiers in Aging Neuroscience. 9:170 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.

6

cancer, chronotherapy B

oth pharmacological and lifestyle-

to administer that drug when in healthy

cancer and doubled two-year-disease-free

related treatments for aging can be

cells, DNA replication is at its lowest

survival rates. It was done by applying

further enhanced by timing. Specifically in

levels. Ultimately, the optimal times for

radiotherapy when tumor temperature was

regards to cancer, delivering an anti-cancer

administering a drug takes into account

at its peak, which was found by analyzing

drug at a particular time improves the

the circadian phase of the cell cycle for

circadian rhythms (2).

outcome of that treatment in comparison

both healthy cells and malignant cells (1).

In metastatic colorectal cancer, timing the

to random application (1). This makes

However, this process, called chronotherapy,

application versus constant infusion "had a

sense because both human physiology and

is not exactly straightforward because

dramatic impact on the level of side effects"

the environment where a tumor resides

there's a ton of factors to consider, like the

experienced by the patient (1). Inflammation

are highly rhythmic (1). The goal for

type of drug, the gender of the patient, etc.

in the digestive tract was reduced by 5x, the

chemotherapy is to kill as many malignant

Nonetheless, chronotherapy has been shown

number of patients who experienced drug

cancer cells as possible without causing

to improve prognosis in cancer patients, as

toxicity issues decreased by 3x. They felt

damage to surrounding healthy tissue.

well as alleviate some of the side effects of

better and are "much more likely to stick with

Let's say there's a clinician who wants

chemotherapy.

the prescribed chemotherapeutic regime" (1).

to administer a drug that inhibits DNA

Chronotherapy led to faster tumor

replication. It makes the most sense, then

regression rates in patients with oral cavity

neurodegenerative disorders A

7

ccording to Circadian Medicine,

by means of improving their symptoms of

cue, the lack of light leads to circadian

neurodegenerative

are

disease, such as the buildup of oxidative

disruptions. The retina and optic nerve

associated with disrupted timing and

stress (3). Additionally, There may be a more

show "degenerative changes in AD," and

quality of sleep. Because these disruptions

direct role between circadian rhythms and

this makes it harder to provide light input

typically occur years before an official

neurodegenerative disorders. For instance,

to the SCN (5). Because the SCN is the

disease

diagnosis,

disorders

these

single mutations of clock genes Bmal1 and

master pacemaker in the body, diminished

disruptions could serve as early warning

measuring

Per1 are associated with increased risk of

ability to receive light cues results in

signs (2). Circadian and sleep disruptions

Parkinson’s (4). Certain clock genes also

circadian disruptions throughout the body.

increase oxidative stress and inflammation

regulate the expression of genes causing

Consequently, light therapy has been shown

in the body. As oxidative stress is a “causal

Alzheimer’s (4).

to alleviate some of the behavioral disorders

factor” of neuronal damage, cell death, and

Firstly, a common age-related disease

of AD, such as sundowning, wandering,

mitochondrial dysfunction observed in AD,

is cataracts and maculopathy, which make

agitation, delirium. In several studies, light

PD, and HD, accumulation of oxidative

it more difficult for light to pass through.

therapy had caused some of these behaviors

stress can initiate or accelerate pathology

Additionally, as one ages, the lens yellows

to disappear, as well as improve sleep-wake

throughout the nervous system (3, 4). Thus,

and thickens naturally, allowing less light

rhythm disorders in AD patients (5).

by fixing circadian function, it may be

absorption (4). As many circadian rhythms

possible to delay neurodegenerative diseases

in the body respond to light as a time

conclusion W

hen 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

sources 1.

2.

3.

4.

5.

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.

Cornelissen G, Otsuka K. 2017. Chronobiology of Aging: A Mini-Review. Gerontology.

63(2):118–128.

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.

Hood S, Amir S. 2017. Neurodegeneration and the Circadian Clock. Frontiers in Aging Neuroscience. 9:170.

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.

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?

8

This booklet was created for an English, natural-science interdisciplinary class at the University of Washington.