A Good Night Sleep

 

SLEEP

A restful good night's sleep can provide a magical sense of restoration and wellness. In recent years, we've gleaned a better understanding for what's going on while we sleep, and why it's so essential to our health. During sleep, metabolic waste products are transported out of the brain by cerebrospinal fluid and interstitial fluid. Not to be confused with our lymphatics and lymph nodes in the rest of our body, the brain's glymphatic system is a network of vessels that interacts with and complements the cerebrospinal fluid's capability to clear the waste products. During non-rapid eye movement sleep, there are large waves of cerebrospinal flow. Impaired waste clearance has been documented in young, healthy individuals with a single night of sleep deprivation, as reflected by increases in the beta-amyloid protein seen in brain imaging. Marked accumulation of this protein is considered a precursor to the development of Alzheimer's disease. The dynamics for cerebrospinal and interstitial fluid flow is influenced by neurovascular coupling and our circadian rhythm: during the day, our waste production is high and our vascular tone is increased, whereas slow wave neuronal activity is low. These dynamics are reversed during the night. In the words of Michael Grandner and Fabian-Xose Fernandez, “Sleep is a non-negotiable biological state required for the maintenance of human life ... our needs for sleep parallel those for air, food, and water.” The relationship between sleep and health outcomes is profound, including all-cause mortality, cardiovascular mortality, cancer mortality, risk of cancer, type 2 diabetes and metabolic dysfunction, immune system function, obesity, Alzheimer's disease, hypertension, stroke, female reproductive health, and mental and behavioral health. A brief review of a few relevant studies provides a sense of

Figure 3.9. The sleep regularity index (SRI) relationship (adjusted hazard ratio (HR), risk metric) for all-cause (A), cardiovascular disease (CVD) (B), and cancer (C) mortality. Adapted from Lachlan Cribb et al., “Sleep regularity and mortality: A prospective analysis in the UK Biobank,” eLife 12 (November 2023): RP88359, https://doi.org/10.7554/eLife.88359.

the big impact. From the UK Biobank cohort, nearly ninety-nine thousand participants with a mean age of sixty-two years using sleep trackers, sleep regularity index (SRI) (probability of an individual being in the same state of sleep or awake at any two time points twenty-four hours apart, averaged over seven days) was correlated with all-cause, cardiovascular, and cancer mortality (fig. 3.9).

Among nearly eight thousand participants with twenty five year follow-up, a sleep duration at age fifty to sixty for six hours or less, compared with seven hours or more of sleep, was associated with a 30 percent in-creased risk of dementia. In a randomized trial of people with habitual sleep duration of less than 6.5 hours and a BMI between 25 and 30 kg/m², simply coaching for better sleep led to an extra 1.2 hours of sleep and a significant decrease in daily caloric intake (270 calories). A study in young, healthy men who underwent adipose tissue and muscle biopsies after one night of deprived, as compared to full, sleep showed deleterious pro-inflammatory changes of the transcriptome, proteome, epigenome, and metabolites in the blood. The loss of one hour of sleep from daylight savings time in Germany and the United States was associated with a significant rise in heart attacks in both countries for four days.

So how much sleep do we need? One of the best studies to tackle this question used data from the UK Biobank, from nearly 500,000 participants, 48,000 of whom underwent brain imaging, and 156,000 had a six- to ten-year follow-up. The principal finding was that about seven hours is the optimal duration of sleep.

As you can see in figure 3.10, the relationship of sleep duration to health was not linear. It may come as a surprise that beyond seven hours there were consistent signs, both acutely and during follow-up, of cognitive and mental health decline, as well as unfavorable changes in brain structure. Also consistent is the relationship of long sleep (more than eight hours) and heightened all-cause mortality (by approximately 30%) that was previously established among nearly 1.4 million people. To sum up all the studies of sleep duration and cardiovascular disease, every one hour a night decrease in sleep below the seven to eight hour threshold is associated with 6 percent higher risk of total cardiovascular disease. Every one hour a night

Figure 3.10. Relationship of sleep duration with cognition and mental health from the UK Biobank study. Adapted from Yuzhu Li et al., “The brain structure and genetic mechanisms underlying the nonlinear association between sleep duration, cognition and mental health,” Nature Aging 2, no. 5 (May 2022): 425–37, https://doi.org/10.1038/s43587-022-00210-2.

increase in sleep duration above that seven to eight hour threshold is associated with 12 percent higher risk of total cardiovascular disease.

In 2017, Matthew Walker, a professor of neuroscience at UC Berkeley, sounded the alarm about the silent sleep loss epidemic as "the greatest public health challenge we face in the twenty-first century.” Even before the COVID-19 pandemic, 35 to 40 percent of Americans were sleeping less than seven hours per night on a regular basis. Intercountry differences for sleep duration were addressed by a study of 1.1 million people with an aggregate of thirty-four studies of participants using sleep trackers in the Netherlands, the UK, and the United States. Americans got the least sleep. That same study zoomed in on insomnia symptoms by age. In people over sixty-five years of age, 15 percent had difficulty in initiating sleep, 20 percent had dif-ficulty in maintaining sleep, and 34 percent had early morning awakenings.

The problem in older adults with sleep is threefold. There's less deep sleep, the precious non-rapid eye movement sleep substage that promotes health across all systems, along with memory and cognition. By late age forties, it's already lowered more than 60 percent than in a teenager; by age seventy, it's down 80 to 90 percent. There's also more fragmented, disrupted sleep—reduced sleep efficiency—the percent of time asleep while in bed. On top of these disruptions, there is regression of circadian timing that leads to earlier bedtimes and earlier awakenings.

The master pacemaker clock for our circadian rhythm is in the suprachiasmatic nucleus, a small region within the hypothalamus, entrained by external cues from light. Exquisite molecular circuitry connects it with our muscle, liver, adrenal gland, kidneys, immune system, heart, and pancreas. Exemplifying the pivotal role of the twenty-four-hour sleep-wake cycle, there's a rare familial condition of short sleep with no adverse consequences due to a mutation in a molecular clock regulator gene. If only we could simulate that clock control, we might be able to promote better quality and efficiency of sleep with less duration (think genome editing someday in the future).

So we're faced with the challenge of promoting better sleep that is essential for healthy aging, while aging itself is compromising sleep quality. There are some things that help, like maintaining the same sleep pattern every day, including weekends. That includes a regular pattern of exercise and meals, with an adequate separation of multiple hours from bedtime (think early time-restricted eating). A cool and fully dark, quiet bedroom as well as avoidance of the blue light from electronic devices that disrupts circadian rhythm and suppresses melatonin production are simple tips. The benefit or risk of napping during the day has been a source of debate, but a large observational study found that napping one to two times weekly was linked to a significant reduction of cardiovascular events. Most epidemiologic studies that have looked at napping suggest their duration is important, and longer afternoon naps, especially more than one hour, are associated with risk.

In recent years, the popularity of sleep trackers has soared, including wearables such as the Oura ring, smartwatches, and fitness bands, and smartphone app "nearables" that can be on or beside the bed. Most of these devices rely on an accelerometer to detect movement during sleep and try to extrapolate the duration of REM, non-rapid eye movement sleep phases, and total sleep duration. You can easily fake out that metric by reading in bed, which I have personally tested. More sophisticated devices, like Oura, integrate heart rate, movement, body temperature, and blood oxygen levels, which provides better alignment with formal sleep lab measurements, yet with the advantage of being in one's own bed. The problem is that there are no standards for the algorithms for their sleep scores and a general lack of validation for accuracy of reporting. Ironically, use of the trackers can induce or exacerbate anxiety, which interferes with sleep quality. On the other hand, self-diagnosis for triggers of poor sleep, such as alcohol, late meals, caffeine, or blue light, can be facilitated with their use.

Few rigorously assessed interventions have been shown to improve sleep quality. Professional organizations recommend cognitive behavioral therapy as first-line treatment because of the body of evidence that has borne out its efficacy. That treatment typically requires a trained therapist along with a significant time commitment and expense. However, in-person coaching of relaxation training, avoidance of stimuli, and improvement in sleep hygiene can be simulated with smartphone apps. A randomized trial of digital cognitive behavioral therapy, using a smartphone app, enrolled over seventeen hundred participants with insomnia and showed improvements of insomnia symptoms along with functional health and psychological well-being. This report and others are encouraging nonpharmacologic ways of improving a healthy sleep schedule.

Supplements such as melatonin or magnesium have been studied in many small randomized trials and have been shown to have relatively small effects for promoting sleep quality, and the quality of evidence for both was deemed low. The same problem with low-quality data exists for the supplement ashwagandha and the prescription medicine trazadone. Several companies are heavily promoting beds that regulate body temperature to promote sleep quality, but again, evidence that they work is thin at best. Many ongoing drug discovery programs aim to find an effective and safe medication to fulfill the unmet need.

Before leaving sleep, I would be remiss not to highlight sleep apnea, a common disruption of sleep that affects 34 percent of men and 17 percent of women in the United States. The most common symptom is excessive daytime sleepiness, but even that is not reported in more than half of people affected. Other symptoms include loud snoring, episodes during sleep when you stop breathing as reported by another person, gasping for air during sleep, and difficulty staying asleep. When suspected, the diagnosis can be made with a home sleep apnea testing with about 80 percent sensitivity and specificity, preempting a formal sleep lab study. In my experience, avoidance of such formal studies is desirable. They are nonphysiologic and expensive, and it is rare to see people get anything but abnormal results. For individuals who are symptomatic, multiple interventions ranging from weight loss and exercise to oral appliances that hold the jaw forward, to positive airway pressure devices, to surgery, have been shown to be effective. Since sleep apnea is associated with a twofold or greater risk of cardiovascular and metabolic diseases, its diagnosis and management in symptomatic individuals is of obvious importance.