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. Author manuscript; available in PMC: 2022 Jun 1.
Published in final edited form as: Curr Opin Endocr Metab Res. 2021 Apr 5;18:159–164. doi: 10.1016/j.coemr.2021.03.021

Sleep and Biological Aging: A Short Review

Judith E Carroll 1, Aric A Prather 2
PMCID: PMC8658028  NIHMSID: NIHMS1701109  PMID: 34901521

Abstract

Obtaining healthy quantity and quality of sleep is a key to optimal mental and physical health, and cumulative evidence points to a role of sleep loss and sleep disturbances as a contributor to early disease onset and shortened survival. We propose that the molecular underpinnings that drive this risk are key drivers of the biological aging process, including altering metabolism, promoting damage, failure in repair and restoration machinery, leaving lasting impacts on cellular health, telomere loss, cellular senescence, and ultimately system failure. Our premise is that biological aging machinery is altered by sleep, and in the current short review we highlight the existing literature that links sleep with aging biology thought to drive age-related disease and shorten lifespan.

Overview

Sleep functions as a restorative process providing time for the brain and body to recover from the activities occurring during waking hours. This restoration not only allows for renewal of energy and mental focus, but also is proposed to provide an opportunity for cellular restoration. This theoretical model posits that sleep is essential to promote health and wellness because it functions as a restorative process key to ensuring biological health and reducing vulnerability to disease. This model builds upon existing paradigms that point to aging biology as the linchpin in the majority of diseases seen with increasing age, including, but not limited to, cardiovascular disease, diabetes, osteoporosis, and dementia. This short review provides a brief definition of biological aging, a conceptual rationale for examination of biological aging in the context of sleep, and a summary of existing evidence relating sleep processes with biological aging pathways.

Biological Aging: A Primer

Although aging itself is associated with a myriad of changes to psychological, social, spiritual, financial and lived experiences that can be constructive and remarkably dynamic, the general description of physical aging is defined in terms of decline and loss. Physically aging systems begin to experience functional declines and gradual deterioration of tissue stability. These changes occur at the molecular level with accumulation of cellular damage and altered signaling patterns. Key hallmarks of biological aging have been defined by a feed forward loop, where cellular damage accumulation is progressive and ongoing over the lifespan. This gradual accumulation of damage results in alterations to molecular machinery (e.g., mitochondrial energy production, DNA damage accumulation, telomeric shortening, altered protein production) and the eventual failure of cells to perform their functions. As a consequence, cells begin to die (e.g., apoptosis, necrosis) or enter a state of permanent cell cycle arrest (i.e., cellular senescence). Cells under stress, senescent cells, and necrotic cells all promote inflammation through release of intracellular factors into the extracellular space, and these factors (e.g., High Mobility Group Box 1 (HMGB1), Heat Shock Proteins (HSPs), s100 proteins, mitochondrial DNA (mtDNA), etc.) act as damage associated molecular patterns (DAMPs) recognized by certain immune cells as a danger signal that activates the sterile inflammatory response. This response occurs naturally following tissue injury and during wound repair, but when the level of cellular damage becomes pervasive as it does with aging, the inflammatory arm of the immune system becomes harmful. This process of increasing inflammation with age has been termed inflammaging.1

Although many elements of the aging machinery can drive inflammaging, senescent cells are thought to be a key source, and removal of senescent cells has demonstrable improvements in health of aging animals.2–5 This suggests cellular senescence is a key to biological aging. Cellular senescence is often the result of excess cell stress or critically short telomeres, the repeat sequence of DNA at the end of chromosomes that shortens with cell replication. Cells entering senescence often express a set of proteins that inhibits the cell from returning to a replicative state, p16INK4a and p53/p21. Indeed, the cellular expression of p16INK4a has recently been proposed as a biomarker of human aging.6,7 The secretome from senescent cells, called the Senescence Associated Secretory Phenotype (SASP) is also a major target for intervention, as it is a source of inflammation. Overlapping with the senescence pathway and aging biology more broadly is mitochondrial function. With aging, mitochondria become dysfunctional in several ways including accumulating mutations and presenting with impaired metabolism, resulting in inefficient nutrient breakdown and energy production and an abundance of reactive oxygen species. Dysfunctional mitochondria is a hallmark of aging and has been linked to several aging related conditions.8–10

The aging biology mechanics are thought to be modifiable through several lifestyle interventions that manipulate metabolic processes, such as caloric restriction, a fasting mimicking diet, and exercise to delay aging, with several relevant papers on this topic (See11–16). Whether sleep can also modulate aging biology remains to be determined, but recent work has begun to ask these questions focusing on key biomarkers of the biological aging process: telomere length, telomerase activity, epigenetic aging, DNA damage, inflammation, and expression of p16INK4a. Importantly, the science of aging as a target for disease prevention and extension of human healthspan has grown into a unique discipline termed Geroscience, and has gained considerable support (i.e., Trans-NIH Geroscience Initiative; Director of NIH).17 Next, we highlight recent findings linking sleep to aging biology and describe important avenues of future research.

Evidence of Biological Aging and Sleep Disturbances

Sleep disturbance, such as having difficulty falling asleep, waking frequently during the night, inability to fall back to sleep after waking, and waking too early in the morning, is experienced with increasing frequency with age, particularly among older adults. Consequently, many older adults experience less sleep on average per night than they obtained in earlier decades.18 Accruing evidence suggests that habitually short, or disturbed sleep may have significant consequences for long term health and longevity. Indeed, short sleep duration (e.g., sleeping 5 or fewer hours per night) is consistently associated with increased risk for a premature development and progression of age-related conditions (e.g., type 2 diabetes, coronary heart disease).19 However, despite convincing epidemiologic data linking poor sleep and diseases of aging, the molecular pathways accounting for these links are not well delineated. Insights from Geroscience may illuminate novel pathways, and potential targets for intervention.

How might poor sleep impact biological aging? Laboratory studies demonstrate that sleep, along with the circadian rhythm, regulates various aspects of the immune system-processes that are readily disrupted under acute and chronic sleep loss (review see Besedovsky, Haack, Lange, 2019).20 Moreover, sleep fragmentation is associated with alterations to numerous endocrine and metabolic processes including activation of the sympathetic nervous system (SNS) and increases in glucocorticoids to release energy to feed the increased metabolic demands. These processes directly impact mitochondrial production of energy at the cellular level and likely alter subsequent release of reactive oxygen species (ROS). These ROS are known to embed themselves into various substrates of the cell including directly damaging mitochondrial and nuclear DNA. Left unrepaired, damage to DNA can contribute to telomere shortening and cellular senescence.21,22 Thus, sleep disturbances and prolonged sleep loss could play a direct role in the biological aging machinery. Here we summarize several key areas linking sleep and key aging processes.

Mitochondrial Metabolism and Function.

As the primary source of metabolic energy, mitochondria are critical to sustaining vitality of the cell. Increased demands for energy will increase mitochondria activity; this activity may then regulates the drive for sleep,23 while excess activity may have detrimental consequences to the health of the mitochondria and the cell. Only a handful of animal studies have directly tested the role of sleep deprivation or fragmentation in altering mitochondrial bioenergetics. Changes in energy regulation have been observed after sleep deprivation,24 including increased mitochondrial uncoupling protein 2 (UCP2), nuclear related factor (NRF)1, NRF2, and complex IV and V in mice cerebral cortex suggesting upregulation of metabolism. Parallel work reported that NADPH Oxidase activity is elevated after sleep fragmentation,25 and mitochondrial electron transport chain is impaired after sleep deprivation.26 Likewise, reduced mitochondrial superoxide dismutase (SOD) activity has been observed after sleep deprivation in mice.27 In the first study to date in humans, monozygotic twins with different sleep duration and sleep efficiency patterns exhibited different mtDNA copy number, evidence that short sleep and sleep disturbances can alter mitochondrial health.28 This later study is correlative and the relevance of mtDNA copy number for health is not clear. Further research is this area is warranted.

DNA Damage and Repair.

Damage to DNA is a common occurrence within cells, typically the result of increased metabolic activity that releases reactive oxygen species that can imbed themselves into the DNA structure. This type of damage is routinely repaired by enzymes that respond to a damage signal, and rapidly remove and replace the damage. Acute sleep loss and sleep fragmentation may alter the amount of damage accumulation by either increasing the damage sustained through greater metabolic demand or disrupting the ability of the cell to effectively repair damage. Several studies have begun examining whether experimental sleep loss could impact levels of DNA damage. Rats exposed to either acute (24 or 96 hours) or chronic (21 days) sleep deprivation displayed elevated DNA damage in brain and immune cells compared to unexposed rats, and that these effects were more pronounced with increasing length of sleep loss. Moreover, recovery sleep in these animals was able to reverse this damage.29 Parallel results were observed across a number of tissues, including intestines, liver, and lungs in rats exposed to 10 days of partial or total sleep deprivation.30 Another study of rats exposed to sleep deprivation showed significant elevations in DNA damage in blood and brain cells, but this effect what only present in the older animals (15 months) and not the younger ones (3 and 6 months), suggesting greater vulnerability to the effects of sleep loss with increasing age.31

To date, two human studies have directly examined the effects of sleep loss and its impacts on DNA damage and repair. In a study of partial sleep deprivation (4 hours of sleep) of older adults, DNA damage response genes were increased from baseline to after sleep deprivation, and this effect remained after a night of recovery sleep.32 In a study of physicians working in the hospital, DNA damage was observed after an overnight shift with acute sleep loss compared to DNA damage after getting 3 nights of normal sleep. In parallel, the doctors also had reduced DNA repair gene expression after sleep loss, suggesting reduced capacity to repair damage that had accumulated during sleep deprivation.33 Together, the existing research provides support that sleep loss may increase risk for disease through DNA damage accumulation.

Cellular Senescence.

Cellular senescence is a key hallmark of biological aging, and there is growing interest in how targeting these cells might reduce aging related conditions. Only a few studies have begun to examine whether sleep fragmentation and sleep loss could increase the accumulation of senescent cells. Increases in the expression of p16INK4a in aortic tissue of mice was observed after exposure to prolonged sleep fragmentation,34 extending prior work that pointed to increase production of reactive oxygen species and DNA damage35 – a pathway to cellular senescence. The proportion of leukocytes that are late differentiated T cells, thought to be senescent or near senescent, can be estimated from methylation arrays. Interestingly, women in the Women’s Health Initiative (WHI) study who reported sleep disturbances or any insomnia symptom had a greater proportion of these late differentiated T cells, suggestive of greater accumulation of senescent T cells among those with disturbed sleep.36 Partial sleep deprivation that increased DNA damage response genes also increased the expression of the gene that encodes p16INK4a in older adults, although the effects were mild and not visible until 24-hrs after the night of sleep loss, which is suggestive of a proposed causal pathway through which DNA damage accumulates after sleep loss, leading to increased cellular sensescence (within 24 hours in this case).32 This work also characterized an upregulation in the signaling of genes characterized as the senescence associated secretory phenotype (SASP). The SASP has a proinflammatory secretome, and several lines of work have highlighted the relationship between sleep loss and inflammation (reviewed elsewhere37 ).

Telomeres and Telomerase.

Telomeres are non-coding sequences of DNA located at the end of chromosomes and function to cap the ends and prevent loss of coding DNA during replication. Over successive replication and cell division events the telomeric end is shortened. Telomerase is an enzyme that can rebuild the telomeric ends and is highly active during events requiring rapid clonal expansion. Low telomerase activity during replication can accelerate the rate a cell’s telomere ends shorten. Telomerase also serves a protective function, providing a structure that caps the chromosome and prevents the cell from entering senescence. When telomere length becomes critically short and there are low levels of telomerase, the cell will enter replication arrest and stops dividing. This is one critical pathway through which senescent cells accumulate throughout the body, and thus telomere length is a biomarker of this component of cell aging.

A number of cross-sectional analyses have tested the relationship of sleep with telomere length, the majority reporting shortened leukocyte telomere length among those with sleep disturbances, poor sleep quality, and insomnia. One of the first studies to examine associations of sleep with telomere length reported that female nurses on rotating night shift and less than 6 hours of sleep on average per day had shorter telomere length than women who had longer duration of sleep despite being on a rotating night shift.38 In a separate study, women in midlife with chronic poor sleep quality had shorter telomere length, but sleep duration was unrelated to telomere length.39 Similar results have been reported in samples of both men and women,40,41 while a study in HIV+ men and women found shorter telomere length in those with less than 7 hours of sleep per night, but no link to sleep quality measures.42 Individuals with clinically diagnosed insomnia disorder have also been reported to have shorter telomere length, with one study of older adults reporting telomere shortening in those with insomnia – effects that were enhances with increasing age,43 and another Brazilian cohort reporting shorter leukocyte telomere length in those with insomnia.44 To date, only one prospective study has examined telomere length shortening over time in relation to measures of sleep. This study reported greater shortening of telomere length over a ten year period among those with more nocturnal micro-arousals measured using polysomnography compared to those with fewer micro-arousals. The finding is suggestive that those with disturbed sleep have an accelerated biological aging pattern.45 Of note, no human studies to date have investigated whether sleep disturbances might perturb telomerase activity, the enzyme that rebuilds and protects telomeres from shortening. However, a study in rodents documents declines in the expression of telomerase in aortic tissue in response to a 20 week protocol of sleep fragmentation,34 suggesting that sleep fragmentation disrupts this enzymes ability to rebuild telomeres. Further work is warranted to determine whether this is a direct effect on the enzyme or a secondary effect of cells entering a non-replicative state where the enzyme is in low demand.

Epigenetic Aging.

To date, only one study has examined the relationship of sleep disturbances with estimates of biological aging derived from epigenetic age acceleration measures that estimate biological aging from distinct methylation changes to DNA that are related to phenotypic characteristics of aging, morbidity, and mortality.46–48 In the only study to date, women with a sleep disturbance had an older epigenetic age (indexed by the extrinsic epigenetic age acceleration measure), with the largest difference in epigenetic age between those who reported waking regularly at night compared to those with few awakenings.36 When analyses were done examining the number of insomnia symptoms, increasing number of insomnia symptoms was associated with an older epigenetic age, suggesting greater biological aging in women with insomnia. This work highlights an exciting new avenue of research, but further refinement is needed to understand how these indicators of biological age using epigenetics represent the underlying aging process.

Sleep Disordered Breathing

Sleep disturbed due to obstruction to the airways that prevents normal oxygenation of the blood during nocturnal sleep, referred to as obstructive sleep apnea (OSA), has been well-documented to cause oxidative stress via hypoxic events. These changes in biological chemistry can increase the accumulation of damage to DNA and other molecular structures, and likely contributes to accelerated aging. Indeed several studies have linked severe OSA to shortened telomere length,45,49–51 including in the offspring of mothers who had sleep apnea during pregnancy.52 Recent evidence has also pointed to accelerated epigenetic aging among those with a high apnea-hypoxic index, indicating severe OSA, which was replicated in an independent cohort.53 Prior reviews have highlighted the specific mechanisms that are thought to be involved in sleep apneas destructive effects, particularly in the brain, and readers interested in this are referred to a more thorough review.54,55

Concluding Remarks

In summary, findings support a role of sleep disturbances in increasing accumulation of damage, increased cellular senescence, shortening telomere length, altering the expression of telomerase activity, and accelerating epigenetic aging. Considerable research remains to be done testing the causal pathways, especially with regards to telomere length and epigenetic aging given the majority of work is cross-sectional to date. Given this limitation, there remains the possibility that cellular aging, indexed by shortened telomere length is associated with more sleep disturbances because biological aging alters brain structure and function that regulates sleep, thus driving risk for insomnia symptoms. However, the evidence in animal models points to a direct causal role of sleep loss driving alterations in mitochondrial bioenergetics, increasing damage accumulation, and leading to cellular senescence accumulation in selective tissue (e.g., brain, aorta). Further characterization of the specific pathways, including mitochondrial metabolism, DNA damage and repair, altered by sleep deprivation and fragmentation across different tissue is warranted, particularly as it relates to specific diseases of aging associated with sleep loss.

Acknowledgements

This paper was supported in part by the University of California, Los Angeles Cousins Center for Psychoneuroimmunology and the National Institute of Health (NIH), National Institute of Aging Grant K01 AG044462 (JEC), R01 AG052655 (JEC), and the National Heart, Lung, Blood Institute (NHLBI) R01HL142051 (AAP).

Footnotes

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