Osteoporosis Linked to Age-Related Changes in Circadian Rhythm

Researchers published a new editorial paper on restoring the circadian rhythm to minimize the risk of aging-related osteoporotic fractures.

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The circadian rhythm is a daily cycle (24 hours) of biological activity that is driven by an internal biological clock. A regular circadian rhythm is important for maintaining numerous facets of human life. Aging-related changes to this delicate rhythm have demonstrated negative consequences in many aspects of health, including bone health.

“Among the many risk factors for osteoporosis, a new kid on the block is disruption of the biological clock.”

On July 19, 2022, an editorial paper was published in Aging‘s Volume 14, Issue 14, entitled, “Restoring rhythm to prevent age-related fractures.” In this editorial, Annelies E. Smit, Maaike Schilperoort and Elizabeth M. Winter from Leiden University Medical Center discuss the treatment of osteoporosis by way of restoring circadian rhythm. The researchers review the use of both medical and lifestyle interventions that aim to restore circadian rhythm to minimize the risk of aging-related osteoporotic fractures.

Osteoporosis & Cortisol

Osteoporosis is a condition characterized by decreased bone mass and an increased risk of bone fracture. Age-related osteoporosis is a major public health concern, particularly in postmenopausal women. Cortisol, a stress hormone and the most important endogenous glucocorticoid (GC), plays a key role in the regulation of circadian rhythm. Circulating cortisol levels are naturally highest in the morning and gradually decline throughout the day. (This high peak in cortisol is responsible for initiating the waking cycle each morning.)

“Rhythm in circulating cortisol levels is regulated by the ‘master clock’, the suprachiasmatic nucleus (SCN) in the hypothalamus.”

Unfortunately, as humans age, SCN rhythmicity frequently becomes decoupled from environmental rhythms. Changes in circadian rhythm can result from aging-related lifestyle changes, such as changes in light exposure (which can occur from decreasing visual capabilities), the sleep-wake cycle, eating habits, and exercise patterns. Over time, cortisol begins to peak earlier in the morning, and average circulating cortisol levels increase. The researchers argue that circadian rhythm-related changes in cortisol secretion result in a loss of bone mass and age-related osteoporosis.

“Since both SCN [5] and cortisol [6] rhythm amplitude decline with age, and because we demonstrated in a preclinical model that flat endogenous GC levels result in osteoporosis, we argue that flattened circadian rhythmicity in the elderly population is causally related to the high incidence of osteoporosis at older age [4].”

Restoring Circadian Rhythm

Glucocorticoid (GC) therapy is a common treatment for osteoporosis. Unfortunately, administering glucocorticoids at an improper time can disrupt the natural circadian rhythm of cortisol secretion, leading to an increased risk of osteoporotic fractures. The researchers suggest that restoring the circadian rhythm is critical for restoring healthy patterns of cortisol secretion, especially in patients receiving glucocorticoid therapy.

“In elderly, physical inactivity and irregular eating patterns are common, and both have been demonstrated to dysregulate bone rhythm [8].”

In addition to lifestyle changes, such as timed exercise and timed feeding, the researchers note that chronotherapy may contribute to reinforcing circadian rhythmicity. Chronotherapy is a promising new field of circadian medicine that aims to optimize the timing of drug administration to match the natural circadian rhythm. The researchers suggest glucocorticoids, and any other bone formation-promoting therapeutic, should be administered in the morning (to mimic the behavior of a healthy circadian rhythm). Chronotherapy can also incorporate lifestyle interventions, such as changes in sleeping patterns, sleep hygiene and light exposure therapy.

“Thus, restoring normal sleep/wake cycles by psychological and behavioural measures, such as strict bedtime routines, may strengthen SCN rhythm.”


Circadian rhythms are important for bone health and preventing age-related osteoporosis. Glucocorticoid therapy can disrupt circadian rhythms, but this disruption can be minimized by administering glucocorticoids in the morning. In addition, lifestyle changes and chronotherapy can help reinforce circadian rhythms.

“In conclusion, the multifaceted origin of age-related fractures asks for a full toolbox of intervention strategies, to which restoring circadian rhythm may provide a valuable addition. Lifestyle and medical interventions may improve sleep quality and decrease risk for osteoporotic fractures (Figure 1). Furthermore, respecting circadian timing through chronotherapy could optimize current and new therapeutic outcomes.”

Figure 1. Bone health depends on diurnal variation in bone turnover, which is regulated by the circadian timing system
Figure 1. Bone health depends on diurnal variation in bone turnover, which is regulated by the circadian timing system

Click here to read the full editorial paper published by Aging.

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Aging is an open-access journal that publishes research papers bi-monthly in all fields of aging research. These papers are available at no cost to readers on Aging-us.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

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Aging and Circadian Rhythm: Does a Conserved Link Exist?

In the Aging (Aging-US) Volume 13, Issue 24, cover paper, researchers conducted a study suggesting that the circadian rhythm is subjected to aging-related gene alterations.

Figure 6. Matching of our CR-related DEGs evidenced to be regulated with aging with a curated human CR network.
Figure 6. Matching of our CR-related DEGs evidenced to be regulated with aging with a curated human CR network.
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Chronobiology is the study of biological rhythms. The human circadian system is a biological process known to regulate the sleeping and waking cycle (circadian rhythm; CR). Components of the circadian system are known as ​​clock genes. Clock genes generate daily oscillations of gene expression and interact as an intricate network to influence biological processes in organisms, tissues and cells. This system is primarily regulated by Earth’s day and night cycles (light and darkness), though it can be affected by other factors, including nutrition, cellular devices, stress, illness, jet lag, and aging.

“It is well established that aging interferes with the regulation of the circadian system, which, in return, contributes to the manifestation and progression of aging-related diseases (reviewed in [45]).”

Across an organism’s lifespan, changes in circadian rhythm take place. These changes can cause aging-related diseases to become more prevalent. Studies have also shown that age-independent alterations to the circadian system can result in premature aging. This interrelation between aging and CR means that aging may play a role in the circadian system and that the circadian system may play a role in aging. However, researchers have not yet fully illuminated the impact of aging-related circadian system changes on healthy organs and tissues. 

“Whether aging-related changes of the circadian system’s regulation follow a conserved pattern across different species and tissues, hence representing a common driving force of aging, is unclear.”

The Study

In an effort to identify circadian rhythm regulatory patterns over the course of aging, researchers—from Friedrich Schiller University JenaFLI Leibniz Institute for Age ResearchJena University HospitalGerman Center for Integrative Biodiversity Research, and European Virus Bioinformatics Center—performed inter-species and inter-organ transcriptional analyses. The research paper was published in December of 2021 as the cover of Aging (Aging-US) Volume 12, Issue 24, and entitled, “Age-dependent expression changes of circadian system-related genes reveal a potentially conserved link to aging.”

“Here, we used RNA-Seq data to profile the regulation of CR-related genes of 4 different species in a cross-sectional study in individuals ranging from young mature to old-age categories.”

In this cross-sectional study, the researchers used data from 329 RNA sequencing libraries to identify differentially expressed genes in transcriptional profiles among humans, house mice, zebrafish, and the extremely short-lived turquoise killifish. All human donors were classified into the following age groups of 14 to 15 individuals: mature (24–29 years), aged (60–65 years), and old-age (75–79 years). The other species were categorized into their respective age groups. Organs, including the brain, blood, liver, and skin, were examined and then compared between the four species.

The researchers found that two circadian rhythm-related genes (dec2 and per2) were altered in all four species, primarily in early- and late-aging groups. Four genes (cirp, klf10, nfil3, and dbp) with aging-related expression patterns were found in several organs and species. In total, the researchers identified six genes (in several tissues from at least three out of the four species) that function at all regulation levels of circadian rhythm with apparently conserved age-associated regulation.


“​​Thus, these genes might represent a conserved link between the circadian system and aging.”

This study confirms work from previous studies and extends them by providing a new dataset linking circadian rhythm factors to physiological aging across four evolutionarily distinct species. Whether circadian rhythm regulation is the cause or a consequence of the aging process still remains to be explored. The researchers note that their non-synchronized cross-sectional approach should be replicated in the future and include an additional dataset based on a longitudinal study design, tissue synchronizations across species of interest and to potentially analyze anatomic sub-regions of the brain.

“In summary, our results show that modulations in CR-related gene transcription throughout aging are a conserved trait that is traceable across evolutionarily diverse species, ranging from humans to mice and fish.”

Click here to read the full research paper published by Aging (Aging-US).

AGING (AGING-US) VIDEOS: YouTube | LabTube | Aging-US.com

Aging (Aging-US) is an open-access journal that publishes research papers bi-monthly in all fields of aging research and other topics. These papers are available to read at no cost to readers on Aging-us.com. Open-access journals offer information that has the potential to benefit our societies from the inside out and may be shared with friends, neighbors, colleagues, and other researchers, far and wide.

For media inquiries, please contact [email protected].

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