Qiu-Ling Zhang ¹, Jun-Yi Cui ¹, Yu-Ying Zhang ¹, Bin Yu ¹, Hao Chen ¹, Ting-Zhi Zhang ³, Shao-Wei Yan ^1, and Maurice A.M. van Steensel ²

Sleep homeostasis plays a critical role in most living organisms’ physiological, cognitive and behavioral function, and long-term health.¹ This is a cyclical state of rest and decreased consciousness and is closely related to the circadian rhythm system, which performs various physiological functions.² The mammalian circadian system, consisting of input, oscillator and output signaling components, is essential for synchronizing the organism’s daily behavioral activities and periodic light-dark changes in the environment. The circadian system can operate at both the systemic and cellular levels. In response to the input signal of ambient light, especially blue light, the central pacemaker located in the suprachiasmatic nucleus (SCN) in the anterior hypothalamus regulates the systemic circadian rhythm through neural and endocrine signals.^3,4

In another way, the circadian rhythm of cells is maintained by cellular autonomous molecular oscillators, which exist in nearly all cells. These molecular oscillators use transcription-translation feedback loops (TTFLs) with a 24-hour cycle (Figure 1).⁵ The core TTFLs are composed of two activators (brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 gene (BMAL1, also ARNTL) and circadian locomotor output cycles kaput gene (CLOCK)) and two repressors (period gene (PER) and cryptochrome gene (CRY)).^6,7 Interference with any of these genes can disrupt circadian rhythm homeostasis.^8-10 However, the problem of insufficient sleep nowadays still afflicts some people with shift work and sleep disorders. Consequently, the risk of certain diseases increases gradually because of the disturbed circadian rhythm, such as the emergence of metabolic disorders, cardiovascular diseases, cancer or aging-related diseases.¹¹ Therefore, therapeutic strategies for some diseases based on circadian rhythms modulation and target show great potential.^12,13

Figure 1. The molecular clock and three TTFLs in mammals. Within Loop 1, BMAL1:CLOCK protein complex can bind to E-box elements and periodically initiate the encoding of repressor proteins PER and CRY as mentioned above, also nuclear receptor subfamily 1, group D member 1 (REV-ERBα, also NR1D1), retinoic acid receptor-related orphan receptor α (RORα) and albumin D-box binding protein (DBP). Further, the expression of these proteins is regulated by posttranslational modifications (PTM) by autoinhibition of casein kinase I ε (CKIε) and then undergo proteasomal degradation. Loop 2 contains REV-ERBα and RORα, acting on ROR response elements (RORE), which can promote the expression of BMAL1 and nuclear factor interleukin 3 (NFIL3). Whereas, NFIL3 and DBP are also contained in loop 3 and alternately regulate on D-box elements, successively promoting PER and clock-controlled genes (CCGs). Reprinted from permission from ref.⁵ Copyright 2014 Elsevier Inc.

Researchers increasingly link circadian rhythms to aging, a chronic disease, by interfering with different circadian genes in model organisms.^14-16 Early studies concluded the absence of the Bmal1 gene in mice could lead to impaired rhythmic behavior, which was also associated with premature aging phenotypes and reduced lifespan.¹⁷ The activity of the Clock gene is crucial in regulating normal physiological states as well as the aging of the lens and skin.¹⁸ Plenty of studies suggest that the molecular mechanisms by which circadian rhythms influence aging are related to multiple factors, including the balance of reactive oxygen species (ROS), oxidative stress responses, cellular and systemic metabolism, DNA repair, and the immune system and inflammatory responses.^6,19 As one of the 12 hallmarks of aging, chronic inflammation has been widely reported to be regulated by the circadian rhythm system.^20,21 A comprehensive analysis of the immune cell atlas in individuals with poor sleep showed that staying up late resulted in the down-regulation of cytotoxic immune cell activity in the blood and the occurrence of inflammatory responses and cellular aging.²² Furthermore, BMAL1 was confirmed to regulate the expression of interferon-sensitive genes (Isg), thereby suppressing skin inflammation in mice.²³ Furthermore, circadian rhythm can also modulate various inflammation-associated receptor-mediated pathways through melatonin, thus affecting the occurrence and development of inflammatory diseases.²⁴

What Is Inflammatory Aging?

Inflammatory aging is the accelerated aging phenomenon caused by systemic and low-grade chronic inflammation generated by the body’s immune response.^25,26 Aging is typically characterized by chronic inflammation, accompanied by cellular senescence, immune-senescence, organ dysfunction and age-related diseases.^27,28 But factors secreted by senescent cells promote chronic inflammation and induce senescence in normal cells. Concurrently, chronic inflammation accelerates the senescence of immune cells, leading to weakened immune functions, an inability to clear senescent cells and inflammatory factors, thus creating a vicious cycle of inflammation and aging.²⁹ However, the molecular pathways that transfer inflammatory signals and their impact on natural aging remain misunderstood.^30-32 Notably, cellular senescence is commonly accompanied by the expression of senescent-associated secretory phenotypes (SASPs), which can affect the surrounding tissue microenvironment and thereby influence the aging process of the entire organism (Figure 2).³³ Currently known factors that regulate the expression of SASPs include dysfunctional mitochondria,³⁴ sustained DNA damage response,³⁵ nuclear factor-kappa B (NF-κB),³⁶ and the mammalian target of rapamycin (mTOR).³⁷ Yet, none of these factors-mediated pathways clearly explain the specific mechanism governing the interaction between circadian systems, inflammation response and organism aging.

Figure 2. The interaction of inflammation and aging and the reflected inflammatory aging at the molecular, cellular, and organ levels. Almost all cells undergo senescence in the body. The accumulation of senescent cells triggers inflammation in organs and SASP, leading to an increased risk of age-related diseases. During the processes, not only immune cells can recognize and eliminate senescent cells, but also SASP causes immune senescence and promotes inflammatory cell death, thus further accelerating aging-related phenotypes. Reprinted with permission from ref.³³ Copyright 2023 Li.

Given the above, this review provided a snapshot of the latest developments regarding how to regain the disordered circadian rhythm and the impact on inflammation and aging. Further, from the perspective of skin, the most apparent human organ, a brief discussion on the solutions for relieving inflammatory aging attributed to turbulent circadian rhythms was presented.

Circadian Rhythm, Chronic Inflammation and Aging Interactions

Circadian rhythms with 24 hours formed from long-term evolution in organisms, aiding in their adaptation to environmental changes and the regulation of physiological activities.³⁸ Despite explosive evolution and mass extinctions, the characteristic of circadian rhythms persists, indicating that it was internalized early in the course of biological evolution rather than being an acquired trait. The circadian rhythm is driven by an endogenous clock system, and nearly exists in all organisms on Earth, from simple unicellular cyanobacteria to mammals and humans.³⁹ The biological clock consists of central and peripheral clocks.⁴⁰

In mammals, the central clock is located in the SCN, which possesses a bilateral structure situated in the anterior part of the hypothalamus and controls physiological rhythms.^41,42 The SCN is composed of approximately 20,000 clock neurons, all containing molecular mechanisms that can function as independent cellular oscillators when isolated and cultured.^43,44 As the central pacemaker, the SCN receives, transduces and integrates light-dark cycle signals from the retina-hypothalamus pathway and gives synchronizing instructions.^45,46 In addition to autologous tissue rhythms, the SCN transfers information to peripheral effectors for synchronizing peripheral clocks through various humoral and certain neuronal signals.⁴⁷ The SCN indirectly regulates hormone rhythms such as adrenocortical hormones and cortisol, and the rhythms of hormones like melatonin by controlling the function of the pineal gland. Hormonal signals from the adrenal glands feedback to the central clock and are transmitted to peripheral clocks.⁴⁸ Peripheral clocks and clock genes regulated by the central clock exist in nearly all peripheral tissues and organs, including the heart, lungs, liver, kidneys and skin. Consequently, many important physiological factors, such as immunity, metabolism, aging, hair growth and pigmentation, exhibit vibrations accompanying with circadian rhythm.^49-54 In summary, circadian rhythms play a crucial role in coordinating various complex life activities in an orderly manner.

At the molecular level, circadian rhythms are constituted by multiple transcription-translation feedback loops that drive the rhythmic transcription of core circadian clock genes, requiring 24 hours to complete one cycle. The 24-hour cycle is precisely controlled by post-translational modifications such as phosphorylation, ubiquitination and acetylation.⁵⁵ In the morning, CLOCK and BMAL1 proteins in mammals form heterodimers and activate the transcription of target genes such as PER and CRY by binding to E-box binding sites in promoters. In the evening, PER and CRY proteins accumulate and dimerize in the cytoplasm, then translocate back to the nucleus to act on the CLOCK-BMAL1 complex to inhibit transcription, realizing a negative feedback regulation.⁵⁶ RORα and REV-ERBα exert their effects through RORE in promoters. REV-ERBα can bind to the BMAL1 promoter to repress BMAL1 transcription, while RORα promotes the transcription of BMAL1, forming a positive and negative feedback network motif.^57-59

Disordered Circadian Rhythm Therapies

Several therapies have been established to improve disordered circadian rhythm therapies. Here are descriptions of several of them—melatonin-, photo- and chronotherapies.

Melatonin therapy: Melatonin is a physiological hormone related to sleep timing, typically secreted by the pineal gland about 2 hours before habitual bedtime, peaking during the night, and then sharply decreasing after the night ends.⁴ Melatonin can be measured from plasma, saliva or urine and is a typical marker of circadian rhythms. At supraphysiological doses, melatonin is considered as drugs and, when taken before sleep, can help increase sleep duration and improve sleep quality.⁶⁰ It has been used exogenously for the treatment of primary and secondary sleep disorders. Taking melatonin at night can advance the biological clock while taking it in the morning can delay it.^61,62 Research indicates that 0.3-3.0mg of melatonin affects resetting circadian rhythms.⁶³ Currently, three subtypes of melatonin receptors have been identified: melatonin 1 (MT₁), melatonin 2 (MT₂), and melatonin 3 (MT₃) receptors. MT₁ and MT₂ receptors are G-protein-coupled receptors, while MT₃ receptors are quinone receptors found in plants. Melatonin primarily acts on melatonin 1 and melatonin 2 receptors, playing a role in resetting circadian rhythms and promoting sleep.^64,65

Phototherapy: Phototherapy influences endogenous circadian rhythms by suppressing melatonin secretion through light exposure.^66,67 Light exposure before the dim light melatonin onset (DLMO) and the nadir of core body temperature can delay circadian rhythms, while light exposure after these times can advance them. Exposure to various light intensities in the evening or at night can induce melatonin suppression, increasing the risk of circadian rhythm disorders.⁶⁸ The beneficial effects of phototherapy on synchronizing circadian rhythms, improving sleep quality and enhancing cognitive abilities depend on the spectral composition as well as the timing and intensity of the exposure.^69,70 Blue light has a more potent effect, with human circadian rhythms being most sensitive to short-wavelength blue light (446-477nm).⁴ Typically, phototherapy is more effective when used in conjunction with melatonin than when either is used alone.⁷¹

Chronotherapy: Chronotherapy can alter the sleep-wake cycle in patients with circadian rhythm disorders. It was invented by Czeisler and colleagues in 1981.⁷² Chronotherapy involves creating an individualized sleep-wake schedule for patients, such as delaying or advancing sleep by 2-3 hours each week, gradually shifting sleep times until the ideal sleep-wake schedule is achieved and maintained.68  Aiming to ensure that patients receive other treatments such as phototherapy and melatonin at appropriate times to restore proper circadian rhythm patterns, chronotherapy helps to establish a continuous self-regulating sleep dynamic.^73,74

Other therapies: Benzodiazepine and non-benzodiazepine hypnotics should be used with caution due to their adverse reactions, especially in patients with dementia or brain injuries, as they may further impair cognitive functions.⁷⁵ Cognitive-behavioral therapy (CBT) involving stimulus control, motivational interviewing and other relaxation strategies, can improve sleep perception.⁷⁶ Improved sleep hygiene behavior also aids in diagnosing and treating sleep disorders.⁷⁷ Metabolic disturbances associated with circadian rhythm disorders may be mediated by specific gut bacteria overgrowth. Probiotic supplementation improves subjective sleep quality.^78,79

Inflammatory Aging Induced by Circadian Rhythm Disturbance

More than 40 years ago, the connection between circadian rhythms and lifespan was proposed. Substantial evidence during the past 20 years demonstrates the involvement of the biological clock in regulating aging. The longstanding hypothesis in this field is that disruptions in circadian rhythm lead to the development of age-related diseases and lifespan reduction, whereas regular circadian oscillations promote organismal health and longevity.^80,81 Additionally, studies on humans have confirmed a close link between the reduction of circadian rhythms in the elderly and increased mortality rates.⁸² Any deviation from the innate 24-hour circadian cycle is likely to induce a reduction in lifespan, suggesting that either the innate rhythmic cycle determines the health status of an organism, or that a healthy organism possesses a more regular biological clock.⁸³

Researchers often establish models by disrupting circadian genes, either mutations or overexpression, to figure out the role of circadian rhythms in aging.⁸⁴ BMAL1, a circadian protein, is one of the most extensively studied aging-related proteins. Lack of BMAL1 leads to the most severe acceleration of aging phenotypes. For instance, compared to the 100% survival rate in wild-type mice during the study, the knockout of the Bmal1 gene in mice results in an average lifespan reduction to eight months, accompanied by various aging-related physiological manifestations such as cataracts, cognitive decline and osteoporosis. Furthermore, BMAL1 deficiency also leads to increased oxidative stress in tissues and the accumulation of senescent cells.⁸⁵ Additionally, Clock, the first discovered mammalian circadian gene, functions through CLOCK protein by binding with BMAL1. Mice with Clock deficiency also show a ~10% decrease in average lifespan and are more inclined to suffer from cataracts and dermatitis compared to wild-type mice.⁸⁶ PER proteins are negative regulatory components in TTFLs, and Period dysfunction also led to a reduced lifespan in Drosophila melanogaster, while overexpression extends lifespan, as is also the case for mice with Per2 mutations.^87-89 Moreover, human keratinocytes with silenced PER3 exhibit upregulated secretion of matrix metalloproteinase 1 (MMP-1), thereby affecting skin aging.⁹⁰

Disordered Circadian Clock and Inflammation

An estimated ~10% of mammalian genes are under circadian transcriptional control.⁹¹ Circadian rhythms play a pivotal role in processes including sleep, metabolism, and immunity. They are regulated by circadian rhythms and exert reciprocally.⁹² A similar mechanism exists in inflammatory diseases, where disruptions in the circadian clock can induce or exacerbate inflammatory responses, while inflammation can also cause circadian rhythm disorders.⁹³ Circadian rhythms can regulate inflammatory responses at both systemic and cellular levels. Systemic regulation of inflammation includes modulation of lymphoid organs through the autonomic nervous system, immunomodulatory functions through the secretion of hormones such as cortisol and catecholamines, and the regulation of immune cell proliferation and differentiation, as well as migration and release from lymphoid tissues, cytokine production and secretion.^49,94,95 In models with circadian gene mutation, the levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) are significantly increased in tissues.⁹⁶  Clinic studies confirmed a dependency between PER1 expression and the activity of inducible nitric oxide synthase (iNOS).⁹⁷ Furthermore, mice with Clock knockout showed significantly weakened physiological functions of nuclear factor kappa-B (NF-κB). This suggests that CLOCK overexpression activated the NF-κB-mediated inflammatory pathway, leading to an abundance of pro-inflammatory cytokines and immune dysregulation.⁹⁸ Additionally, CRY proteins have been proven to be fundamental immunomodulatory components of innate immunity and inflammatory responses, with regulatory functions on the glucocorticoid receptor (GR), a nuclear receptor superfamily member.⁹⁹

Signal Pathway Mediating Chronic Inflammation and Aging

The relationship between inflammation-related pathways and aging is a well-researched theory of aging-related mechanisms. Chronic inflammation has been identified as an endogenous factor in aging. Eliminating inflammation may be a potential anti-aging strategy.²⁰ Inflammatory pathways play a crucial role in regulating the aging process, with pathways such as NF-κB, insulin and the insulin-like growth factor 1 (IGF-1), sirtuins (SIRT), mammalian target of rapamycin (mTOR), and Toll-like receptors (TLR), regulating inflammation through various mechanisms, ultimately affecting the aging process (Figure 3).^100-102

Figure 3. The signaling pathways of chronic inflammation associated with aging. A = adenine, AID = activation-induced cytidine deaminase, Akt = the protein kinase B, AMPK = AMP-activated protein kinase, ATP = adenosine triphosphate, CASP1 = caspase-1, cGAS = cyclic GMP-AMP synthase, DAMPs = damage-associated molecular patterns, DDR = deoxyribonucleic acid damage response, DNMT = methyltransferase, EV = extracellular vesicle, FoxO = forkhead box protein O, G = guanine, GSTM2 = glutathione S-transferase Mu 2, GTP = guanine triphosphate, hTERT = human telomerase reverse transcriptase, IFN = interferon, IGFR = IGF receptor, IKK = inhibitor of NF-κB (IkB) kinase, IR = insulin receptor, IRF3 = interferon regulatory factor 3, JNK = Jun N-terminal kinase, LKB-1 = liver kinase B1, Me3 = methyl, MMR = mismatch repair, mtDNA = mitochondrial deoxyribonucleic acid, mTORC = mTOR complex, NAD = nicotinamide adenine dinucleotide, NER = nucleotide excision repair, NLRP3 = nod-like receptor family pyrin domain-containing 3, PAMPs = pathogen-associated molecular pattern molecules, PDK1 = 3-phosphoinositide-dependent protein kinase-1, PP2C = Protein phosphatase 2C, S6K = Ribosomal protein S6 kinase, SCFA = short chain fatty acid, STING = stimulator of interferon genes, TBK = tank-binding kinase 1, TSC = tuberous sclerosis complex. Reprinted with permission from ref.¹⁰¹ Copyright 2023 Baechle.

NF-κB, as a nuclear transcription factor, can be activated by various pathological factors and is involved in regulating the expression of numerous inflammatory genes, especially pro-inflammatory genes. Extensive research indicates that the NF-κB pathway is involved in processes such as tissue stress and damage, cell differentiation and apoptosis, and organismal defense responses.^33,103 AMPK-sirtuin pathway deregulation also induces inflammatory aging. Sirtuins are a group of class III histone deacetylases that regulate lifespan. Sirtuins are involved in many important biological processes, including DNA repair to maintain genomic stability, metabolism regulation, mitochondrial biogenesis control to reduce oxidative stress, cell cycle regulation and cell mitosis extension through deacetylation, thereby delaying aging.¹⁰⁴

AMPK activation can increase the cellular NAD⁺:NADH ratio, leading to the expression of sirtuins, which restricts the activation of NF-κB. mTOR-mediated pathway is also linked to lifespan. mTOR is a highly conserved serine/threonine protein kinase involved in regulating cell growth, differentiation, proliferation, migration and survival.¹⁰⁵ mTOR signaling pathway participates in cell growth during embryonic development and in cell metabolism during maturity. It tends to be overactivated in old age, leading to the occurrence of various aging-related diseases. mTOR exists within mTORC1 and mTORC2 in mammals. mTORC1 as the downstream signals of Akt, together with mTORC2 as the upstream signals of Akt can respond to insulin resistance and activate NF-κB signals, fuelling inflammation and accelerating aging progression.^106-108 To be mentioned, molecular damage induced by oxidative stress engaged in chronic inflammation. The innate immune sensing of cytosolic chromatin fragments through cGAS-STING and the downstream mediators, including IRF3, NF-κB and SASPs also play a potential role in the spreading of senescence.^109,110

Strategies for Delaying Skin Inflammatory Aging Ascribed to Disordered Circadian Rhythm

In recent decades, the increased use of electronic devices and other artificial light sources has altered the exposure patterns to blue light (400-500nm), arousing growing research on the biological effects of blue light on the skin. Blue light has lower energy than ultraviolet (UV) radiation (280-400 nm) and can penetrate the dermis, reaching depths of up to 1mm (Figure 4a).¹¹¹ The direct impact of blue light on the skin is primarily manifested through the interaction with chromophores, including flavins, porphyrins, nitrosylated proteins, and opsins (OPN), which lead to an overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS, such as nitric oxide).¹¹² Such ROS generation mainly located in mitochondria, damages mtDNA and nuclear DNA, further impacting cell proliferation and activity, propelling pro-inflammatory signals, and inducing collagen metabolism disorders. ROS activates the intracellular mitogen-activated protein kinase (MAPK) signaling pathway, inhibiting collagen genesis and leading to skin photoaging. ROS gives rise to the reduction of mitochondrial membrane potential, the opening of the mitochondrial permeability transition pore (MPTP), and causes mitochondrial outer membrane permeabilization (MOMP) and the release of mtDNA into the cytoplasm, thereby activating the cGAS-STING inflammatory pathway and triggering the senescence-associated secretory phenotype (SASP) (Figure 4b).^113,114

Figure 4. The biological effects of blue light on the skin. (a) The exposure pattern of light with different wavelengths to skin; (b) Schematic diagram for showing the effect of blue light on skin and the associated signalling pathways. CAMKII = calcium/calmodulin-dependent protein kinase II, CREB = cAMP response element-binding protein, DCT = dopachrome tautomerase, ERK = extracellular signal-regulated kinase, MITF = microphthalmia-associated transcription factor. Reprinted with permission from ref. 113. Copyright 2022 Silverchair Publisher.

In addition to its direct effects on the skin, blue light can also influence skin indirectly by disrupting circadian rhythm through central and peripheral regulation, with the former involving the stimulation of photoreceptors in the retina and the latter involving direct interactions with skin cells. Blue light interferes with circadian rhythm, negatively impacting the skin repair processes at night.¹¹⁵ Melanopsin is a member of the opsin family found in intrinsically photosensitive retinal ganglion cells (ipRGCs) and is responsible for the systematic circadian rhythm based on the light/dark cycle. Blue light stimulation of ipRGCs can reset the circadian clock and inhibit melatonin generation.¹¹⁶ In addition, some peripheral mechanisms also regulate circadian rhythms as mentioned above, including certain clock-related genes expressed in skin cells, such as BMAL1 and PER1. For example, blue light could reduce the transcriptional levels of PER1 in human keratinocytes.¹¹⁷ Blue light also influences the activation of external nicotinamide adenine dinucleotide phosphate oxidase (ECTO-NOX) in mice, which is essential for biological clock homeostasis.¹¹⁸ Such factors all contribute to skin photo-aging caused by the direct and indirect effects of blue light.

Blue Light Protectants

There are two guidelines when combating the direct and indirect effects of blue light on the skin. Some active ingredients can absorb, scatter or reflect blue light, building the first line of defense. Skin damage brought from ROS and RNS generation should be avoided by applying certain antioxidants, acting as the second line of defense. Inorganic materials, such as titanium dioxide, zinc oxide and cerium oxide have always been used as the first line of defense. However, the defects in refractivity and photolytic activity restricted their extensive use, thus promoting the development of more excipients.¹¹⁹ Cerium oxide can shield blue radiation and is transparent to the skin when dispersed in water.¹²⁰ Iron oxides have also been used in sunscreen products and contributed to blue light protection. By combining different amounts of iron oxides and pigmentary titanium dioxide, sunscreen products could benefit patients with visible-light-induced photo-dermatosis.¹²¹ Besides, calcium sodium borosilicate protects skin from the blue light effect and could be applied as a cosmetic ingredient.¹²²

Botanical extracts are also exploited as ingredients beneficial for blue light protection, especially for their antioxidant activity. Extracts of Vaccinium vitis-idaea (lingonberry) could act as a free radical scavenger due to the abundance of antioxidants (polyphenols, and vitamins A, C and E) properties, thus preventing photoaging and skin wrinkles.¹²³ Root extract of Withania somnifera, claims to target fibroblasts and boost the synthesis of dermal proteins, combating the deleterious effects of artificial visible light (AVL).¹²⁴ Other popular sources of botanical ingredients, like extract derived from rice and rice germ,¹²⁵ cocoa seed,¹²⁶ and Hedychium coronarium root¹²⁷ also show blue-light resistance. Certain algae-derived extracts, such as freshwater microalgae seaweed, brown seaweed and marine extracts, were claimed to shield from blue light and protect from oxidative stress. Especially, Scenedesmus rubescens extract was identified to protect blue light-induced cutaneous signs of photo-aging, such as hyperpigmentation, erythema and decreased collagen synthesis.^122,128 Extracts from the brown seaweed, Zonaria tournefortii, could act as an anti-blue light ingredient to prevent skin photoaging.¹²⁹ In addition, Pseudoalteromonas ferment extract could protect skin from blue light and reduce the level of MMP1 with the capacity to degrade collagen.¹³⁰

Carotenoids such as carotene, lutein, zeaxanthin and lycopene are outstanding antioxidants and blue light protectants derived from plants.¹³¹ Such antioxidants could be available in the dietary intake of dark green leafy, orange, red and yellow vegetables or applied locally to the treatment site. Topically, β-carotene could be enriched in carrot root extract and seed oil¹³² and Physalis alkekengi calyx extract,¹³³ which provided a powerful defensive shield against blue light and prevented skin aging. Lutein, known for its key role in macular function, is found to have superior blue light-filtering properties.¹³⁴ Lutein extracted from marigold oleoresin was identified to be a valuable ingredient in maintaining skin youth by serving as an antioxidant and blue light absorber.¹³⁵

Anti-Circadian Rhythm Disturbance

The circadian rhythm system is very sensitive to external signals such as environmental changes, intracellular dynamic effects and the accumulation of endogenous metabolites. Consequently, certain molecular regulators can directly target or affect the circadian rhythm system through feedback mechanisms. Currently, researchers primarily employ large-scale screening of molecular compound libraries to identify molecular regulators that can modulate circadian rhythms.^13,136 One approach involves transfecting cell lines with luciferase reporters driven by exogenous clock gene promoters, allowing for phenotypic analysis at the cellular level by recording the dynamic expression of clock-related genes and proteins over extended periods, analyzing circadian parameters such as period, phase and amplitude, constantly monitoring changes in cellular circadian rhythms.¹³⁷ Another approach involves analyzing the transcriptional activity of clock genes at specific time points.¹³⁸ This method first constructs cell lines that express luciferase under the control of circadian rhythm genes. Compounds are then screened and validated for their effects on the transcriptional levels of clock-related genes, followed by kinetic measurements to verify their efficacy in modulating circadian rhythms, thereby identifying compounds that specifically target components of the circadian rhythm system. After identifying small molecules with therapeutic potential at the cellular level, it is typically necessary to perform pharmacokinetic and pharmacodynamic structural modifications on the compounds. This optimization of lead compounds is essential to accelerate drug development.

In addition to the above preclinical or clinical drugs, skincare ingredients can target circadian rhythm. Tripeptide-32, a synthetic peptide with the sequence Ser-Thr-Pro-NH₂, was confirmed to activate CLOCK and PER1 in keratinocytes.¹³⁹ Further research identified that extracts from Adansonia digitata could upregulate PER1 expression related to circadian rhythm in skin by promoting the expression of miR-146a, resulting in increased collagen-1 production and DNA repair in skin cells.140 An antioxidant ingredient consisting of Helianthus Annuus seed oil, ethyl ferulate, Rosmarinus Officinalis leaf extract and tocopherol was claimed to preserve the skin’s natural biorhythm, especially in skin hydration, reinforce the skin barrier and reduce the UV stress.¹⁴¹ Another ingredient obtained from Lindera strychnifolia and rich in oligo-α-glucans could restore the expression of CLOCK, and even have a comparable effect to photo-therapy and potential in skin anti-aging treatment.¹⁴² A combination of a peptide, a flavone and a rosemary leaf extract resynchronized OPN5 and PER2 production and increased melatonin production under blue light stress. The clinical studies showed that the composition improved skin hydration, radiance, smoothness and viscoelasticity.¹⁴³ Extracts from Andrographis paniculata reduce oxidative stress and inflammation in fibroblasts and keratinocytes.^144,145 Andrographis paniculata leaf extract modulates circadian rhythm in aging skin cells and promotes skin revitalization.¹⁴⁶ The hydrolyzed yeast protein was developed through molecular biology. The ingredient exhibited an increased capacity for keratinocytes and keratinocytes to express CLOCK, BMAL1 and PER1 in vitro and provided an age-defying approach.^147,148 Nonapeptide-1 was claimed to enhance the expression of JARID1A gene, which could activate CLOCK and BMAL1 expression in cells, thus upregulating PER and CRY, arousing the metabolism and the mitochondrial activity of senescent cells.^149,150 The mixture of glycoproteins, derived from cytoplasmic and mitochondrial constituents of the yeast Saccharomyces cerevisiae, and three amino acids consisting of glutamic acid, valine and threonine was found to activate mitochondria in skin cells from the perspective that circadian rhythms affect the body’s blood flow and oxygen and energy supply, further affecting the appearance of the skin, thereby improving the circadian rhythm imbalance under UV pressure and accelerating epidermal cell regeneration.^151,152

Ingredients or nutrients for sleep improvement have also opened new avenues for circadian rhythm regulation. Currently, the active ingredients for sleep expensively reported can be broadly categorized into hormone-based substances such as melatonin, amino acids and the derivatives like γ-aminobutyric acid (GABA) and theanine, botanic extracts such as valerian, passionflower and lavender, traditional Chinese medicine ingredients like Stigma croci and Semen ziziphi spinosae, prebiotics derived from yeast and lactobacillus, and milk proteins like α-lactalbumin and casein hydrolysates.^153-157 Inspired by this research, some ingredients were developed based on sleep improvement; thereby mitigating the negative effects of circadian rhythms disturbance on the skin. By combining oil-soluble natural extract from lavandin in Provence or Australian tea tree oil with triheptanoin, both were developed to improve sleep quality by inhaling the olfactory compounds. The former boosted melatonin production, thus resynchronizing the circadian rhythm in skin cells, and the latter could enhance the expression of melatonin pathway genes and antioxidant capacity, reducing the appearance of skin aging.¹⁵⁸ A postbiotic natural active ingredient, obtained from the plant-based fermentation of Lactococcus lactis was demonstrated to resynchronize the circadian expression rhythms of CLOCK and CRY1 in skin cells after blue light overexposure. Moreover, the significantly upregulated expression of melatonin receptor 1 (MTR1), the longevity protein SIRT1, and two key detoxifying enzymes referring to NAD(P)H quinone oxidoreductase 1 (NQO-1) and heme oxygenase 1 (HMOX1) all contributed to the outstanding capacity on skin anti-aging.¹⁵⁹ The melatonin-like compound, croctin acid was also exploited as an active anti-aging skin protectant, which was transformed from natural sourced saffron extracted from gardenia fruit by skin microflora. Such a compound was claimed to restore melatonin homeostasis under late night and blue light pressure, activate the skin antioxidant cascade, protect mitochondria and improve sleep quality.¹⁶⁰

Pathway Blockade of Inflammation Modulated by Circadian Rhythm

Circadian genes play a significant role in the interplay between biological rhythms and oxidative stress or inflammation. Therefore, pathway blockers of inflammation modulated by circadian rhythm could also be exploited in delaying the aging process. Recent studies have found that Per2 is associated with inflammation-induced diseases, with Per2 deficiencies in mice potentially leading to aging-related phenotypes through the activated regulation of chemokines such as regulated upon activation, normal T cell expressed and secreted (RANTES, also known as C-C chemokine ligand 5) (RANTES/CCL5).¹⁶¹ Lower methylation levels of CLOCK, have been shown to correlate with higher levels of the inflammatory cytokine IL-8.¹⁶² Sleep rhythm disorder can also lead to elevated IL-6 levels by activating NF-κB, while significantly restricting PER2 expression in hippocampal tissue. Animal studies found that blocking NF-κB activity can reverse the reduced levels of PER2 protein, suggesting that the NF-κB signaling pathway may play a key role in the interaction between biological rhythms and immune inflammation.¹⁶³

Alterations in the expression of clock-related genes can also participate in the development of aging-related diseases through the TLR4/NF-κB signaling pathway. Toll-like receptor (TLR) family is an important mediator between immune responses, inflammation, and lipid metabolism disorders, located on the cell membrane surface. TLR4 can activate NF-κB to promote the production of inflammatory cytokines. Sleep deprivation in rats led to circadian rhythm disturbances, thus upregulating pro-inflammatory cytokines including TNF-α, IL-1 and IL-6, leading to increased vascular inflammation, as well as upregulation of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1).^164,165 This process could be reversed by Cry1 overexpression, which also inhibited NF-κB activity. Further findings show that overexpression of Cry1 significantly reduced the protein levels of TLR2, TLR4, and phosphorylated p65 (p-p65), and downregulated pro-inflammatory factor expression.¹⁶⁶

Studies have found that the activity and expression of downstream targets of Akt signaling pathway in macrophages, such as ERK, Akt and mitogen-activated protein kinase kinase 1(MEK1), also exhibit dependency on circadian rhythms. The loss of Rev-erbα or Bmal1 genes in macrophages can enhance inflammatory cytokine production and disrupt the rhythmic expression of Akt.^167,168 Additionally, the Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is an important component of the insulin signaling pathway, affecting the metabolism and contractile function of the heart.^169-171

Dysregulation of Bmal1 expression attributed to sleep rhythm disturbances could also lead to activation of MAPK/ERK signaling pathway, with increasing levels of phosphorylated ERK, further upregulating the expression of inflammatory factors IL-6 and extracellular matrix degradation-related enzymes MMP3, MMP13, etc.¹⁷² MAPKs are found only in eukaryotes but exist in all animals, fungi, and plants, and even in a range of single-celled eukaryotes. The MAPK family includes conventional and atypical subfamilies: ERK1/2, JNK1, 2 and 3, p38 (α, β, γ, δ), ERK5, ERK3, 4 and 7, Nemo-like kinase (NLK), which are involved in mediating cellular responses to a variety of stimuli.¹⁷³

In mammals, CRY also regulates the cyclic adenosine 3, 5′-monophosphate- protein kinase A (cAMP-PKA) signaling pathway. Reports have indicated that overexpression of CRY could inhibit the cAMP-PKA signaling pathway, preventing PKA from phosphorylating and activating the transcription factor, CREB, and might also block the activation of the p65 subunit phosphorylation of the transcription factor NF-κB by PKA, therefore reducing inflammatory responses.^174,175 cAMP, as an important intracellular second messenger, primarily functions by binding to the regulatory subunit of PKA, causing the regulatory subunit to dissociate from the catalytic subunit, thereby activating PKA. Activated PKA can phosphorylate proteins, so essential for maintaining normal cell metabolism and various inflammatory responses.^176,177 A large body of experimental evidence has shown that the cAMP-PKA signaling pathway can also interact with other pathways, such as Ca²⁺-dependent signaling pathways, NF-κB signaling pathways, cytokine-induced Janus kinase (JAK)-signal transducer and activator of transcription 3 (JAK-STAT3) signaling pathways, Ras protein-mediated MAPK signaling pathways, and having an indispensable impact on the systematic function.^178-181

Conclusions

Circadian rhythms influence the normal physiological activities of the body, and increasing studies have elucidated the connection between circadian rhythms and aging, and thereinto chronic inflammation plays a crucial role in the linking mechanism. Starting from the molecular mechanisms of the circadian clock system, we progressively explored various clinical therapies for circadian rhythm disorders, the relationship between circadian rhythms and inflammation, and the signaling pathways mediating inflammation and aging, aiming to identify more clear pathways or mechanisms by which inflammation-mediated circadian rhythm disruptions contribute to aging.

Given that the skin is the largest and most visible organ of the human body, we also target skin aging, summarizing current strategies to address inflammation-induced aging brought by circadian rhythm disturbances. Specifically, since blue light induces inflammatory skin aging through direct oxidative stress and indirect rhythm imbalance effects, researchers developed various rooted solutions to counteract blue light-induced aging. To mitigate peripheral clock disruptions in the skin caused by external factors such as staying up late, light pollution and stress, apart from the development of various clinical and preclinical drugs, a variety of ingredients that directly act on the molecular biological clock of skin cells have emerged in dermatology. Finally, we introduced several inflammatory pathways currently reported to be influenced by circadian rhythms. By figuring out the interactions of circadian rhythms, inflammatory pathways and aging, molecular drug blockers or pathway-targeting ingredients are expected to show promising prospects in aging treatment, such as targeting TLR4/NF-κB signaling pathway, PI3K/Akt signaling pathway, MAPK/ERK signaling pathway, AMPK/SIRT signaling pathway, cGAS-STING signaling pathway. We also hope that this review will succeed in the future to contribute to more anti-aging investigations for organisms other than dermatology.

Author Contributions: Conceptualization, Q.L.Z. and S.W.Y.; writing—original draft preparation, Q.L.Z.; writing—review and editing, J.Y.C., Y.Y.Z., B.Y. and H.C.; supervision, T.Z.Z., S.W.Y. and M.A.M.v.S.; funding acquisition, S.W.Y. and T.Z.Z.; All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Conflicts of Interest: The authors declare no conflicts of interest.

About the Authors

¹    Late-Night Skin Research Laboratory, Shanghai 200125, China; qingtan@syounggroup.com

²    Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 308205, Singapore; maurice_vansteensel@ntu.edu.sg

³    S’Young Cosmetic Manufacturing Co., Ltd., Changsha, Hunan 410000, China; dongfang@syounggroup.com

Correspondence: mufeng@syounggroup.com (S.W.Y.), maurice_vansteensel@ntu.edu.sg (M.A.M.v.S.)

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