PER2
Period circadian protein homolog 2 (hPER2) (Circadian clock protein PERIOD 2) [KIAA0347]
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Disrupted sleep-wake and molecular circadian rhythms are a feature of aging associated with metabolic disease and reduced levels of NAD , yet whether changes in nucleotide metabolism control circadian behavioral and genomic rhythms remains unknown. Here, we reveal that supplementation with the NAD precursor nicotinamide riboside (NR) markedly reprograms metabolic and stress-response pathways that decline with aging through inhibition of the clock repressor PER2. NR enhances BMAL1 chromatin binding genome-wide through PER2 deacetylation, which in turn primes PER2 phosphorylation within a domain that controls nuclear transport and stability and that is mutated in human advanced sleep phase syndrome. In old mice, dampened BMAL1 chromatin binding, transcriptional oscillations, mitochondrial respiration rhythms, and late evening activity are restored by NAD repletion to youthful levels with NR. These results reveal effects of NAD on metabolism and the circadian system with aging through the spatiotemporal control of the molecular clock.
MeSH Terms
- ARNTL Transcription Factors
- Age Factors
- Aging
- Animals
- CLOCK Proteins
- Circadian Clocks
- Circadian Rhythm
- Cytokines
- Female
- HEK293 Cells
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- NAD
- Period Circadian Proteins
- Sirtuin 1
- Sirtuins
Keywords
- NAD( )
- SIRT1
- aging
- circadian
- clock
- heat shock factor 1
- liver
- nicotinamide mononucleotide
- nicotinamide riboside
- transcriptomics
Aging process in mammals is associated with a decline in amplitude and a long period of circadian behaviors which are regulated by a central circadian regulator in the suprachiasmatic nucleus (SCN) and local oscillators in peripheral tissues. It is unclear whether enhancing clock function can retard aging. Using fibroblasts expressing per2::lucSV and senescent cells, we revealed cycloastragenol (CAG), a natural aglycone derivative from astragaloside IV, as a clock amplitude enhancing small molecule. CAG could activate telomerase to antiaging, but no reports focused on its effects on circadian rhythm disorders in aging mice. Here we analyze the potential effects of CAG on d-galactose-induced aging mice on the circadian behavior and expression of clock genes. For this purpose, CAG (20 mg/kg orally), was administered daily to d-galactose (150 mg/kg, subcutaneous) mice model of aging for 6 weeks. An actogram analysis of free-running activity of these mice showed that CAG significantly enhances the locomotor activity. We further found that CAG increase expressions of per2 and bmal1 genes in liver and kidney of aging mouse. Furthermore, CAG enhanced clock protein BMAL1 and PER2 levels in aging mouse liver and SCN. Our results indicated that the CAG could restore the behavior of circadian rhythm in aging mice induced by d-galactose. These data of present study suggested that CAG could be used as a novel therapeutic strategy for the treatment of age-related circadian rhythm disruption.
MeSH Terms
- ARNTL Transcription Factors
- Aging
- Animals
- Chronobiology Disorders
- Galactose
- Mice
- Mice, Transgenic
- Period Circadian Proteins
- Sapogenins
Keywords
- aging
- circadian clock
- cycloastragenol
The discovery of musculoskeletal tissues, including muscle, tendons, and cartilage, as peripheral circadian clocks strongly implicates their role in tissue-specific homeostasis. Age-related dampening and misalignment of the tendon circadian rhythm and its outputs may be responsible for the decline in tendon homeostasis. It is unknown which entrainment signals are responsible for the synchronization of the tendon clock to the light-dark cycle. We sought to examine any changes in the expression levels of core clock genes (BMAL1, CLOCK, PER2, CRY1, and NR1D1) in healthy human patellar tendon biopsies obtained from three different intervention studies: increased physical activity (leg kicks for 1 h) in young, reduced activity (2 weeks immobilization of one leg) in young, and in old tendons. The expression level of clock genes in human tendon in vivo was very low and a high variation between individuals was found. We were thus unable to detect any differences in core clock gene expression neither after acute exercise nor immobilization. We are unable to find evidence for an effect of exercise or immobilization on circadian clock gene expression in human tendon samples.
MeSH Terms
- Adult
- Aged
- Circadian Rhythm Signaling Peptides and Proteins
- Exercise
- Humans
- Immobilization
- Male
- Patellar Ligament
Keywords
- Aging
- Circadian clock
- Exercise
- Gene expression
- Immobilization
- Tendon
It has been shown - mostly in animal models - that circadian clock genes are expressed in granulosa cells and in corpora luteum and might be essential for the ovulatory process and steroidogenesis. We sought to investigate which circadian clock genes exist in human granulosa cells and whether their expression and activity decrease during aging of the ovary. Human luteinized granulosa cells were isolated from young (age 18-33) and older (age 39-45) patients who underwent in-vitro fertilization treatment. Levels of clock genes expression were measured in these cells 36 h after human chorionic gonadotropin stimulation. Human luteinized granulosa cells were isolated from follicular fluid during oocyte retrieval. The mRNA expression levels of the circadian genes CRY1, CRY2, PER1, PER2, CLOCK, ARNTL, ARNTL2, and NPAS2 were analyzed by quantitative polymerase chain reaction. We found that the circadian genes CRY1, CRY2, PER1, PER2, CLOCK, ARNTL, ARNTL2, and NPAS2, are expressed in cultured human luteinized granulosa cells. Among these genes, there was a general trend of decreased expression in cells from older women but it reached statistical significance only for PER1 and CLOCK genes (fold change of 0.27 ± 0.14; p = 0.03 and 0.29 ± 0.16; p = 0.05, respectively). This preliminary report indicates that molecular circadian clock genes exist in human luteinized granulosa cells. There is a decreased expression of some of these genes in older women. This decline may partially explain the decreased fertility and steroidogenesis of reproductive aging.
MeSH Terms
- Adolescent
- Adult
- Aging
- Circadian Rhythm Signaling Peptides and Proteins
- Female
- Gene Expression
- Granulosa Cells
- Humans
- Luteinization
- Middle Aged
- RNA, Messenger
- Young Adult
Keywords
- Circadian clock genes
- Granulosa cells
- Reproductive aging
In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus coordinates daily rhythms including sleep-wake, hormone release, and gene expression. The cells of the SCN must synchronize to each other to drive these circadian rhythms in the rest of the body. The ontogeny of circadian cycling and intercellular coupling in the SCN remains poorly understood. Recent [i]in vitro[/i] studies have recorded circadian rhythms from the whole embryonic SCN. Here, we tracked the onset and precision of rhythms in PERIOD2 (PER2), a clock protein, within the SCN isolated from embryonic and postnatal mice of undetermined sex. We found that a few SCN cells developed circadian periodicity in PER2 by 14.5 d after mating (E14.5) with no evidence for daily cycling on E13.5. On E15.5, the fraction of competent oscillators increased dramatically corresponding with stabilization of their circadian periods. The cells of the SCN harvested at E15.5 expressed sustained, synchronous daily rhythms. By postnatal day 2 (P2), SCN oscillators displayed the daily, dorsal-ventral phase wave in clock gene expression typical of the adult SCN. Strikingly, vasoactive intestinal polypeptide (VIP), a neuropeptide critical for synchrony in the adult SCN, and its receptor, VPAC2R, reached detectable levels after birth and after the onset of circadian synchrony. Antagonists of GABA or VIP signaling or action potentials did not disrupt circadian synchrony in the E15.5 SCN. We conclude that endogenous daily rhythms in the fetal SCN begin with few noisy oscillators on E14.5, followed by widespread oscillations that rapidly synchronize on E15.5 by an unknown mechanism. We recorded the onset of PER2 circadian oscillations during embryonic development in the mouse SCN. When isolated at E13.5, the anlagen of the SCN expresses high, arrhythmic PER2. In contrast, a few cells show noisy circadian rhythms in the isolated E14.5 SCN and most show reliable, self-sustained, synchronized rhythms in the E15.5 SCN. Strikingly, this synchrony at E15.5 appears before expression of VIP or its receptor and persists in the presence of blockers of VIP, GABA or neuronal firing. Finally, the dorsal-ventral phase wave of PER2 typical of the adult SCN appears ∼P2, indicating that multiple signals may mediate circadian synchrony during the ontogeny of the SCN.
MeSH Terms
- Aging
- Animals
- Circadian Rhythm
- Female
- GABA Antagonists
- Male
- Mice
- Mice, Inbred C57BL
- Neurons
- Period Circadian Proteins
- Pregnancy
- Receptors, Vasoactive Intestinal Peptide, Type II
- Suprachiasmatic Nucleus
- Vasoactive Intestinal Peptide
Keywords
- VIP
- clock genes
- ontogeny
Menopause is characterized by the depletion of estrogen that has been proposed to cause oxidative stress. Circadian rhythm is an internal biological clock that controls physiological processes. It was analyzed the gene expression in peripheral blood mononuclear cells and the lipids and glucose levels in plasma of a subgroup of 17 pre-menopausal women, 19 men age-matched as control group for the pre-menopausal women, 20 post-menopausal women and 20 men age-matched as control group for the post-menopausal women; all groups were matched by body mass index. Our study showed a decrease in the expression of the oxidative stress-related gene GPX1, and an increase in the expression of SOD1 as consequence of menopause. In addition, we found that the circadian rhythm-related gene PER2 decreased as consequence of menopause. On the other hand, we observed a decrease in the expression of the oxidative stress-related gene GPX4 and an increase in the expression of CAT as a consequence of aging, independently of menopause. Our results suggest that the menopause-induced oxidative stress parallels a disruption in the circadian clock in women, and part of the differences in oxidative stress observed between pre- and post-menopausal women was due to aging, independent of menopause. Clinical Trials.gov.Identifier: NCT00924937.
MeSH Terms
- Adult
- Aging
- Biomarkers
- Catalase
- Circadian Rhythm
- Female
- Glutathione Peroxidase
- Humans
- Male
- Menopause
- Middle Aged
- Oxidative Stress
- Period Circadian Proteins
- Phospholipid Hydroperoxide Glutathione Peroxidase
- Superoxide Dismutase-1
Keywords
- Biology of aging
- Gender differences
- Genomics
- Oxidative stress
- Senescence
Sirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. Using Sirt1-deficient mice, we found that Sirt1 and Period 2 (Per2) constitute a reciprocal negative regulation loop that plays important roles in modulating hepatic circadian rhythmicity and aging. Sirt1-deficient mice exhibited profound premature aging and enhanced acetylation of histone H4 on lysine16 (H4K16) in the promoter of Per2, the latter of which leads to its overexpression; in turn, Per2 suppresses Sirt1 transcription through binding to the Sirt1 promoter at the Clock/Bmal1 site. This negative reciprocal relationship between SIRT1 and PER2 was also observed in human hepatocytes. We further demonstrated that the absence of Sirt1 or the ectopic overexpression of Per2 in the liver resulted in a dysregulated pace of the circadian rhythm. The similar circadian rhythm was also observed in aged wild type mice. The interplay between Sirt1 and Per2 modulates aging gene expression and circadian-clock maintenance.
MeSH Terms
- Aging
- Animals
- Circadian Rhythm
- Hepatocytes
- Humans
- Liver
- Mice
- Mice, Knockout
- Period Circadian Proteins
- Sirtuin 1
Polyamines are essential polycations present in all living cells. Polyamine levels are maintained from the diet and de novo synthesis, and their decline with age is associated with various pathologies. Here we show that polyamine levels oscillate in a daily manner. Both clock- and feeding-dependent mechanisms regulate the daily accumulation of key enzymes in polyamine biosynthesis through rhythmic binding of BMAL1:CLOCK to conserved DNA elements. In turn, polyamines control the circadian period in cultured cells and animals by regulating the interaction between the core clock repressors PER2 and CRY1. Importantly, we found that the decline in polyamine levels with age in mice is associated with a longer circadian period that can be reversed upon polyamine supplementation in the diet. Our findings suggest a crosstalk between circadian clocks and polyamine biosynthesis and open new possibilities for nutritional interventions against the decay in clock's function with age.
MeSH Terms
- ARNTL Transcription Factors
- Aging
- Animals
- CLOCK Proteins
- Circadian Clocks
- Circadian Rhythm
- Cryptochromes
- Feeding Behavior
- Humans
- Mice
- NIH 3T3 Cells
- Period Circadian Proteins
- Polyamines
Mammalian circadian control is determined by a central clock in the brain suprachiasmatic nucleus (SCN) and synchronized peripheral clocks in other tissues. Increasing evidence suggests that SCN-independent regulation of peripheral clocks also occurs. We examined how activation of excitatory receptors influences the clock protein PERIOD 2 (PER2) in a contractile organ, the urinary bladder. PERIOD2::LUCIFERASE-knock-in mice were used to report real-time PER2 circadian dynamics in the bladder tissue. Rhythmic PER2 activities occurred in the bladder wall with a cycle of ∼ 24 h and peak at ∼ 12 h. Activation of the muscarinic and purinergic receptors by agonists shifted the peak to an earlier time (7.2 ± 2.0 and 7.2 ± 0.9 h, respectively). PER2 expression was also sensitive to mechanical stimulation. Aging significantly dampened PER2 expression and its response to the agonists. Finally, muscarinic agonist-induced smooth muscle contraction also exhibited circadian rhythm. These data identified novel regulators, endogenous receptors, in determining local clock activity, in addition to mediating the central control. Furthermore, the local clock appears to reciprocally align receptor activity to circadian rhythm for muscle contraction. The interaction between receptors and peripheral clock represents an important mechanism for maintaining physiological functions and its dysregulation may contribute to age-related organ disorders.
MeSH Terms
- Animals
- CLOCK Proteins
- Cells, Cultured
- Circadian Rhythm
- Mice, Inbred C57BL
- Muscle Contraction
- Period Circadian Proteins
- Suprachiasmatic Nucleus
- Transcription Factors
- Urinary Bladder
Keywords
- aging
- circadian
- muscarinic
- purinergic
SIRT1 is a NAD( )-dependent protein deacetylase that governs many physiological pathways, including circadian rhythm in peripheral tissues. Here, we show that SIRT1 in the brain governs central circadian control by activating the transcription of the two major circadian regulators, BMAL1 and CLOCK. This activation comprises an amplifying circadian loop involving SIRT1, PGC-1α, and Nampt. In aged wild-type mice, SIRT1 levels in the suprachiasmatic nucleus are decreased, as are those of BMAL1 and PER2, giving rise to a longer intrinsic period, a more disrupted activity pattern, and an inability to adapt to changes in the light entrainment schedule. Young mice lacking brain SIRT1 phenocopy these aging-dependent circadian changes, whereas mice that overexpress SIRT1 in the brain are protected from the effects of aging. Our findings indicate that SIRT1 activates the central pacemaker to maintain robust circadian control in young animals, and a decay in this activity may play an important role in aging.
MeSH Terms
- ARNTL Transcription Factors
- Aging
- Animals
- Brain
- Circadian Clocks
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Neurons
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- Promoter Regions, Genetic
- Sirtuin 1
- Suprachiasmatic Nucleus
- Trans-Activators
- Transcription Factors
The elderly population shows various circadian disturbances, including dampened amplitude of rhythmicity and decreased responsiveness to light. The common poor folate status in the elderly might account for these aging-related circadian disturbances. To test this hypothesis, we investigated whether folate deficiency in mice affects circadian oscillations of the master clock in the suprachiasmatic nuclei, and the shifting responses to light. Mice fed a diet without folate for 6 weeks displayed markedly reduced (4.5-fold) erythrocyte folate concentration and increased (2.3-fold) homocysteinemia compared with control mice. Folate deficiency decreased the circadian amplitude of vasopressin and the clock protein PERIOD 2 (PER2) in the master clock, slowed the rate of re-entrainment of behavioral rhythms after delayed light-dark cycle and reduced light-induced phase-delays, without detectable morphologic changes in the retina, such as the number of melanopsinergic ganglion cells, that might have impaired photodetection. In conclusion, folate deficiency and consecutive hyperhomocysteinemia led to dampened PER2 and vasopressin oscillations in the master clock and reduced responsiveness to photic resetting, which constitute hallmarks of aging effects on circadian rhythmicity.
MeSH Terms
- Aging
- Animals
- Brain
- Circadian Rhythm
- Folic Acid Deficiency
- Male
- Mice
- Mice, Inbred C57BL
- Period Circadian Proteins
- Retina
- Vasopressins