Deciphering clock genes as emerging targets against aging

Zhu, Yanli; Liu, Yanqing; Escames, Germaine; Yang, Zhi; Zhao, Huadong; Lu, Qian; Xue, Chengxu; Xu, Danni; Acuña-Castroviejo, Darı́o; Yang, Yang

doi:10.1016/j.arr.2022.101725

Cited by 14 publications

(13 citation statements)

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“…Our findings may be summarized in: (1) GM of iMS-Bmal1 −/− mice displays significant behavioral, morphological, and functional changes that clarify the participation of the intrinsic muscle clock (Bmal1) in the skeletal muscle homeostasis; (2) because iMS-Bmal1 −/− mouse is prone to sarcopenia in the GM and shares many similarities with other models of sarcopenia including aged mice, it can be considered as an adequate acute model for the study of the disease; (3) the results support exercise and mainly melatonin as therapeutic tools to counteract sarcopenia by a mechanism that does not require the presence of Bmal1 in skeletal muscle, and (4) clock genes constitute emerging targets against agerelated diseases. 68 AUTHOR CONTRIBUTIONS Darío Acuña-Castroviejo took responsibility for the study design; José Fernández-Martínez and Yolanda Ramírez-Casas performed the experiments; Paula Aranda-Martínez, Alba López-Rodríguez, and Ramy KA Sayed analyzed the data; Germaine Escames, José Fernández-Martínez, and Yolanda Ramírez-Casas prepared the manuscript, and Darío Acuña-Castroviejo critically revised the manuscript. All the authors participated in drafting the manuscript and approved the final version for publication.…”

Section: Discussionmentioning

confidence: 99%

iMS‐Bmal1^−/− mice show evident signs of sarcopenia that are counteracted by exercise and melatonin therapies

Fernández‐Martínez,

Ramírez‐Casas,

Aranda‐Martínez

et al. 2023

Journal of Pineal Research

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Sarcopenia is an age‐related disease characterized by a reduction in muscle mass, strength, and function and, therefore, a deterioration in skeletal muscle health and frailty. Although the cause of sarcopenia is still unknown and, thus, there is no treatment, increasing evidence suggests that chronodisruption, particularly alterations in Bmal1 clock gene, can lead to those deficits culminating in sarcopenia. To gain insight into the cause and mechanism of sarcopenia and the protective effect of a therapeutic intervention with exercise and/or melatonin, the gastrocnemius muscles of male and female skeletal muscle‐specific and inducible Bmal1 knockout mice (iMS‐Bmal1−/−) were examined by phenotypic tests and light and electron microscopy. Our results revealed a disruption of the normal activity/rest rhythm, a drop in skeletal muscle function and mass, and increased frailty in male and female iMS‐Bmal1−/− animals compared to controls. A reduction in muscle fiber size and increased collagenous tissue were also detected, accompanied by reduced mitochondrial oxidative capacity and a compensatory shift towards a more oxidative fiber type. Electron microscopy further supports mitochondrial impairment in mutant mice. Melatonin and exercise ameliorated the damage caused by loss of Bmal1 in mutant mice, except for mitochondrial damage, which was worsened by the latter. Thus, iMS‐Bmal1−/− mice let us to identify Bmal1 deficiency as the responsible for the appearance of sarcopenia in the gastrocnemius muscle. Moreover, the results support the exercise and melatonin as therapeutic tools to counteract sarcopenia, by a mechanism that does not require the presence of Bmal1.

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Section: Discussionmentioning

confidence: 99%

iMS‐Bmal1^−/− mice show evident signs of sarcopenia that are counteracted by exercise and melatonin therapies

Fernández‐Martínez,

Ramírez‐Casas,

Aranda‐Martínez

et al. 2023

Journal of Pineal Research

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“…Circadian (~24 h) clocks regulate a wide range of rhythmic metabolic, physiological and behavioral parameters to acclimate to environmental changes in light, temperature, and food availability (Patke et al, 2020). Circadian clock disruption has been implicated in advanced aging and the longevity response to caloric or dietary restriction (CR or DR) (Froy, 2018; Galikova and Flatt, 2010; Manoogian and Panda, 2017; Nakahata and Fukada, 2022; Zhu et al, 2022). DR, reduction in food intake without causing malnutrition, robustly extends longevity in various animal models including yeast, worms, flies, and monkeys (Green et al, 2022; Mc Auley, 2022).…”

Section: Introductionmentioning

confidence: 99%

Dietary Restriction Impacts Peripheral Circadian Clock Output Important for Longevity inDrosophila

Hwangbo

Kwon

Iwanaszko

et al. 2023

Preprint

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Circadian clocks may mediate lifespan extension by caloric or dietary restriction (DR). We find that the core clock transcription factor Clock is crucial for a robust longevity and fecundity response to DR in Drosophila. To identify clock-controlled mediators, we performed RNA-sequencing from abdominal fat bodies across the 24 h day after just 5 days under control or DR diets. In contrast to more chronic DR regimens, we did not detect significant changes in the rhythmic expression of core clock genes. Yet we discovered that DR induced de novo rhythmicity or increased expression of rhythmic clock output genes. Network analysis revealed that DR increased network connectivity in one module comprised of genes encoding proteasome subunits. Adult, fat body specific RNAi knockdown demonstrated that proteasome subunits contribute to DR-mediated lifespan extension. Thus, clock control of output links DR-mediated changes in rhythmic transcription to lifespan extension.

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“…Additionally, PER1 protein levels were significantly decreased, while CLOCK levels exhibited an apparent increase, which is consistent with its down-regulation via PER1. 33 The western blot results also show markedly greater levels of phosphorylated GSK3β; however, we did not observe significant alterations in BMAL1 expression (Figure 3A-F). The latter is probably because of the bi-directional regulation of BMAL1 by PER1 and the p-GSK3β/GSK3β pathway.…”

Section: Exogenous Cellular Iron Can Regulate the Expression Of Per1 ...mentioning

confidence: 49%

Cellular iron depletion enhances behavioral rhythm by limiting brain Per1 expression in mice

Wu,

Ren,

Wang

et al. 2024

CNS Neurosci Ther

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AimsDisturbances in the circadian rhythm are positively correlated with the processes of aging and related neurodegenerative diseases, which are also associated with brain iron accumulation. However, the role of brain iron in regulating the biological rhythm is poorly understood. In this study, we investigated the impact of brain iron levels on the spontaneous locomotor activity of mice with altered brain iron levels and further explored the potential mechanisms governing these effects in vitro.ResultsOur results revealed that conditional knockout of ferroportin 1 (Fpn1) in cerebral microvascular endothelial cells led to brain iron deficiency, subsequently resulting in enhanced locomotor activity and increased expression of clock genes, including the circadian locomotor output cycles kaput protein (Clock) and brain and muscle ARNT‐like 1 (Bmal1). Concomitantly, the levels of period circadian regulator 1 (PER1), which functions as a transcriptional repressor in regulating biological rhythm, were decreased. Conversely, the elevated brain iron levels in APP/PS1 mice inhibited autonomous rhythmic activity. Additionally, our findings demonstrate a significant decrease in serum melatonin levels in Fpn1cdh5 ‐CKO mice compared with the Fpn1flox/flox group. In contrast, APP/PS1 mice with brain iron deposition exhibited higher serum melatonin levels than the WT group. Furthermore, in the human glioma cell line, U251, we observed reduced PER1 expression upon iron limitation by deferoxamine (DFO; iron chelator) or endogenous overexpression of FPN1. When U251 cells were made iron‐replete by supplementation with ferric ammonium citrate (FAC) or increased iron import through transferrin receptor 1 (TfR1) overexpression, PER1 protein levels were increased. Additionally, we obtained similar results to U251 cells in mouse cerebellar astrocytes (MA‐c), where we collected cells at different time points to investigate the rhythmic expression of core clock genes and the impact of DFO or FAC treatment on PER1 protein levels.ConclusionThese findings collectively suggest that altered iron levels influence the circadian rhythm by regulating PER1 expression and thereby modulating the molecular circadian clock. In conclusion, our study identifies the regulation of brain iron levels as a potential new target for treating age‐related disruptions in the circadian rhythm.

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Deciphering clock genes as emerging targets against aging

Cited by 14 publications

References 244 publications

iMS‐Bmal1^−/− mice show evident signs of sarcopenia that are counteracted by exercise and melatonin therapies

iMS‐Bmal1^−/− mice show evident signs of sarcopenia that are counteracted by exercise and melatonin therapies

Dietary Restriction Impacts Peripheral Circadian Clock Output Important for Longevity inDrosophila

Cellular iron depletion enhances behavioral rhythm by limiting brain Per1 expression in mice

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Deciphering clock genes as emerging targets against aging

Cited by 14 publications

References 244 publications

iMS‐Bmal1−/− mice show evident signs of sarcopenia that are counteracted by exercise and melatonin therapies

iMS‐Bmal1−/− mice show evident signs of sarcopenia that are counteracted by exercise and melatonin therapies

Dietary Restriction Impacts Peripheral Circadian Clock Output Important for Longevity inDrosophila

Cellular iron depletion enhances behavioral rhythm by limiting brain Per1 expression in mice

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iMS‐Bmal1^−/− mice show evident signs of sarcopenia that are counteracted by exercise and melatonin therapies

iMS‐Bmal1^−/− mice show evident signs of sarcopenia that are counteracted by exercise and melatonin therapies