The 'middle-aging' brain

Trends in Neurosciences, Год журнала: 2024, Номер 47(4), С. 259 - 272

Опубликована: Март 19, 2024

Middle age has historically been an understudied period of life compared to older age, when cognitive and brain health decline are most pronounced, but the scope for intervention may be limited. However, recent research suggests that middle could mark a shift in aging. We review emerging evidence on multiple levels analysis indicating midlife is defined by unique central peripheral processes shape future trajectories health. Informed developments aging lifespan studies humans animal models, we highlight utility modeling non-linear changes study samples with wide subject ranges distinguish stage-specific from those acting linearly throughout lifespan.

Язык: Английский

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Tumor circadian clock strength influences metastatic potential and predicts patient prognosis in luminal A breast cancer

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(7)

Опубликована: Фев. 6, 2024

Studies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular rhythms noncancerous cancerous human tissues their clinical relevance are largely unknown. We reconstructed informatically, integrating locally collected, time-stamped biopsies with public datasets. For tissue, inflammatory, epithelial–mesenchymal transition (EMT), estrogen responsiveness pathways show modulation. Among tumors, clock correlation analysis demonstrates subtype-specific changes organization. Luminal A organoids informatic ordering of luminal samples exhibit continued, albeit dampened reprogrammed rhythms. CYCLOPS magnitude, a measure global rhythm strength, varied widely among samples. Cycling EMT pathway genes was markedly increased high-magnitude tumors. Surprisingly, patients tumors had reduced 5-y survival. Correspondingly, 3D cultures invasion following disruption. This study links cancer EMT, metastatic potential, prognosis.

Язык: Английский

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Why does circadian timing of administration matter for immune checkpoint inhibitors’ efficacy?

British Journal of Cancer, Год журнала: 2024, Номер 131(5), С. 783 - 796

Опубликована: Июнь 4, 2024

Abstract Background Tolerability and antitumour efficacy of chemotherapy radiation therapy can vary largely according to their time administration along the 24-h scale, due moderation molecular cellular mechanisms by circadian rhythms. Recent clinical data have highlighted a striking role dosing for cancer immunotherapy, thus calling critical evaluation. Methods Here, we review analyse through which rhythms influence outcomes on ICI therapies. We examine how rhythm disorders affect tumour immune microenvironment, as main mechanism linking clock cycles in ICIs efficacy. Results Real-life from 18 retrospective studies revealed that early time-of-day (ToD) infusion checkpoint inhibitors (ICIs) could enhance progression-free and/or overall survival up fourfold compared late ToD dosing. The involved total 3250 patients with metastatic melanoma, lung, kidney, bladder, oesophageal, stomach or liver 9 countries. Such large consistent differences effects only result previously ignored robust chronobiological mechanism. timing system coordinates cellular, tissue whole-body physiology timescale. Circadian are generated at level involves 15 specific genes. disruption trigger accelerate carcinogenesis, contribute treatment failure, possibly evasion resulting immunosuppressive microenvironment. Conclusions perspective emerging understanding regulation immunity now calls randomised trials establish recommendations personalised chrono-immunotherapies current forthcoming drugs.

Язык: Английский

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Circadian clock communication during homeostasis and ageing

Nature Reviews Molecular Cell Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Язык: Английский

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Circadian Regulation of Drug Responses: Toward Sex-Specific and Personalized Chronotherapy

The Annual Review of Pharmacology and Toxicology, Год журнала: 2023, Номер 64(1), С. 89 - 114

Опубликована: Сен. 19, 2023

Today's challenge for precision medicine involves the integration of impact molecular clocks on drug pharmacokinetics, toxicity, and efficacy toward personalized chronotherapy. Meaningful improvements tolerability and/or medications through proper administration timing have been confirmed over past decade immunotherapy chemotherapy against cancer, as well commonly used pharmacological agents in cardiovascular, metabolic, inflammatory, neurological conditions. Experimental human studies recently revealed sexually dimorphic circadian responses. Dedicated randomized clinical trials should now aim to issue recommendations daily medical practice, integrating innovative technologies remote longitudinal monitoring metrics, statistical prediction clock function from single-timepoint biopsies, multiscale biorhythmic mathematical modelling. Importantly, chronofit patients with a robust function, who would benefit most chronotherapy, need be identified. Conversely, nonchronofit could emerging class chronobiotics targeting clock.

Язык: Английский

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Circadian Rhythms in Cardiovascular Metabolism

Circulation Research, Год журнала: 2024, Номер 134(6), С. 635 - 658

Опубликована: Март 14, 2024

Energetic demand and nutrient supply fluctuate as a function of time-of-day, in alignment with sleep-wake fasting-feeding cycles. These daily rhythms are mirrored by 24-hour oscillations numerous cardiovascular functional parameters, including blood pressure, heart rate, myocardial contractility. It is, therefore, not surprising that metabolic processes also over the course day, to ensure temporal needs for ATP, building blocks, metabolism-based signaling molecules met. What has become increasingly clear is addition classic signal-response coupling (termed reactionary mechanisms), cardiovascular-relevant cells use autonomous circadian clocks temporally orchestrate pathways preparation predicted stimuli/stresses anticipatory mechanisms). Here, we review current knowledge regarding regulation metabolism, how synchronized function, whether misalignment/disruption contribute toward pathogenesis disease.

Язык: Английский

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Autonomous circadian rhythms in the human hepatocyte regulate hepatic drug metabolism and inflammatory responses

Science Advances, Год журнала: 2024, Номер 10(17)

Опубликована: Апрель 24, 2024

Critical aspects of physiology and cell function exhibit self-sustained ~24-hour variations termed circadian rhythms. In the liver, rhythms play fundamental roles in maintaining organ homeostasis. Here, we established characterized an vitro liver experimental system which primary human hepatocytes display oscillations. By generating gene expression profiles these over time, demonstrated that their transcriptional state is dynamic across 24 hours identified a set cycling genes with functions related to inflammation, drug metabolism, energy We designed tested treatment protocol minimize atorvastatin- acetaminophen-induced hepatotoxicity. Last, documented circadian-dependent induction pro-inflammatory cytokines when triggered by LPS, IFN-β, or

Язык: Английский

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TimeTeller: A tool to probe the circadian clock as a multigene dynamical system

PLoS Computational Biology, Год журнала: 2024, Номер 20(2), С. e1011779 - e1011779

Опубликована: Фев. 29, 2024

Recent studies have established that the circadian clock influences onset, progression and therapeutic outcomes in a number of diseases including cancer heart diseases. Therefore, there is need for tools to measure functional state molecular its downstream targets patients. Moreover, multi-dimensional stochastic oscillator are few analysing it as noisy multigene dynamical system. In this paper we consider methodology behind TimeTeller, machine learning tool analyses system aims estimate function from single transcriptome by modelling clock. We demonstrate potential systems assessment applying mouse, baboon human microarray RNA-seq data show how visualise quantify global structure clock, quantitatively stratify individual transcriptomic samples dysfunction globally compare clocks across individuals, conditions tissues thus highlighting relevance advancing medicine.

Язык: Английский

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Rhythm is essential: Unraveling the relation between the circadian clock and cancer

Critical Reviews in Oncology/Hematology, Год журнала: 2025, Номер unknown, С. 104632 - 104632

Опубликована: Янв. 1, 2025

Язык: Английский

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Learning from circadian rhythm to transform cancer prevention, prognosis, and survivorship care

Trends in cancer, Год журнала: 2023, Номер 10(3), С. 196 - 207

Опубликована: Ноя. 23, 2023

Circadian timekeeping mechanisms and cell cycle regulation share thematic biological principles in responding to signals, repairing cellular damage, coordinating metabolism, allocating resources for optimal function. Recent studies show interactions between regulators circadian clock components, offering insights into potential cancer treatment approaches. Understanding control of metabolism informs timing therapies reduce adverse effects enhance efficacy. adaptability lifestyle factors, such as activity, sleep, nutrition sheds light on their impact cancer. Leveraging regulatory prevention care is vital, most risk stems from modifiable lifestyles. Monitoring factors aids assessment targeted interventions across the continuum.

Язык: Английский

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