Multimodal cell atlas of the ageing human skeletal muscle

Nature, Год журнала: 2024, Номер 629(8010), С. 154 - 164

Опубликована: Апрель 22, 2024

Abstract Muscle atrophy and functional decline (sarcopenia) are common manifestations of frailty critical contributors to morbidity mortality in older people 1 . Deciphering the molecular mechanisms underlying sarcopenia has major implications for understanding human ageing 2 Yet, progress been slow, partly due difficulties characterizing skeletal muscle niche heterogeneity (whereby myofibres most abundant) obtaining well-characterized samples 3,4 Here we generate a single-cell/single-nucleus transcriptomic chromatin accessibility map limb muscles encompassing over 387,000 cells/nuclei from individuals aged 15 99 years with distinct fitness levels. We describe how cell populations change during ageing, including emergence new people, cell-specific multicellular network features (at epigenetic levels) associated these changes. On basis cross-comparison genetic data, also identify key elements architecture that mark susceptibility sarcopenia. Our study provides identifying targets amenable medical, pharmacological lifestyle interventions late life.

Язык: Английский

---

Circadian clock communication during homeostasis and ageing

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

Опубликована: Янв. 3, 2025

Язык: Английский

---

The Mammalian Circadian Time-Keeping System

Journal of Huntington s Disease, Год журнала: 2023, Номер 12(2), С. 91 - 104

Опубликована: Апрель 25, 2023

Our physiology and behavior follow precise daily programs that adapt us to the alternating opportunities challenges of day night. Under experimental isolation, these rhythms persist with a period approximately one (circadian), demonstrating their control by an internal autonomous clock. Circadian time is created at cellular level transcriptional/translational feedback loop (TTFL) in which protein products Period Cryptochrome genes inhibit own transcription. Because accumulation slow delayed, system oscillates spontaneously ∼24 hours. This cell-autonomous TTFL controls cycles gene expression all major tissues underpin our metabolic programs. In turn, innumerable clocks are coordinated central pacemaker, suprachiasmatic nucleus (SCN) hypothalamus. When isolated slice culture, SCN its dependent neural activity indefinitely, operating as "a clock dish". vivo, synchronized solar direct innervation from specialized retinal photoreceptors. circadian cycle action potential firing signals SCN-generated hypothalamic brain stem targets, co-ordinate downstream autonomic, endocrine, behavioral (feeding) cues synchronize sustain distributed network. therefore pervades every biological organization, molecules society. Understanding mechanisms offers important mitigate consequences disruption, so prevalent modern societies, arise shiftwork, aging, neurodegenerative diseases, not least Huntington's disease.

Язык: Английский

---

Impact of Environmental Factors on Hypertension and Associated Cardiovascular Disease

Canadian Journal of Cardiology, Год журнала: 2023, Номер 39(9), С. 1229 - 1243

Опубликована: Июль 6, 2023

Язык: Английский

---

Rev-erb-α antagonism in alveolar macrophages protects against pneumococcal infection in elderly mice

Cell Reports, Год журнала: 2025, Номер 44(2), С. 115273 - 115273

Опубликована: Фев. 1, 2025

Язык: Английский

---

The Cardiac Circadian Clock

JACC Basic to Translational Science, Год журнала: 2023, Номер 8(12), С. 1613 - 1628

Опубликована: Июнь 21, 2023

Virtually all aspects of physiology fluctuate with respect to the time day. This is beautifully exemplified by cardiovascular physiology, for which blood pressure and electrophysiology exhibit robust diurnal oscillations. At molecular/biochemical levels (eg, transcription, translation, signaling, metabolism), cardiovascular-relevant tissues (such as heart) are profoundly different during day vs night. Unfortunately, this in turn contributes toward 24-hour rhythms both risk adverse event onset arrhythmias, myocardial infarction) pathogenesis severity extent ischemic damage). Accumulating evidence indicates that cell-autonomous timekeeping mechanisms, termed circadian clocks, temporally govern biological processes known play critical roles function/dysfunction. In paper, a comprehensive review our current understanding cardiomyocyte clock health disease detailed. Unprecedented basic, translational, epidemiologic studies support need implement chronobiological considerations strategies designed prevention treatment disease.

Язык: Английский

---

Selective transcriptomic dysregulation of metabolic pathways in liver and retina by short- and long-term dietary hyperglycemia

iScience, Год журнала: 2024, Номер 27(2), С. 108979 - 108979

Опубликована: Янв. 19, 2024

A high glycemic index (HGI) diet induces hyperglycemia, a risk factor for diseases affecting multiple organ systems. Here, we evaluated tissue-specific adaptations in the liver and retina after feeding HGI to mice 1 or 12 month. In liver, genes associated with inflammation fatty acid metabolism were altered within month of diet, whereas 12-month diet-fed group showed dysregulated expression cytochrome P450 overexpression lipogenic factors including

Язык: Английский

---

Translation is an emerging constraint on protein homeostasis in ageing

Trends in Cell Biology, Год журнала: 2024, Номер 34(8), С. 646 - 656

Опубликована: Фев. 28, 2024

Proteins are molecular machines that provide structure and perform vital transport, signalling enzymatic roles. expressed by cells require tight regulation of their concentration, folding, localisation, modifications; however, this state protein homeostasis is continuously perturbed tissue-level stresses. While in healthy tissues able to buffer against these perturbations, for example, expression chaperone proteins, lost ageing, can lead aggregation characteristic folding diseases. Here, we review reports a progressive disconnect between transcriptomic proteomic during cellular ageing. We discuss how age-associated changes responses specific stressors the tissue microenvironment exacerbated loss ribosomal pausing, mistranslation.

Язык: Английский

---

Transcriptomic Hallmarks of Mortality Reveal Universal and Specific Mechanisms of Aging, Chronic Disease, and Rejuvenation

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 7, 2024

SUMMARY Health is strongly affected by aging and lifespan-modulating interventions, but the molecular mechanisms of mortality regulation remain unclear. Here, we conducted an RNA-seq analysis mice subjected to 20 compound treatments in Interventions Testing Program (ITP). By integrating it with data from over 4,000 rodent tissues representing responses genetic, pharmacological, dietary interventions established survival data, developed robust multi-tissue transcriptomic biomarkers mortality, capable quantifying change lifespan both short-lived long-lived models. These tools were further extended single-cell human demonstrating common across cell types species. Via a network analysis, identified annotated 26 co-regulated modules longevity tissues, interpretable module-specific clocks that capture aging- mortality-associated phenotypes functional components, including, among others, inflammatory response, mitochondrial function, lipid metabolism, extracellular matrix organization. captured characterized acceleration biological age induced progeria models chronic diseases rodents humans. They also revealed rejuvenation heterochronic parabiosis, early embryogenesis, cellular reprogramming, highlighting universal signatures shared age-related disease. included Cdkn1a Lgals3 , whose plasma levels demonstrated strong association all-cause disease incidence risk factors, such as obesity hypertension. Overall, this study uncovers hallmarks mammalian organs, types, species rejuvenation, exposing fundamental longevity.

Язык: Английский

---

Circadian Regulation of Cardiac Arrhythmias and Electrophysiology

Circulation Research, Год журнала: 2024, Номер 134(6), С. 659 - 674

Опубликована: Март 14, 2024

Circadian rhythms in physiology and behavior are ≈24-hour biological cycles regulated by internal clocks (ie, circadian clocks) that optimize organismal homeostasis response to predictable environmental changes. These present virtually all cells the body, including cardiomyocytes. Many decades ago, clinicians researchers became interested studying daily patterns of triggers for sudden cardiac death, incidence arrhythmias. This review highlights historical contemporary studies examining role day/night timing cardiovascular events, delves into changes these events over last few decades, discusses disease-specific differences events. The current understanding environmental, behavioral, mechanisms regulate electrophysiology is examined with a focus on regulation ion channels channel regulatory genes. Understanding contribution arrhythmia susceptibility death will be essential developing future chronotherapies.

Язык: Английский

---