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Alzheimer's disease involves a drastic departure from the cognitive, functional, and behavioural trajectory of normal ageing, and is both a dreaded and highly prevalent cause of disability to individuals, and a leading source of health and social care expenditure for society. Before the advent of biomarkers, post-mortem examination was the only method available to establish a definitive diagnosis. In this first paper of the Series, we review state-of-the-art diagnostic practices and the typical...

Over the last three decades, the evidence on how to best treat the cognitive and non-cognitive symptoms of patients with Alzheimer's disease has increased. Although these pharmacological and non-pharmacological strategies have significantly improved health outcomes for patients with Alzheimer's disease, many lack stringent evidence of efficacy. In this second paper of the Series, we provide practical and realistic advice on how to prioritise pharmacological and non-pharmacological strategies to...

For the first time, reductions in cerebral β-amyloid pathology load and rate of cognitive and functional decline have been achieved in Alzheimer's disease, through pharmacological intervention in randomised controlled trials. However, the results from phase 3 randomised controlled trials of anti-β amyloid monoclonal antibodies are interpreted in different ways, with some experts supporting a clinically meaningful disease-modifying effect, and others judging insufficient benefit-to-risk ratio and...

Statistical Learning (SL) is the ability to implicitly extract and learn statistical regularities from the environment. SL processes are ubiquitous across the lifespan through their proven role in language acquisition and adaptive behaviors. While recent neuroimaging research has identified networks of active brain regions during SL processes, less is known about whether structural differences in these regions may contribute to SL abilities. Here, we explore the extent to which visual SL (VSL)...

Arterial pulsation is crucial for promoting neurofluid circulation. Most previous studies quantified pulsatility via blood velocity-based indices in large arteries. Here we propose an innovative method to quantify the microvascular volumetric pulsatility index (mvPI) across cortical layers and white matter (WM) using high-resolution four-dimensional (4D) vascular space occupancy (VASO) and arterial spin labeling (ASL) magnetic resonance imaging (MRI) at 7 T with simultaneous pulse recording. We...

Studies suggest that diets rich in highly/ultra-processed foods may contribute to the development of diseases. In rodents, the intake of refined (purified) diets has also been associated with the development of various metabolic diseases. Here, performing two experiments, we assess the impact of a refined diet with and without fiber enrichment on aging related health decline in mice. Experiment 1: Male C57BL/6J mice were fed standard chow or refined diet until the age of 86 weeks. Experiment 2:...

The inferior colliculus (IC) is a nucleus in the auditory midbrain that plays an important role in sound and speech processing through how it encodes temporal precision. Temporal precision depends on the balance of inhibition and excitation within the IC. This balance degrades during aging. Age-related changes in synapses have been described in the lemniscal IC as a contributing factor for this imbalance. However, it is unknown if aging affects synapses throughout the non-lemniscal IC in a...

Extreme human lifespan, exemplified by supercentenarians, presents a paradox in understanding aging: despite advanced age, they maintain relatively good health. To investigate this duality, we have performed a high-throughput multiomics study of the world's oldest living person, interrogating her genome, transcriptome, metabolome, proteome, microbiome, and epigenome, comparing the results with larger matched cohorts. The emerging picture highlights different pathways attributed to each process:...

The human cortex undergoes extensive epigenetic remodeling during development, although the precise temporal and cell-type-specific dynamics of DNA methylation remain incompletely understood. In this study, we profiled genome-wide DNA methylation across human cortex tissue from donors aged 6 post-conception weeks to 108 years of age. We observed widespread, developmentally regulated changes in DNA methylation, with pronounced shifts occurring during early- and mid-gestation that were distinct...

Alzheimer's disease involves a drastic departure from the cognitive, functional, and behavioural trajectory of normal ageing, and is both a dreaded and highly prevalent cause of disability to individuals, and a leading source of health and social care expenditure for society. Before the advent of biomarkers, post-mortem examination was the only method available to establish a definitive diagnosis. In this first paper of the Series, we review state-of-the-art diagnostic practices and the typical...

The United Nations World Population Statistics reported that 10% of the global population, approximately 830 million people, were aged 65 years and older in 2024. This number is projected to double, reaching almost 20% or 1.7 billion, by 2050. With a growing aging population world-wide, age-associated diseases are also expected to increase, which has prompted research into geroscience to optimize the healthspan of aging individuals. For women, menopause significantly increases the risks of...

Programmed Cell Death (PCD) in eukaryotes is a regulated process occurring during development, cell differentiation and aging. Apoptosis is a particularly well studied morphotype of PCD, only observed in animal cells (metazoan). Its most definitive hallmark is the formation and release of membrane-enclosed extracellular vesicles called Apoptotic Bodies (ABs). Although apoptotic-like features have been described in plants, yeast, protozoa and phytoplankton, the production of ABs has been thought...

Age-related increases in cancer have traditionally been attributed to compromised antitumor immunity of exhausted and dysfunctional CD8⁺ T cells. Here we provide an alternative mechanism: in aging, cancer also progresses with the help of fully functional CD8⁺ T cells. These transcriptionally and epigenetically distinct cells (termed double-positive CD8^(+) T cells (DP8)) express CD39, CD73, CD101 and CXCR6 on their surface and accumulate during healthy aging in mice, requiring B cells presenting...

Ageing progressively impairs skeletal muscle regeneration, contributing to reduced mobility and quality of life. While the molecular changes underlying muscle ageing have been well characterised, their impact on muscle stem cell (muSC) behaviour during regeneration remains poorly understood. Here, we leverage telomerase-deficient tert mutant zebrafish larvae as an in vivo model of accelerated ageing to perform real-time analysis of muSC dynamics following muscle injury. We demonstrate that the...

Recent studies have established a reciprocal causal link between aging and the activation of transposable elements, characterized in particular by a de-repression of LINE-1 retrotransposons. These LINE-1 elements represent 21% of the human genome, but only a minority of these sequences retain the coding potential essential for their mobility. LINE-1 encoded proteins can induce cell toxicity implicated in aging and neurodegenerative diseases. However, our knowledge of the expression and...

This study investigated 17α-estradiol's effects on aged hypothalamic physiological activity via long-term administration. Single-nucleus transcriptomic sequencing (snRNA-seq) was performed on pooled hypothalami from each group: aged male Norway brown rats treated with 17α-estradiol (O.T), aged controls (O), and young controls (Y). Supervised clustering of neurons (based on neuropeptides/receptors) evaluated subtype responses to aging and 17α-estradiol. Aging-induced elevation of neuronal...