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Transglutaminase 2 (TG2) is implicated in synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies, as it promotes α-Synuclein (α-Syn) aggregation in vitro, and evidence for its activity is detected in Lewy bodies in human postmortem brains. Additionally, TG2 overexpression exacerbates α-Syn toxicity in double transgenic mice, while TG2 deletion mitigates the phenotype of α-Syn transgenic mice. Considering that TG2 is a multidomain and multifunctional protein, the...

Mitochondrial transplantation holds significant potential for the treatment of mitochondrial diseases. However, how to efficiently deliver exogenous mitochondria to somatic cells or tissues remains unresolved. We present a mitochondrial transplantation approach to deliver mitochondria into the cells and tissues of mice and monkeys with high efficiency, based on encapsulating mitochondria with vesicles derived from the plasma membrane of erythrocytes. Treatment with encapsulated mitochondria...

Neurofibrillary tangles, composed of excessively phosphorylated tau, are a core neuropathological hallmark of Alzheimer's disease (AD). However, therapeutic strategies aimed at directly clearing neurofibrillary tangles have demonstrated limited clinical efficacy, shifting the research focus towards the fundamental underlying mechanism- the dysregulation of tau phosphorylation. Evidence indicates that tau physiological phosphorylation is indispensable for microtubule stability and normal neuronal...

Aging is often associated with a maladaptive "stiffness" strategy of postural control, which limits adaptability and increases fall risk. Complex visuomotor training (e.g., juggling) may counteract this decline, but the relationship between biomechanical reorganization and cognitive cost reduction remains unclear. We hypothesized that juggling would induce a shift from stiffness to "active monitoring" and reduce the dual-task cost. This exploratory secondary analysis of a randomized crossover...

Natural light is severely affected by human impact on Earth, yet little is known about the roles light receptors have outside vision and rhythmic processes, despite their tremendously wide abundance. Here we show that loss-of-function of the light-receptive cryptochrome (l-cry) in marine bristleworms significantly increases lifespan and adult size, similarly to wild-types reared in constant darkness. Quantitative transcriptomics revealed hormonal players crucial for invertebrate and vertebrate...

Partial cellular reprogramming can modulate aging-associated decline across multiple tissues. However, whether targeting memory-encoding ensembles within specific brain regions is sufficient to restore cognitive function has remained unknown. In this issue of Neuron, Berdugo-Vega et al. show that engram rejuvenation rescues memory deficits and restores epigenetic-transcriptional features and intrinsic excitability.

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White matter (WM) is a key substrate for interregional neural communication and cognitive function but the role of WM glucose metabolism in cognitive aging has been understudied. Using multimodal neuroimaging (MRI, FDG-PET, amyloid-PET) from 3142 participants (15,287 visits) across two studies, we examined the contribution of WM to cognition and identified divergent WM signatures. Higher glucose metabolism in expected WM (EWM; corpus callosum and cingulum) was associated with better cognition,...

Alzheimer's Disease (AD) is a neurodegenerative condition affecting millions worldwide. Defining early pathobiological events remains challenging, in part due to inaccessibility of neural tissue. Because olfactory neurons are accessible, and olfactory loss is prevalent in AD, we evaluated olfactory brush biopsies from controls, individuals with cerebrospinal fluid (CSF) biomarker-confirmed AD, and cognitively typical individuals whose positive CSF biomarkers signal a pre-clinical AD stage. Here...

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White matter (WM) is a key substrate for interregional neural communication and cognitive function but the role of WM glucose metabolism in cognitive aging has been understudied. Using multimodal neuroimaging (MRI, FDG-PET, amyloid-PET) from 3142 participants (15,287 visits) across two studies, we examined the contribution of WM to cognition and identified divergent WM signatures. Higher glucose metabolism in expected WM (EWM; corpus callosum and cingulum) was associated with better cognition,...

Mesenchymal stem cells (MSCs) in bone marrow (BM) play a role in the development of BM adipose tissue (BMAT). Here, we propose ways to restock the BM-MSC niche to meet the needs of BMAT in ageing, including the activation of pluripotent precursor cells, the breakdown of BM-MSC grafts and the mobilisation of extramedullary MSCs. It can be exploited to understand the BM-MSC-adipocyte axis in ageing and better target anti-ageing interventions.

Age-associated hematopoietic stem cell (HSC) dysfunction is accompanied by dramatic transcription changes, but it remains unclear whether specific transcripts could orchestrate these HSC aging phenotypes. Here, we perform epigenetic profiling in male mice to investigate the regulatory mechanisms underlying the HSC aging transcriptome and screen for potential aging driver genes. We identify a looping structure formed between part of the Btaf1 gene and the whole Ide gene in old HSCs which is...

Senescent cells contribute to degenerative processes in multiple tissues, including the retina. In the retinal pigment epithelium (RPE), their accumulation is closely associated with retinal aging and disease progression. Eliminating senescent RPE cells has shown therapeutic potential, but conventional senolytics often lack the specificity required to spare non-senescent cells, raising safety concerns. To overcome this, we performed integrated transcriptomic analyses of male mouse-derived RPE...

The biological feasibility of human rejuvenation remains a subject of intense debate, yet answering this question is critical for guiding research strategies. Should aging research focus only on reversing aging in older individuals, or pausing its progression at mid-ages, be more accessible? Here, we attempt to address this question with evolutionary biology. Rejuvenation occurs in a few species, and, paradoxically, is typically induced by stress but not used under optimal conditions. Using...

The thymus is essential for establishing T cell diversity early in life, but undergoes profound involution with age and has therefore traditionally been regarded as largely nonfunctional in adults^(1,2). Here we propose that preserving thymic functionality is integral to adult health and longevity. We developed a deep learning framework to quantify thymic health from routine radiographic images and evaluated its association with longevity and risk of major age-associated diseases in two large...

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