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Single-cell resolution spatial transcriptomics provides a great opportunity to explore the complex cellular contents in different tissues. Here we introduce SpatialZoomer, a spectral graph-based method that applies a set of low-pass filters to efficiently extract spatial molecular features from spatial transcriptomics data at multiple resolutions or scales, including the single cell scale, the niche scale with dozens of closely interacting cells and the domain scale with spatially organized cell...

An elevated NADH/NAD^(+) ratio (NADH-reductive stress) is a hallmark of mitochondrial dysfunction, yet how it drives pathologies ranging from primary mitochondrial disorders to ageing remains poorly understood^(1,2). Here, we show that mitochondrial respiratory chain inhibition in primary human fibroblasts induces NADH-reductive stress that coexists with profound NADPH depletion. Using the Escherichia coli soluble transhydrogenase (EcSTH)³ to model this redox coupling in cells with intact...

Rheumatoid arthritis (RA) is an autoimmune disease marked by joint and systemic inflammation. Anticitrullinated protein antibodies identify an at-risk stage that precedes clinical RA, yet the mechanisms driving disease progression remain poorly understood. Here we show that anticitrullinated-protein-antibody-positive individuals who progressed to RA exhibited a marked expansion of CXCR5^(+)CD69^(+)-activated naive B cells (aNAVs) before disease onset. These cells displayed inflammatory and...

Age-related cognitive decline is associated with altered inhibitory signaling in hippocampal circuits, but the mechanisms underlying this dysfunction remain incompletely understood. Neural stem cells (NSCs) persist in the adult hippocampus and influence brain function beyond generating new neurons, although the molecular signals involved remain unclear. Here we show that phospholipase A2 group VII (PLA2G7), a secreted lipid-metabolizing enzyme expressed in NSCs, negatively regulates inhibitory...

Aging is characterized by progressive functional decline accompanied by distinct transcriptomic and epigenetic alterations. Although partial reprogramming via Yamanaka factors can reverse these signatures and improve cell function, toxicity and efficacy concerns limit their in vivo application, necessitating alternative geroprotective interventions. Here we develop an interpretable transcriptomic age predictor in human fibroblasts and perform a cDNA overexpression screen to identify factors that...

Population aging has accelerated globally, making successful aging a key public health priority. Zhuang and Gao address the prospective association between cumulative average grip strength and successful aging using three international cohorts. While their multi-cohort design offers valuable cross-population insights, several methodological choices warrant consideration. Grip strength may not fully capture functional determinants of successful aging. Self-reported chronic disease introduces...

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Pleiotrophin (PTN) is a heparin-binding growth factor that plays a pivotal role in neurodevelopment, neuroplasticity, and neuroinflammation. PTN signals through a multi-receptor network involving protein tyrosine phosphatase receptor type ζ (PTPRZ1), syndecans (particularly syndecan-3), integrins, nucleolin, and neuropilin-1. Anaplastic lymphoma kinase (ALK) has also been functionally linked to PTN signaling, although whether PTN directly binds and activates it remains debated. This review...

Attention deficit-hyperactivity disorder (ADHD) is a medical condition that is present in approximately 2.5% of adults worldwide and manifests in a variety of different ways across the lifespan. Adults with ADHD often have coexisting psychiatric disorders such as anxiety, mood, sleep, substance use, and personality disorders and are at increased risk for coexisting somatic conditions such as obesity, cardiovascular and cerebrovascular disease, type 1 and type 2 diabetes, and immune and...

Senescent cells develop a persistent inflammatory signature with broad consequences for tissue function and disease. Martini et al.¹ show that mitochondrial citrate metabolism drives inflammation through a pathway that acts independently of mitochondrial DNA-driven immune signaling yet cooperates with it to amplify the inflammatory response.

Loss of skeletal muscle mass is a major driver of frailty and disability, yet how systemic metabolic cues protect muscle integrity remains unclear. We identify Serpina3n, an adipose-derived adipokine, as a key mediator of the protective effects of nicotinamide adenine dinucleotide (NAD^(+)) supplementation against muscle atrophy. Elevation of NAD^(+) in adipose tissue activates signal transducer and activator of transcription (STAT)1-dependent transcription of Serpina3n, leading to its systemic...

Population ageing has increased the burden of cardiovascular disease, cognitive decline and frailty in older adults. These conditions are often studied separately, yet increasing evidence suggests that the ageing heart, vasculature and brain are biologically interconnected. Using a hybrid design that combines a systematic literature search with narrative synthesis, this review summarizes current knowledge on heart-brain co-ageing, with emphasis on phenotypic heterogeneity, molecular mechanisms...

Immune aging comprises heterogeneous changes in hematopoietic output, immune-cell function, inflammatory regulation, and tissue-specific immune states. In parallel, the gut microbiome undergoes ecological and functional remodeling across the bacteriome, mycobiome, virome, and archaeome, but these changes do not define a single "aged microbiome" and vary with host health, frailty, diet, medication exposure, and environmental context. Here, we examine how multikingdom gut microbiome remodeling...

Neuroimaging-derived brain age has emerged as an intuitive marker of brain health and cognitive longevity. The difference between brain age and chronological age, termed brain-predicted age difference (brain-PAD), quantifies deviation from normative brain ageing and may help evaluate whether interventions could attenuate brain ageing trajectories. This review synthesizes the methodological foundations of brain age estimation, factors linked to brain-PAD across healthy ageing and disease,...

CONCLUSION: FGF-19 concentration showed exploratory negative associations with functional capacity. FGF-19 was not associated with the change in functional capacity following the exercise intervention.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no effective cure, characterized by the cerebral parenchymal and vascular accumulation of aggregated amyloid-β (Aβ) and hyperphosphorylated tau. Cerebrovascular and mitochondria dysfunction are early causal events in the progression of AD. Previous studies support that inhibiting carbonic anhydrases (CAs) may prevent mitochondrial and cerebrovascular dysfunction in AD models. Here, we selectively target the mitochondrial...

Microglial dysfunction is increasingly implicated in Alzheimer's disease (AD) pathogenesis, with loss-of-function variants in the microglial receptor TREM2 as major risk factors for late-onset AD. We report VG-3927, an oral, CNS-penetrant small-molecule TREM2 agonist that engages the transmembrane domains of TREM2 and its adaptor DAP12 to promote higher-order receptor complex formation and downstream signaling. VG-3927 and tool compound VG-3909 exhibited (sub)nanomolar potency, cooperated with...

As life expectancy increases globally, ageing has emerged as the main risk factor driving the increasing burden of neurological disorders. Although advances have been made in understanding their pathogenesis, current therapies remain largely symptomatic and do not prevent disease progression. There is a growing body of evidence that these disorders share common molecular mechanisms, including oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy, ferroptosis, and...

Physical performance declines with age, but its association with circulating neurodegeneration biomarkers remains unclear. Blood biomarkers including NT1, NfL, oAβ, and pTau217 may reflect early neurodegenerative changes linked to physical performance decline. Evidence linking these biomarkers to physical performance is limited. We analyzed older adults in the COSMOS Clinic substudy with baseline and two-year follow-up assessments of plasma NT1, NfL, and oAβ and a single assessment of pTau217....