Longevity Papers

Dysregulation of the adaptive immune system is a key feature of aging and is associated with age-related chronic diseases and mortality. Here, we find that T cell aging, especially in the CD4 subset, is controlled by B cells. B cells contributed to the age-related reduction of naive CD4 T cells, their differentiation toward immunosenescent T cell subsets, and age-associated T cell receptor clonal restriction. Concurrently, mice lacking B cells displayed improvements in health span and life span. We uncovered a role for B cell-intrinsic insulin receptor signaling in influencing age-related B cell phenotypes that in turn induces CD4 T cell dysfunction, a process that is in part driven by major histocompatibility complex class II. These results identify B cells as critical mediators driving age-associated adaptive immune dysfunction and health-span outcomes and suggest previously unrecognized modalities to manage aging and related health decline.

The elegant work by Maejima et al. recently published in Aging Cell reveals a previously unrecognized mechanism linking age-related oxytocin (OXT) decline to epigenetic remodeling, mitochondrial dysfunction, and systemic inflammation (Maejima et al. 2025). Beyond documenting this relationship, the authors demonstrate its remarkable reversibility through nasal OXT administration. These findings provide the first molecular evidence supporting what has long been proposed: that the OXT system functions as a fundamental long-term regulator of health across the entire lifespan, from early development through aging (Moberg 2024, 2003; Uvnas-Moberg 1998). The current work now gives a tantalizing glimpse into the epigenetic mechanism behind this life course regulation.

Perineuronal nets (PNNs), specialised extracellular matrix structures enriched in chondroitin sulphate proteoglycans (CSPGs), are key regulators of synaptic plasticity, learning, and memory. Aging is characterised by a shift in chondroitin sulphate composition toward increased chondroitin-4-sulfation (C4S) and reduced C6S, a pattern associated with declining cognitive flexibility. Here, we investigated how selective reduction of C4S affects PNN structure, PV-interneuron connectivity, and cognitive performance across the lifespan. Conditional deletion of the C4-sulfotransferase Chst11 markedly reduced C4S levels and diminished dendritic PNN complexity while preserving somatic PNN structure. This partial destabilisation of PNNs increased excitatory synaptic input onto PV interneurons in both young and aged mice, without major alterations in basal hippocampal transmission or long-term potentiation. Behaviourally, Chst11 knockout mice showed robust and persistent protection against age-related cognitive decline. Working memory performance remained stable across aging, short-term spatial memory was enhanced from early adulthood onward, and object recognition memory was significantly prolonged at all retention delays, even in old age. Sociability and social novelty preference were also preserved longer in aging knockouts compared with controls. These improvements occurred despite an overall preservation of PNN architecture, indicating that modifying sulphation rather than removing CSPGs is sufficient to enhance plasticity. Our findings demonstrate that reducing C4S through Chst11 deletion confers long-lasting enhancements in cognitive function and mitigates aging-related decline. Targeting CS-GAG sulphation patterns may therefore represent a promising strategy for maintaining cognitive resilience and restoring plasticity in aging or neurodegenerative conditions.

Cellular senescence is a state of stable arrest and secretion linked to aging and disease. Here we identify that senescent cells dispose of large fragments of themselves through cell-to-cell adhesion, which we term senescent-cell adhesion fragments (SCAFs). Found across all senescent types examined, SCAFs lack nuclear material but contain organelles, including damaged mitochondria. Disrupting adherens junctions decreased SCAF formation but induced senescent-cell death, which was caused by an inability to shed damaged mitochondria. Dynamic analyses show that SCAFs ultimately rupture, releasing a complex proteome including damage-associated molecular patterns (DAMPs) and proteins linked to neurodegenerative disease. Functionally, SCAFs activate wound-healing and cancer-related programs, promoting migration and invasion. Altogether, these findings identify a new feature that facilitates senescent cell survival, but the consequence of which is external deposition of damaged intracellular contents, with implications for cancer and aging.

Spatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naive mouse pluripotent stem cells leads to upregulation of the cysteine-generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naive to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature ageing, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Notably, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases.

Epigenetic remodeling is a hallmark of aging, yet which epigenetic layers are most affected during aging-and the extent to which they are interrelated-is not well understood. Here, we perform a comprehensive analysis of epigenetic aging encompassing 6 histone marks and DNA methylation measured across 12 tissues from > 1000 humans and mice. We identify a synchronized pattern of age-related changes across these epigenetic layers, with all changes converging upon a common set of genes. Notably, an epigenetic clock based on these genes can accurately predict age using data from any layer (Spearman ρ: 0.70 in humans, 0.81 in mice). Applying this "pan-epigenetic" clock, we observe that histone modification and DNA methylation profiles agree in the prediction of which individuals are aging more rapidly or slowly. These results demonstrate that epigenetic modifications are subject to coordinated remodeling over the lifespan, offering a unified view of epigenetic aging.

Somatic mutations accumulate throughout life and can serve as endogenous markers to trace cellular lineage relationships. In hematopoietic stem cells (HSCs), aging is associated with functional decline and clonal skewing, yet how somatic mutational histories shape clonal architecture at single-cell resolution remains incompletely understood. Here, we leverage single-cell RNA sequencing from murine and human long-term HSCs to identify expressed somatic single-nucleotide variants and reconstruct mutation-based genealogies. To address technical noise inherent to single-cell transcriptomes, we implement a stringent joint variant filtering strategy that exploits daughter cell relationships and probabilistic modeling to distinguish true somatic events from artifacts. Using these high-confidence variants, we infer phylogenetic and clonal relationships among individual HSCs and uncover striking age-dependent differences in lineage structure. Whereas young HSCs show little evidence of hierarchical clonal organization, aged HSCs frequently exhibit structured genealogies consistent with clonal expansion. Integration of mutational, transcriptional, and signature-based analyses further reveals that genetically distinct clones in aged samples are transcriptionally divergent and enriched for pathways linked to aging and DNA damage responses. Together, our findings demonstrate that somatic mutations recovered from single-cell transcriptomes can resolve HSC clonal evolution and reveal age-associated alterations in stem cell dynamics.

Exercise induces extensive, cell type specific transcriptional remodeling in skeletal muscle to support metabolic flexibility and adaptation. However, the regulatory mechanisms underlying these transcriptional programs, and the extent to which they differ between sexes, remain poorly defined. We previously reported that lifelong, muscle-specific overexpression of human Transcription Factor E-B (cTFEB;HSACre transgenic mice) recapitulates many adaptive features of endurance training in both sexes, leading to profound geroprotective effects during aging even in the absence of exercise. Here, we profile transcriptional adaptations to voluntary wheel running (VWR) and TFEB-overexpression at single-nucleus resolution in young male and female mouse tibialis anterior muscle. This represents, to our knowledge, the first integrated analysis of exercise and TFEB signaling using sex as a biological variable. Using robust bioinformatic and single-nuclei RNA-sequencing approaches, we profiled six muscle-resident cell populations and uncover previously unrecognized, sex-dependent signaling nodes governing exercise-associated metabolic plasticity. TFEB activation and endurance training by VWR elicit strongly correlated transcriptional programs enriched for lipid metabolism, mitochondrial remodeling, and immune modulation, establishing TFEB-overexpression as a partial exercise mimetic. In general, female muscle exhibited enhanced extracellular matrix and lipid-associated responses to endurance training and TFEB overexpression, whereas males preferentially engaged in angiogenic and oxidative networks, revealing distinct sex-specific, sex-dimorphic, or sex-agnostic regulatory routes to metabolic flexibility. Integration with independent multi-omics datasets from endurance -trained rats (MoTrPAC) confirms the conservation of TFEB-exercise transcriptional convergence in skeletal muscle across species and potentially muscle types. Together, these findings define TFEB as a regulator of exercise transcriptional programs and reveal sex-specific molecular frameworks that drive metabolic adaptation in skeletal muscle. Furthermore, the resulting sex-resolved, single-nucleus transcriptional atlas provides a unique resource for the field, enabling comparative, mechanistic, and hypothesis-driven exploration of exercise-responsive skeletal muscle regulatory networks across sexes.