Longevity Papers

Recent studies report that epithelial differentiated cells can undergo a reverse process called dedifferentiation in response to stem cell loss. However, the extent of this reversion and the plasticity of young versus aged-differentiated cells remain unclear. Here we show that dedifferentiated corneal epithelial cells acquire a transcriptomic state closely resembling native stem cells, sustain tissue homeostasis across lifespan and efficiently repair repeated tissue injury. Transplantation of stage-specific genetically traceable aged differentiated epithelial cells onto a denuded niche reveals reversion into a stemness-like state, restoring both quiescent and active stem cell compartments. This plasticity operates within the epithelial lineage, allowing transitions along the differentiation axis, but remains restricted across lineages, as transplanted conjunctival cells fail to regenerate the corneal stem cell pool. Mechanistically, we identify niche-derived cytokines that trigger reprogramming in vivo and enhance stemness in primary human corneal epithelial cells, revealing a conserved and therapeutically exploitable pathway for epithelial regeneration.

Immunosenescence-the age-related decline of immune function-drives a state of chronic, sterile inflammation termed inflammaging. Far from passive deterioration, this process is actively orchestrated by distinct but interconnected hallmarks: erosion of lymphoid organs, myeloid-biased hematopoiesis, accumulation of immune-evasive senescent cells, and metabolic-epigenetic reprogramming that locks cells into dysfunctional states. These core nodes form a self-perpetuating cycle that propagates pathology across multiple organ systems, fueling neurodegeneration, cancer, musculoskeletal decline, and gut dysbiosis. Critically, the field has transitioned from descriptive phenomenology to mechanism-based intervention. This review synthesizes emerging therapeutic strategies targeting specific nodes of the immunosenescence network. We examine senotherapeutics that sensitize senescent cells for immune clearance, HSC and thymic rejuvenation to restore lymphocyte production, and metabolic-epigenetic interventions to correct intracellular deficits. By integrating these insights, we propose a precision medicine framework that moves beyond broad immunosuppression toward rational combinatorial regimens. This roadmap aims to decouple protective immunity from pathological drivers, extending healthspan and redefining the paradigm of geriatric care.

The specific neuroanatomy of mild cognitive impairment (MCI) is obscured by its clinical heterogeneity and confounding effects from normative variation. This problem is compounded by the inability of conventional neuroimaging methods to disentangle these overlapping influences. Leveraging data from the Beijing Aging Brain Rejuvenation Initiative (BABRI, n = 918) and the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1293), this study employed a conditional variational autoencoder (CVAE) to: (1) systematically distinguish between aging-related cognitive decline and MCI-specific cognitive impairments; (2) implicitly disentangle latent, unknown confounding effects to identify MCI-specific structural brain alterations; and (3) construct individualized scores for predicting the risk of conversion to Alzheimer's disease (AD). The CVAE effectively extracted MCI-specific latent features from T1 structural MRI, significantly correlated with episodic memory, attention, and executive function impairments. Reconstructions revealed characteristic deformation in regions including the middle and medial temporal lobes, frontal lobe, limbic system, and cerebellum. The robustness of this structural-cognitive impairment association model established in BABRI dataset was validated in the ADNI dataset. Moreover, predictive modeling using these features achieved superior AD-conversion prediction (AUC = 0.83) versus whole-brain atrophy (AUC = 0.74; p < 0.001) or CSF biomarkers (AUC = 0.77; p < 0.001).This work establishes a novel paradigm for isolating MCI-specific brain alterations from physiological aging.

Sleep disruption increases with age and is associated with adverse age related outcomes, yet the molecular mechanisms linking these phenomena remain unclear. Here, through integrative analysis of human and mouse transcriptomic and proteomic datasets, we identify proteostasis related pathways whose aging trajectories align with transcriptional responses to chronic sleep disruption across tissues and cell types. In the human prefrontal cortex, gene expression exhibits coherent age associated directional shifts. Across human peripheral blood following sleep restriction and multiple aging mouse tissues and cell types, proteostasis pathways exhibit concordant downregulation. Among these, heat shock response pathways emerge as the most persistent and cross modal signatures, with components of the heat shock factor 1 (HSF1) mediated proteostasis network displaying diminished inducibility with age and chronic sleep insufficiency, in contrast to transient activation following short term sleep deprivation. This attenuation is particularly pronounced in neurons, where age-associated suppression of HSF1 target programs indicates selective vulnerability of neuronal proteostasis. Spatial and single cell analyses map this vulnerability to hippocampal circuits during aging and to superficial cortical layers and glutamatergic neurons in Alzheimers disease. These findings support a model in which repeated sleep disruption progressively reduces the inducible capacity of proteostatic stress responses, shifting from adaptive activation to progressive attenuation and accelerating age related decline in proteome maintenance. Consistent with emerging functional evidence, this identifies HSF1 mediated proteostasis as an integrative axis linking sleep stability and molecular aging, suggesting a self reinforcing relationship in which sleep disruption and proteostasis decline reciprocally exacerbate one another. These results connect transient molecular responses to sleep perturbations with long term aging trajectories, revealing a systems level mechanism through which cumulative sleep disruption may increase vulnerability during aging.

Cardiorespiratory fitness (CRF) is a heritable trait associated with improved metabolic health and longevity. To identify regulatory mechanisms underlying CRF, we integrated 546 transcriptomic and epigenomic profiles from skeletal muscle of 128 genetically heterogeneous rats selectively bred for high and low running capacity, a model that mirrors CRF-associated traits in humans. Selection drove genetic convergence in coordinated skeletal muscle enhancer networks linked to lipid metabolism and angiogenesis genes. We validated thousands of these genetic effects through integration of 426 genotype, gene expression, and chromatin accessibility profiles in an independent HCRxLCR F2 population (n=147). These 972 multi-omics profiles show that CRF-associated genetic variation reshapes the chromatin landscape to support energy metabolism and oxygen delivery, offering a molecular framework for identifying targets to reduce cardiometabolic disease risk.

Centenarians - individuals aged 100 years or older - constitute a biologically distinct human population that achieves exceptional longevity while frequently retaining functional independence and avoiding major age-related diseases or postponing their onset. Despite their advanced age, many centenarians show relatively preserved immune function and resistance to conditions linked to immunosenescence and chronic low-grade inflammation (inflammageing). These features are especially pronounced in semi-supercentenarians (105-109 years) and supercentenarians (≥110 years), whose immune profiles often resemble those of much younger individuals. In this Review, we explore how centenarians modulate key hallmarks of immune ageing across innate and adaptive immune compartments. We discuss evidence that they limit the pathological effects of inflammageing, potentially through reduced NLRP3 inflammasome activation, enhanced autophagy and a tempered senescence-associated secretory phenotype. Omics studies further reveal transcriptomic, epigenetic and microbial signatures consistent with preserved immune function, including youth-like gene expression patterns in circulating immune cells and beneficial shifts in gut microbiome composition. Together, these findings suggest that centenarians achieve longevity through coordinated adaptations that maintain immune homeostasis and disease resistance and may inform strategies to enhance healthspan in ageing societies.

DNA variants modulate mortality risks across an entire lifespan but their dynamic age-dependent effects have not been resolved in any species for either sex. Here we mapped variants that shape mortality using an actuarial approach, starting with a base population of 6,438 pubescent mice and ending with 559 survivors that lived beyond 1,100 days of age. Twenty-nine Vita loci influence lifespan with strong age- and sex-specific effects. Most act during distinct stages with polarities that often invert with age, but a minority have consistent age-dependent effects in one or both sexes. A separate set of 30 Soma loci influence correlations between body mass and life expectancy. Nineteen Soma loci mediate higher mortality in larger young mice, whereas 11 mediate lower mortality in larger old mice. All effects are stronger in male mice than in female mice. Vita and Soma loci form epistatic networks split strictly by sex. These findings provide a genetic bridge between evolutionary theories of ageing and molecular mechanisms that can guide interventions to extend healthy lifespan.

Cellular senescence, driven by the interaction between FOXO4 and p53, is increasingly recognized as a crucial mechanism in brain aging and the development of neurodegenerative disorders. The senolytic peptide FOXO4-DRI, which has been thoughtfully designed, selectively disrupts the FOXO4-p53 complex, inducing apoptosis in senescent cells while preserving healthy tissue. In aged mammalian models, administering FOXO4-DRI decreases the accumulation of senescent cells, restores cerebral blood flow and the integrity of the blood-brain barrier (BBB), reverses hippocampal atrophy, and enhances cognitive function. Furthermore, in models of Alzheimer's disease (AD) and tauopathy, this intervention eliminates amyloid-β and pathological tau, leading to improved memory performance. Preliminary human studies involving FOXO4-axis modulators, such as high-dose fisetin, show a reduction in the senescence-associated secretory phenotype (SASP) and enhancements in cognitive and physical measures among older adults. These findings collectively identify the FOXO4-p53 axis as a potential pharmacological target in brain aging and highlight senolytic therapy as a promising strategy for altering diseases to postpone or reverse age-related cognitive decline. This review consolidates recent findings indicating that FOXO4-dependent senescence significantly contributes to neuroinflammation, synaptic dysfunction, and impaired neurogenesis in the aging brain.