Aging & Longevity

Machine learning can unravel heterogeneous patterns of brain aging and neurodegeneration, but existing methods offer limited insights into disease progression due to reliance on cross-sectional data. We introduce Coupled Cross-sectional and Longitudinal Non-negative Matrix Factorization (CCL-NMF) to capture dominant brain aging patterns by simultaneously leveraging cross-sectional and longitudinal neuroimaging data. CCL-NMF allows individuals to co-express multiple patterns, capturing mixed...

CONCLUSIONS: About four in five older Brazilians meeting dementia criteria had no prior clinical diagnosis, with marked sociodemographic and regional disparities. Both individual factors-such as age, education, and multimorbidity-and structural inequities across regions influenced diagnostic likelihood. Strengthening early-detection strategies, improved health professional training, and regionally tailored approaches may improve recognition of dementia in Brazil's public health system.

The existence and functional significance of immature neurons in the adult human brain, particularly in the context of neurodegenerative disorders, remain an open question. Although rodent studies have highlighted active roles for adult-born immature neurons in the hippocampus both under healthy conditions and in Alzheimer's disease (AD), evidence from the human brain is limited and lacks detailed molecular characterization. To address this gap, we performed single-nucleus RNA sequencing in aged...

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...

Cellular senescence plays a significant role in age-related conditions like osteoarthritis (OA) and intervertebral disc degeneration, in part due to the accumulation of senescent cells (SCs) in musculoskeletal tissues. Identifying novel therapeutics that can clear SCs is crucial for improving musculoskeletal health in the elderly. The present study aimed to elucidate the changes in Class I histone deacetylases (HDACs) and their role during senescence. All Class I HDACs except HDAC1 were...

Aging is commonly viewed as a passive consequence of accumulated damage; however, emerging evidence suggests that it may also represent an adaptive response to environmental stress. Here, we combined transcriptomic and metabolomic profiling of Saccharomyces cerevisiae to investigate how short-term, long-term, and recovery phases of stress exposure shape cellular physiology and lifespan. Short-term stress-induced protective pathways and longevity-associated metabolites, including trehalose and...

While exercise is shown to reduce hippocampal atrophy, the underlying molecular mechanisms remain to be fully elucidated. Animal studies suggest the myokine irisin underlies exercise-related hippocampal benefits, though human evidence is lacking. We cross-sectionally examined 74 healthy older adults (age 65.47 ± 8.56 years). Participants completed Godin Leisure-Time exercise questionnaires, provided fasting blood for irisin measurement and underwent structural MRI with hippocampal subfield...

Epithelial ovarian cancer (EOC) incidence and mortality increase with age, driven in part by chronic inflammation, diminished T cell output, and heightened regulatory T cell (Treg) mediated immunosuppression. In aged EOC-bearing mice, we observed reduced survival, accompanied by impaired CD4^(+) and CD8^(+) T cell responses and a marked expansion of FOXP3^(+) Tregs exhibiting elevated IL-10 and TGFβ expression. Metabolic profiling revealed enhanced oxidative phosphorylation in Tregs from aged...

Complex phenotypes, including aging, are influenced by a connected gene regulatory network with many interacting nodes. It has been proposed that some genes, termed "core genes," directly contribute to a trait, whereas "peripheral genes" influence the trait indirectly through network interactions. Yet demonstrating such a layered architecture and assigning genes to layers remains challenging. Using yeast aging, we developed an approach to infer network architecture underlying complex traits....

The transient upregulation of cellular senescence within wound tissues has been demonstrated to be an important biological process facilitating efficient tissue repair. Dysregulation of this transient wound-induced senescence response can result in impaired healing outcomes. Given the established age-related decline in tissue regenerative capacity, we hypothesized that alterations in this senescence response contribute to the delayed healing of cutaneous wounds in aged individuals. Our...

Cellular senescence and mitochondrial dysfunction are prevalent in adipose tissues and disrupt metabolic homeostasis during aging, but the mechanisms are poorly understood. Here, we investigated the role of histone deacetylase 9 (HDAC9), an epigenetic regulator of adipogenic differentiation, in aging-related adipose tissue senescence and mitochondrial dysfunction. HDAC9 expression correlated positively with age in mouse adipose tissues. Compared to age-matched wild-type (WT) mice, Hdac9 knockout...

Resident myeloid cells are the main constituents of the healthy central nervous system's (CNS) immune compartment. They usually seed the developing CNS prior to birth, remain there lifelong, and essentially contribute to neuronal network formation and establishment of physiology. While CNS anatomy is optimized for efficient connectivity, function, and maintenance of neuronal cells, distinct structures facilitate selective postnatal immune cell trafficking, including entry of myeloid cells. These...

Age-related neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and related dementias, are increasingly understood as multifactorial proteinopathies involving co-aggregation of amyloidogenic proteins such as Tubulin-associated unit protein (Tau), α-synuclein (α-syn), amyloid-β (Aβ), and TAR DNA-binding protein 43 (TDP-43). Rather than acting independently, these proteins often cross-seed, co-localize, and modulate each other's aggregation dynamics and...

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Senescent cells drive ageing and age-related pathologies, including cancer. Consequently, senolytics, drugs that selectively kill senescent cells, have broad therapeutic appeal. Here we report a senolytic screen of a library of 10,480 electrophilic compounds. Among 38 identified hits, we found a subset of chloroacetamides with broad senolytic activity. Activity-based protein profiling, coupled with functional assays, identified the glutathione peroxidase GPX4 as a target. We show that senescent...

A youthful molecular profile reflects attenuated aging and preserved health in advanced age. Long-lived individuals (LLIs) show youthful patterns in DNA methylation and gut microbiota, yet their transcriptional trajectories remain undercharacterized. We analyze transcriptomes from 811 LLIs and 940 younger controls (YCs) to map transcriptional aging trajectories. Clocks trained on YCs reveal that LLIs possess markedly younger transcriptional ages than expected. We identify gene clusters deviating...

CONCLUSIONS: A community-based multicomponent program was linked to sustained IC improvement, mainly through locomotion, while vitality benefits were short-term.

CONCLUSIONS: Dynapenic-metabolic obesity is strongly associated with incident stroke, but even obesity alone increases risk. Systemic inflammation and impaired intrinsic capacity partially mediate these effects, highlighting the importance of integrated strategies targeting adiposity, metabolic health, and muscle function to prevent stroke in aging populations.

Clock-like mutational signatures, principally the single base substitution signatures SBS1 and SBS5, with smaller contributions from SBS18 and SBS40, accumulate approximately linearly with chronological age across nearly all normal human somatic tissues. Initially viewed as simple molecular odometers of lifetime cell divisions, these signatures are now recognised to reflect a far more complex interplay of replication-associated polymerase errors, spontaneous cytosine deamination, oxidative...