Aging & Longevity

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...

Dysfunctional autophagy, a key cellular cleaning process, is a key driver of brain ageing and neurodegenerative diseases such as Alzheimer's disease (AD). However, developing effective treatments by enhancing autophagy has been challenging, as most known compounds act through the broad mTOR pathway, risking side effects, and few can effectively penetrate the brain. To address this, we developed DeepDrugDiscovery-a mechanism-aware, AI-powered screening platform incorporating ADMET and blood-brain...

Although the prevalence of type 2 diabetes (T2D) increases with age, most adults maintain normoglycaemia despite rising insulin resistance owing to the adaptive capacity of pancreatic beta cells to meet increased metabolic demand. However, persistent insulin resistance can lead to beta cell dysfunction and T2D onset. Here we show the mapping of genome-wide DNA methylation (DNAm) patterns and the epigenomic basis of beta cell adaptations by leveraging cell-type-specific methylome data from the...

Age-related skeletal muscle deterioration is a commonly reported disability among older adults, attributed to several factors including mitochondrial dysfunction, a major hallmark of aging. Therapies to attenuate or reverse mitochondrial decline are limited. Despite identified positive relationships between vitamin B12 (B12) and mitochondrial biology, the impact of B12 supplementation on skeletal muscle mitochondria, in advanced age, has not been examined. Thus, the impact of B12 supplementation...

Aging strongly impacts CD8^(+) T cells, including the loss of naive cells and the emergence of age-associated GZMK^(+)CD8^(+) T cells (T(AA) cells). Although T(AA) cells constitute a major population in aged mice, the pathway underlying their differentiation remains unknown. Here, we demonstrate that T(AA) cell development is cell extrinsic and requires antigen exposure within aged non-lymphoid tissues. Using a TNF^(Δ69AU/+) mouse model, we show that low-grade inflammation accelerates CD8^(+) T...

ObjectiveThis study examined whether older adults with informal, professional, or both types of care coordinators (CCs) reported different healthcare quality than those without CCs.MethodsData came from the 2016 Health and Retirement Study (n = 1,555) Module 10 on coordinated care. CC type and the helpfulness of professional CCs were independent variables. Outcomes included perceived confusion about care, conflicting advice from different providers, care satisfaction, and person-centered care....