Aging & Longevity

Epidemiological links between cognition and body physiology in aging are well established, but their strength and drivers remain unclear. Which physiological systems - from body composition to cardiovascular, pulmonary, renal, hepatic, immune, metabolic, and musculoskeletal - best predict cognition, and to what extent are cognition-body associations linked to brain variation across aging? We examined 19 physiological phenotypes alongside three neuroimaging modalities in over 30,000 UK Biobank...

Myeloid cells, including microglia and perivascular macrophages, are central to Alzheimer's disease (AD) neurobiology, yet their role remains incompletely understood. We profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 donors spanning the lifespan and showing varying degrees of AD neuropathology. We delineated six subclasses comprising 13 transcriptionally distinct subtypes and identified adaptive changes associated with aging and AD progression. Here we show that a...

Senescence, which is defined as a state of stable cell cycle arrest, can occur in all tissues of the body. The surveillance and clearance of senescent cells by the immune system is necessary for tissue homeostasis; when this immune surveillance does not occur efficiently, for example, during tumorigenesis and ageing, it has pathological consequences. For example, if the immune clearance of senescent cells is evaded, such as through recruitment of immunosuppressive cells, expression of immune...

CONCLUSION: Isoorientin alleviates age-related bone loss by suppressing TLR4-mediated inflammation, reducing osteoclast activation, and restoring impaired osteogenesis. These findings identify isoorientin as a promising therapeutic candidate for age-associated osteoporosis.

No abstract

Aging is characterized by a decline in function of intestinal stem cells (ISCs), but the extent to which this is shaped by systemic factors is unclear. Here we show that the ISC aging phenotype can be propagated from old to young mice utilizing heterochronic parabiosis, and implicate a role for inflammation in these effects, as anti-inflammatory drugs, including TNF antibodies, restored function. Parabiotic rescue experiments demonstrate that TNFR1 knockout protected young ISCs from the old...

Aging is the major risk factor for neurodegenerative disease, yet the mechanisms linking physiological aging to brain dysfunction remain unclear. We investigated the brains of telomere-shortened mice and observed lipofuscinosis, hypomyelination, microglial atrophy, and cognitive deficits. Single-nucleus RNA sequencing (snRNA-seq) revealed accelerated glial aging and elevated microglial senescence pathways. In a senescence model of human induced pluripotent stem cell (iPSC)-derived microglia,...

Clonal hematopoiesis of undetermined potential (CHIP), initially discovered as a mere hematological curiosity, now represents a clinically significant factor that is changing our view of ageing, inflammaging and the risk of age-related diseases (ARDs). In line with this, new meta-analyses link the presence of CHIP to higher all-cause mortality from ARDs and to an increase in adverse events in the presence of larger clones. Mechanistically, CHIP induces inflammaging, but a bidirectional...

Aging is a complex, irreversible physiological process characterized by gradual deterioration of tissue structure and function, accompanied by impaired regenerative capacity, dysregulated immune homeostasis, and increased susceptibility to chronic age-related diseases (e.g., neurodegenerative disorders, metabolic syndromes, age-related skin lesions, and inflammatory bowel disease). In recent years, plant-derived extracellular vesicles (PDEVs), the lipid bilayer membrane vesicles released by...

Cellular senescence is a stress-response program characterized by durable proliferative arrest, but senescence entry does not determine a single biological outcome. Confusion between the fate of an individual cell and the behavior of a senescent-cell population has obscured interpretation across development, ageing and disease. This Review develops a fate-resolved framework that distinguishes continued arrest, cell death, physical shedding and, under restricted conditions, sustained...

No abstract

Phenotypic traits often covary through shared genetic and environmental influences, shaping the evolution of integrated life-history strategies. In particular, correlations between behavioral and life-history traits form the core of the pace-of-life syndrome (POLS) hypothesis, yet direct experimental tests of its evolutionary and molecular foundations remain limited. Here, we combined experimental evolution and transcriptomic analyses to investigate the phenotypic and molecular architecture of...

Astrocytes, oligodendrocyte lineage cells, and microglia dynamically shape the neural extracellular matrix (ECM) across brain development and aging. Recent findings highlight the potential of glial regulation of the ECM as a framework for understanding circuit formation and identify previously unrecognized targets in neurological diseases.

CpG dinucleotides are mutational hotspots due to spontaneous deamination of 5-methylcytosine (5mC), resulting in T:G mismatches that can lead to CpG>TpG transitions. These mutations are a hallmark of aging and cancer and play a central role in the evolution of vertebrate genomes. We have previously uncovered MBD4 as the primary base excision repair (BER) glycosylase responsible for 5mC deamination repair. Here, we employ an APOBEC1 deaminase fused to a catalytically dead Cas9 to induce targeted...

Reductive stress has remained underappreciated as a significant disrupter of redox homeostasis. Recent studies have begun to link the accumulation of NADH and NADPH to the development and progression of metabolic diseases such as cancer, cardiac disease, and diabetes. In this study we use the nematode Caenorhabditis elegans to examine the phenomenon of catastrophic reductive-death caused by combined biguanide treatment and fasn-1 deficiency. This process of synergistic biguanide-induced...

BackgroundAmenable mortality, deaths preventable through timely and effective healthcare, is a widely used indicator of health system performance, yet evidence is lacking on its individual-level determinants in Brazil.MethodsWe used data from the Brazilian Longitudinal Study of Aging (ELSI-Brazil), a representative cohort of adults aged 50 and older. Deaths were classified as amenable using both the Brazilian and the Pan American Health Organization's definitions. Semi-parametric competing risks...

Neurons accumulate somatic mutations with age, but how mutation processes vary among neuronal types remains unclear. Characterizing this variability may elucidate the role of genome integrity in brain function and disease and reveal determinants of mutation rates and patterns. Using high-fidelity duplex DNA sequencing, we profiled somatic mutations across the lifespan in human cerebellar Purkinje and granule neurons, which differ markedly in size and physiology. Surprisingly, they exhibited...

Dioscin, a naturally occurring steroidal saponin isolated from various kinds of herbs with pleiotropic pharmacological properties, remains mechanistically undefined regarding its mammalian aging modulation. This study discovered that dioscin extended the lifespan of Caenorhabditis elegans. Concurrently, dioscin improved the motor function of C. elegans and reduced age pigment accumulation, while having no effect on the reproductive performance of the C. elegans. By pathway screening, we...

Cardiac aging is a central biological process underlying most cardiovascular diseases. Lysosomes, once regarded as terminal degradative compartments, are now recognized as dynamic metabolic and signaling hubs whose dysfunction has profound consequences for the aging heart. Human lysosomal storage disorders provide compelling evidence that isolated lysosomal defects are sufficient to cause early cardiomyopathy, underscoring the myocardium's exceptional dependence on sustained lysosomal...

Parkinson's disease (PD) is an age-associated neurodegenerative disorder in which affective non-motor symptoms substantially contribute to disease burden, yet their neurobiological basis remains incompletely understood. We investigated region-specific alterations of corticotropin-releasing hormone (CRH) family neuropeptides in a rotenone-induced rat model of PD and evaluated the effects of combined dopaminergic (benserazide/L-DOPA) and antidepressant (fluoxetine) treatment. Motor performance,...