Aging & Longevity

Circumventricular organs (CVOs) are small brain regions lacking a blood-brain barrier, giving neurons direct access to blood-borne signals, yet how these microenvironments shape the origin and phenotype of local macrophages remains unclear. Using multi-omics, we characterized the immune landscape of two CVOs, the area postrema (AP) and median eminence (ME), revealing brain-border-like environments with a unique macrophage compartment. CVO microglia showed a distinct, heterogeneous phenotype,...

AMP-activated protein kinase (AMPK) is a key evolutionarily conserved sensor of energy homeostasis and plays a central role in metabolic health and disease. AMPK has also been implicated in ageing; however, most in vivo drug studies rely on the use of indirect activators, such as metformin, which have complex modes-of-action, therefore making conclusions on the specific role of AMPK more challenging. Here, we demonstrate that direct activation of AMPK with the compound 991 extends lifespan in...

Cellular senescence and chronic low-grade inflammation occupy a central, mechanistically coupled position among the hallmarks of aging. Natural killer (NK) cells decline in per-cell cytotoxicity with age, and lower NK cell cytotoxicity has been associated with higher cancer incidence and infection-related mortality in older adults. NK cells are also endogenous effectors of senescent-cell clearance, engaging stress-induced NKG2D and DNAM-1 ligands and depending on perforin-mediated cytolysis....

Large-scale functional connectivity gradients provide a compact description of cortical organization, capturing hierarchical transitions from unimodal sensory systems to transmodal association cortex. Although these gradients have become a central framework for studying macroscale brain organization, it remains unclear whether they systematically map onto regional cortical biology. Here we show that functional gradient position robustly predicts cortical thickness and regional glucose...

Tauopathies, including Alzheimer's disease, are age-related neurodegenerative disorders characterized by abnormal phosphorylation and buildup of microtubule-associated protein tau. Gene expression dysregulation is a key molecular feature of tauopathies, but how aging and disease interact to disrupt crucial transcriptional regulators and pathways remains largely unknown. Here, we examined how pathological tau affects gene expression programs in age-related neurodegenerative disease using a...

CONCLUSION: The prevalence of pain is relatively high among older people in Mexico. Targeted intervention measures should be taken to improve awareness of the risk factors and the prevention of pain.

Age-related megakaryocyte (MK) dysfunction disrupts platelet production and may increase thrombotic risk, but whether coenzyme Q10 (CoQ10) restores MK homeostasis through autophagy remains unclear. Male C57BL/6J mice aged 1, 9, 15, 19, 21, or 23 months received CoQ10 for 12 weeks. Bone marrow MK proliferation, CD41/CD61 expression, DNA polyploidy, autophagy-associated proteins, and platelet phenotypes were evaluated. H(2)O(2)-induced senescent MEG-01 cells were used for pharmacological...

Age-related hearing loss (ARHL) is a prevalent sensory disorder in the elderly, yet the molecular mechanisms underlying cochlear aging remain incompletely understood. While insulin-like growth factor 1 (IGF-1) has been implicated in ARHL, its role in the stria vascularis, particularly in pericyte-mediated blood-labyrinth barrier (BLB) regulation, is poorly defined. We performed transcriptomic analysis of FACS-purified pericytes from young and aged mouse stria vascularis. Functional studies were...

Senolytic CAR-T cells targeting uPAR induce dose-dependent toxicities. Although dosage adjustment mitigates these toxicities in laboratory mice, clinical translation remains challenging owing to the unpredictability of CAR-T cell proliferation across heterogeneous patient populations. In contrast, bispecific T-cell engagers (BiTEs) offer a safer alternative with superior dose-titratability. Here, we have developed a GFD-CD3 BiTE by employing the growth factor-like domain (GFD) of the natural...

Maintenance of lipid and redox homeostasis is essential for stress resistance and longevity, but the transcriptional networks coordinating these processes remain incompletely understood. In Caenorhabditis elegans, the transcription factors SKN-1A/Nrf1 and SKN-1C/Nrf2 mediate distinct stress responses that promote proteostasis, lipid homeostasis, and oxidative stress resistance. Here, we identify the Krüppel-like factor KLF-1 as a regulator of lipid accumulation that modulates SKN-1 activity....

Cognitive impairment (CI) associated with aging and immunosenescence is linked to metabolic alterations. Microglial senescence and dysregulated autophagy have been implicated as major contributors to this process, but the underlying metabolic regulators remain unclear. This study aimed to identify key metabolic regulators of CI and elucidate their underlying mechanisms. Human cohort analyses, older and D-galactose (D-gal)-induced mouse models, and microglial cell models were integrated to...

Interactions between nervous system and adipose tissue are involved in the regulation of adipocyte browning. However, whether microglial activation participates in the regulation of cold exposure-induced sympathetic innervation and adipocyte browning is unclear. Here, we demonstrate that RNA m6A demethylase ALKBH5 in the microglia nucleus of hypothalamus (PVH) region inhibits cold exposure-induced adipocyte browning in the subcutaneous white adipose tissue (sWAT) of male mice. The single...

As delayed childbearing becomes increasingly common, elucidating the mechanisms of age-related placental senescence is critical for the development of effective therapeutic strategies. Here, we integrate metabolomics, single-cell RNA sequencing, and spatial transcriptomics to uncover conserved features of aged placentas in humans, mice, and pigs, namely, increased macrophage CD38 expression and NAD⁺ deficiency. Through pharmacological and genetic approaches, we demonstrate that macrophage CD38...

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Aging is an inevitable and progressive physiological process marked by a decline in cellular function, accumulation of somatic mutations, decreased ability to maintain homeostasis, and increased tissue and organ dysfunction. These changes contribute to the onset and progression of various age-related diseases. Accumulation of reactive oxygen species (ROS) has been identified as a key mediator of the aging process. Mitochondria, the primary producers of ROS, accumulate defects with aging, leading...

Mineralized blood vessels (MBV) are a form of vascular pathology associated with cerebrovascular aging and neurodegeneration; however, their regional distribution and clinicopathological correlates in Alzheimer disease (AD) remain poorly characterized. We examined 265 decedents with intermediate/high AD neuropathologic change from three Alzheimer's Disease Research Centers (Columbia University, University of California San Diego, and University of California Davis). Hematoxylin and eosin-stained...

Antiretroviral therapy (ART) has significantly increased life expectancy of people living with HIV (PLWH). Nonetheless, despite effective virological control, PLWH are faced with accelerated aging, characterized by higher prevalence of age-related comorbidities than the general population. Persistent inflammation and activation of innate immunity seem to drive this immunosenescent phenotype. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is increasingly...

Neuronal loss is a hallmark of neurodegenerative diseases. Phosphatidylserine (PS), a key "eat me" signal, is exposed on stressed viable neurons, triggering their premature phagocytosis by activated glia. We investigated whether PS masking could serve as a universal strategy to prevent neuronal loss in two distinct Drosophila models of neurodegeneration: an adult-stage-specific knockdown of skpA and a Huntington's disease model initiated during embryogenesis. Both models exhibit neuronal loss,...

The functional decline of the hematopoietic system during aging affects organismal function and contributes to reduced healthspan. Quantifying hematopoietic aging holds great scientific and clinical relevance. Alterations in chromatin architecture are a well-established hallmark of aging that encode rich and informative signatures of the aging process, yet they remain largely unexplored as quantitative markers. Here, we present an interpretable deep learning approach based on convolutional...