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Circulating factors play an important role in tissue aging. Here, the authors show that serum EV subpopulations and cargoes remodel with age and that EVs from young mouse serum rejuvenate aged skeletal muscle.
The authors demonstrate that release of peroxidated lipids from mouse neurons following ablation of the small GTPase ARF1 leads to activation of a neurotoxic microglial NLRP3 pathway and show that ARF1 is reduced in human brain tissue from patients with neurodegenerative diseases.
The authors found that deleting an ovary-rich gene called Bin2 improved fertility and oocyte quality in mice. Inhibiting BIN2 with a cell-penetrating peptide improved ovarian function in aging and in chemotherapy-treated mice.
A brain-imaging study in humans demonstrates that older age brain network decline varies in relation to an individual’s education and predicts future dementia severity beyond other markers of Alzheimer’s disease-related genetic risk and pathology.
Integrative single-cell RNA sequencing and immunological profiling reveal that older adults have reduced antigen-specific cellular and humoral responses accompanied by increased cytokine storm and myeloid cell recruiting factors in response to acute SARS-CoV-2 infection.
The authors found that the Alzheimer’s disease-linked APOEε4 allele may prime microglia towards a phagocytic and pro-inflammatory state in the normal aging brain, even before Alzheimer’s amyloid plaques and neurofibrillary tangles develop.
Through computational drug repurposing, Taubes et al. identified bumetanide as a potential drug for APOE4-related Alzheimer’s disease (AD). The effectiveness of bumetanide was validated in AD mouse models and via real-world health record databases.
The hypothalamus controls systemic aging via involving the production of gonadotropin-releasing hormone (GnRH). The authors show that aging is preceded by irregularity and acceleration of GnRH pulses, while lowering GnRH pulse frequency by castration or optogenetically slows aging and promotes longevity.
Using live imaging, the study shows, in mice, that epithelial cells escape from the hair follicle stem cell compartment during aging. Stem cell escape is associated with reduced cell adhesion and extracellular matrix gene expression and leads to hair follicle miniaturization.
Transient expression of the pluripotency factors Oct4, Sox2, Klf4 and c-Myc can mitigate the effects of stem cell aging on tissue health. Neumann and colleagues show that Myc expression alone converts aged oligodendrocyte progenitor cells into neonatal-like cells, and is sufficient to enhance central nervous system regeneration in an otherwise aged environment.
Aging is the most important risk factor for breast cancer in women without genetic mutations. Shalabi and colleagues now show that histologically normal mammary epithelial cells genetically predisposed to cancer exhibit features of accelerated aging, such as the loss of cell lineage markers, differentiation defects and transcriptome-wide enrichment of expression of genes related to aging and inflammation.
Aged mesenchymal stem cells exhibit decreased osteogenesis. Pouikli et al. link impaired MSC differentiation to histone hypoacetylation caused by lower mitochondrial acetyl-CoA export due to enhanced lysosomal degradation of the citrate carrier Slc25a1. Restoring histone acetylation to youthful levels rescues osteogenesis.
In this whole-exome sequencing study of the largest centenarian cohort to date, Lin et al. demonstrate that conserved pathways—for example, IIS and AMPK signaling—are as relevant to human longevity and healthy aging as they are in worms, flies and mice.
Changes in hair and skin can be the most obvious and earliest signs of aging. The authors report that skin and hair follicle stem cell (HFSC) aging is driven by stress-induced upregulation of miR-31, which targets Clock to activate MAPK/ERK and deplete HFSCs via transepidermal elimination. Blocking the pathway with MAPK/ERK inhibitors protects against skin aging.
In a mouse model of atherosclerosis, Childs and colleagues show that senescent cells inhibit the promigratory phenotype switching of vascular smooth muscle cells by secreting IGFBP3 and that senolysis promotes the repair of fibrous caps in advanced lesions.
The authors show that aged mammalian stem cells produce aberrant transcripts due to profound yet characteristic changes to chromatin during aging, a phenomenon only previously known to occur in simple invertebrate models, limiting their lifespan.
From the blood immunome of 1,001 individuals aged 8–96 years, the authors used deep learning to develop an inflammatory clock of aging (iAge) that tracks with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The main contributor to iAge is the chemokine CXCL9, which is shown to control endothelial cell senescence and function.
The authors show that glial AP1 is initially protective after traumatic brain injury (TBI) but remains active chronically, driving tau pathology and degeneration. Glial AP1 similarly activates with normal aging, suggesting this may be accelerated by TBI.
The authors present the results of a 24-month phase 2 study of AADvac1, a tau vaccine against Alzheimer’s disease. AADvac1 was safe and induced high levels of antibodies. In the whole study sample, there were no significant changes on clinical outcomes.
This study shows that APOE4, one of the largest genetic risk factors for Alzheimer’s disease, promotes advanced-stage vascular dysfunction and neurodegeneration in old mice via activation of the cyclophilin A pathway in pericytes and independently of the presence of amyloid-β.