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The epigenetic mark H3K9me3 is associated with silencing of lineage-inappropriate genes. Here the authors show that some lineage-inappropriate genes are derepressed in senescent cells through physical decompaction of H3K9me3-heterochromatic regions.
Naked mole rat (NMR) is an exceptionally long-lived rodent species that on the phenotypic level seems to evade aging. Here the authors show that NMRs age epigenetically, while epigenetic clocks detect that NMR queens age more slowly than nonbreeding females.
Using a treatment that activates the peripheral immune system in an animal model of amyloidosis, the authors show that monocyte-derived macrophages can modify Alzheimer’s disease progression via a TREM2-independent mechanism.
The authors link neuronal expression of telomerase reverse transcriptase to amyloid pathology and cognitive dysfunction in preclinical models of Alzheimer’s disease.
Using an in silico network-based discovery approach, the authors identified sildenafil as a repurposable drug for Alzheimer’s disease. Analyzing insurance claims data from over 7 million individuals, they found that sildenafil usage was associated with a reduced risk of Alzheimer’s disease diagnosis.
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.