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The authors show that liver sinusoidal endothelial cell (LSEC) senescence promotes steatosis by reprogramming liver endothelial zonation and inhibiting C-kit, a type III receptor tyrosine kinase. Infusing C-kit-expressing LSECs in aged or diet-induced NASH mice counteracts senescence and steatosis.
Nuclear morphology changes with aging, but the role of these changes and the underlying mechanisms are not fully understood. The authors find that the nuclear envelope anchor protein ANC-1 in worms, and its counterpart nesprin-1 and nesprin-2 in mammals, promotes the degradation of nuclear components to limit nucleolar size and function in a soma longevity and germline immortality mechanism.
Kirkland et al. identify conserved age-dependent nuclear remodeling in Drosophila cardiomyocytes, dependent on declining Lamin C. They show that Lamin C loss induces reversible heart dysfunction by repressing myogenic transcription factors.
The authors show that sphingolipids, a class of fat molecules, accumulate in skeletal muscle during aging. They demonstrate that reducing sphingolipids improves age-related fitness in mice by enhancing the myogenic response of muscle and present genetic evidence that these findings may also translate to humans.
Martínez Corrales et al. show that the activation of the conserved pro-longevity transcription factor FOXO solely in youth promotes subsequent health and survival in female fruit flies, via chromatin remodeling and induction of Xbp1.
Understanding sex differential responses to geroprotective interventions is key to developing personalized longevity treatments. Here, Regan, Lu et al. show that the sexual identity of intestinal enterocytes regulates autophagy to determine the response to the drug rapamycin.
This study shows that intermittent fasting (IF) protects against Alzheimer’s disease in a transgenic mouse model. The authors demonstrate that altered metabolism through remodeling of the gut microbiota mediates the beneficial effects of IF regimen.
Genetic inactivation of the plant homeodomain 6 gene (Phf6) counteracts transcriptional and epigenetic aging programs in the hematopoietic system and can reverse the decline of hematopoietic stem cell function associated with age.
Immune system dysfunction has been implicated in the development of dementias, but its causal role remains unknown. Providing converging results from different lines of human research, this study by Lindbohm et al. suggests that autoimmunity may be a modifiable component in diseases causing dementia.
A metagenomic study of gut, oral and skin microbiota describes a pattern of microbial dysbiosis in more frail institutionalized older adults and identifies the skin as the major reservoir of pathogenicity.
Splicing dysfunction has been observed in Alzheimer’s disease but it remains unclear whether splicing defects have a causal role. Here the authors generate a mouse model with perturbed U1 snRNP activity, recapitulating RNA splicing defects, neuron hyperexcitability, neurodegeneration and synergy with the amyloid cascade when crossed with 5xFAD mice.
Skin thickness and bone density decrease with age; however, the interactions between skin and bone during aging are unclear. Here the authors show that cystatin-A is a skin-derived protein that decreases with age and causes age-related bone loss. Further, topical application of calcipotriol stimulates cystatin-A production in the skin and alleviates bone loss.
In this multi-omics study, the authors identified C1q-dependent synapse elimination by both astrocytes and microglia in Alzheimer’s mouse models. While astrocytes preferentially removed excitatory synapses, microglia preferred inhibitory synapses.
RNA splicing has a role in aging and longevity, but the mechanisms involved are incompletely understood. Here the authors show that mRNA splicing components, RNP-6 and RBM-39, act in concert to regulate intron retention, inhibit mTORC1 signaling and prolong life in Caenorhabditis elegans.
Sexual interactions with males shorten the lifespan of the opposite sex in several species, including Caenorhabditis elegans, but the mechanisms are not fully understood. Here the authors use transcriptomic profiling in C.elegans to systematically identify the genetic pathways involved in male-induced demise, which include upregulation of a conserved ion channel that regulates fat metabolism.
A key challenge for repurposing the licensed drug rapamycin for geroprotection is to avoid side effects from chronic dosing regimens. The authors show in model organisms that a brief administration of the drug early in adulthood has long-lasting beneficial effects that are similar to lifelong treatment.
Somatic mutations accumulate with age; however, the role they have in cardiac aging is unclear. Here Choudhury et al. describe the somatic mutation landscape of human heart muscle cells by single-cell whole-genome sequencing and report mutational signatures indicative of increased oxidative DNA damage and failed repair.
A new population of dysfunctional astrocytes in the aging mouse hippocampus called autophagy-dysregulated astrocytes (APDAs) show impaired protein homeostasis and defective regulation of synapse formation and elimination and appear early in a mouse model of Alzheimer’s disease.
Measuring the rate of aging holds potential for capturing heterogeneity in aging. Here, the authors use longitudinal trajectories of aging phenotypes in the Baltimore Longitudinal Study of Aging and create a longitudinal phenotypic score that is associated with accelerated decline in health and physical and cognitive function.
This study finds that sST2 is a disease-causing factor for Alzheimer’s disease. Higher sST2 levels impair microglial Aβ clearance in APOE4+ female individuals. A genetic variant, rs1921622, is associated with a reduction in sST2 level and protects against AD in APOE4+ female individuals.