Aging & Longevity
Identification of aberrant luminal progenitors and mTORC1 as a potential breast cancer prevention target in BRCA2 mutation carriers
Inheritance of a BRCA2 pathogenic variant conveys a substantial life-time risk of breast cancer. Identification of the cell(s)-of-origin of BRCA2-mutant breast cancer and targetable perturbations that contribute to transformation remains an unmet need for these individuals who frequently undergo prophylactic mastectomy. Using preneoplastic specimens from age-matched, premenopausal females, here we show broad dysregulation across the luminal compartment in BRCA2^(mut/+) tissue, including...
Targeting COPIng liabilities of senescent cells
No abstract
The forecasted prevalence of comorbidities and multimorbidity in people with HIV in the United States through the year 2030: A modeling study
CONCLUSIONS: The PEARL forecasts suggest a continued rise in comorbidity and multimorbidity prevalence to 2030, marked by heterogeneities across race/ethnicity, gender, and HIV acquisition risk subgroups. HIV clinicians must stay current on the ever-changing comorbidities-specific guidelines to provide guideline-recommended care. HIV clinical directors should ensure linkages to subspecialty care within the clinic or by referral. HIV policy decision-makers must allocate resources and support...
Mathematical recapitulation of the end stages of human ovarian aging
Ovarian aging in women can be described as highly unpredictable within individuals but predictable across large populations. We showed previously that modeling an individual woman's ovarian reserve of primordial follicles using mathematical random walks replicates the natural pattern of growing follicles exiting the reserve. Compiling many simulations yields the observed population distribution of the age at natural menopause (ANM). Here, we have probed how stochastic control of primordial...
OXR1 maintains the retromer to delay brain aging under dietary restriction
Dietary restriction (DR) delays aging, but the mechanism remains unclear. We identified polymorphisms in mtd, the fly homolog of OXR1, which influenced lifespan and mtd expression in response to DR. Knockdown in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and it interacts with the retromer, which regulates trafficking of proteins and lipids. Loss of mtd/OXR1 destabilized the retromer, causing improper protein trafficking...
Cell type-specific regulation of m<sup>6</sup> A modified RNAs in the aging Drosophila brain
The aging brain is highly vulnerable to cellular stress, and neurons employ numerous mechanisms to combat neurotoxic proteins and promote healthy brain aging. The RNA modification m⁶ A is highly enriched in the Drosophila brain and is critical for the acute heat stress response of the brain. Here we examine m⁶ A in the fly brain with the chronic stresses of aging and degenerative disease. m⁶ A levels dynamically increased with both age and disease in the brain, marking integral neuronal identity...
Massive study of dog aging likely to lose funding
Organizers hope to save long-running project on canine aging and longevity.
Age-regulated cycling metabolites are relevant for behavior
Circadian cycles of sleep:wake and gene expression change with age in all organisms examined. Metabolism is also under robust circadian regulation, but little is known about how metabolic cycles change with age and whether these contribute to the regulation of behavioral cycles. To address this gap, we compared cycling of metabolites in young and old Drosophila and found major age-related variations. A significant model separated the young metabolic profiles by circadian timepoint, but could not...
Nutritional regulation of microbiota-derived metabolites: Implications for immunity and inflammation
Nutrition profoundly shapes immunity and inflammation across the lifespan of mammals, from pre- and post-natal periods to later life. Emerging insights into diet-microbiota interactions indicate that nutrition has a dominant influence on the composition-and metabolic output-of the intestinal microbiota, which in turn has major consequences for host immunity and inflammation. Here, we discuss recent findings that support the concept that dietary effects on microbiota-derived metabolites potently...
TRIM22 induces cellular senescence by targeting PHLPP2 in hepatocellular carcinoma
The ubiquitin-proteasome system is a vital protein degradation system that is involved in various cellular processes, such as cell cycle progression, apoptosis, and differentiation. Dysregulation of this system has been implicated in numerous diseases, including cancer, vascular disease, and neurodegenerative disorders. Induction of cellular senescence in hepatocellular carcinoma (HCC) is a potential anticancer strategy, but the precise role of the ubiquitin-proteasome system in cellular...
Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson's disease model
Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson's Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn)...
Publisher Correction: Transcriptional and epigenetic decoding of the microglial aging process
No abstract
Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage
Cerebrospinal fluid (CSF) in the subarachnoid space around the brain has long been known to drain through the lymphatics to cervical lymph nodes^(1-17), but the connections and regulation have been challenging to identify. Here, using fluorescent CSF tracers in Prox1-GFP lymphatic reporter mice^(18), we found that the nasopharyngeal lymphatic plexus is a major hub for CSF outflow to deep cervical lymph nodes. This plexus had unusual valves and short lymphangions but no smooth-muscle coverage,...
Drain 'pipes' behind the nose clear cerebrospinal fluid from the brain
No abstract
TIMely connections: APOE4, aging, and Alzheimer's
How do APOE4 and aging, two of the strongest risk factors for late-onset Alzheimer's disease (AD), promote disease progression? In this issue of Immunity, Millet et al. examine microglia in AD mice bearing different APOE alleles at distinct ages and identify a conserved exhausted-like microglial state enriched in very elderly and APOE4 AD brains.
Emerging role of NEDD8-mediated neddylation in age-related metabolic diseases
Aging in humans is associated with abdominal distribution and remodeling of body fat and a parallel gradual increase in the prevalence of metabolic diseases such as obesity, type 2 diabetes mellitus and fatty liver disease, as well as the risk of developing metabolic complications. Current treatments might be improved by understanding the detailed mechanisms underlying the onset of age-related metabolic disorders. Neddylation, a post-translational modification that adds the ubiquitin-like...
A single-cell atlas of the aging mouse ovary
Ovarian aging leads to diminished fertility, dysregulated endocrine signaling and increased chronic disease burden. These effects begin to emerge long before follicular exhaustion. Female humans experience a sharp decline in fertility around 35 years of age, which corresponds to declines in oocyte quality. Despite a growing body of work, the field lacks a comprehensive cellular map of the transcriptomic changes in the aging mouse ovary to identify early drivers of ovarian decline. To fill this...
TIME-seq reduces time and cost of DNA methylation measurement for epigenetic clock construction
Epigenetic 'clocks' based on DNA methylation have emerged as the most robust and widely used aging biomarkers, but conventional methods for applying them are expensive and laborious. Here we develop tagmentation-based indexing for methylation sequencing (TIME-seq), a highly multiplexed and scalable method for low-cost epigenetic clocks. Using TIME-seq, we applied multi-tissue and tissue-specific epigenetic clocks in over 1,800 mouse DNA samples from eight tissue and cell types. We show that...
The structure of B-ARR reveals the molecular basis of transcriptional activation by cytokinin
The phytohormone cytokinin has various roles in plant development, including meristem maintenance, vascular differentiation, leaf senescence, and regeneration. Prior investigations have revealed that cytokinin acts via a phosphorelay similar to the two-component system by which bacteria sense and respond to external stimuli. The eventual targets of this phosphorelay are type-B ARABIDOPSIS RESPONSE REGULATORS (B-ARRs), containing the conserved N-terminal receiver domain (RD), middle DNA binding...
Rapid and synchronous chemical induction of replicative-like senescence via a small molecule inhibitor
Cellular senescence is acknowledged as a key contributor to organismal ageing and late-life disease. Though popular, the study of senescence in vitro can be complicated by the prolonged and asynchronous timing of cells committing to it and by its paracrine effects. To address these issues, we repurposed a small molecule inhibitor, inflachromene (ICM), to induce senescence to human primary cells. Within 6 days of treatment with ICM, senescence hallmarks, including the nuclear eviction of HMGB1...
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