Telomeres are repetitive nucleotide sequences at the ends of each chromosome. It has been hypothesized that telomere attrition evolved as a tumor suppressor mechanism in large long-lived species. Long telomeres can silence genes millions of bases away through a looping mechanism called telomere position effect over long distances (TPE-OLD). The function of this silencing mechanism is unknown. We determined a set of 2322 genes with high positional conservation across replicatively aging species that includes known and candidate TPE-OLD genes that may mitigate potentially harmful effects of replicative aging. Notably, we identified PPP2R2C as a tumor suppressor gene, whose up-regulation by TPE-OLD in aged human fibroblasts leads to dephosphorylation of p70S6 kinase and mammalian target of rapamycin suppression. A mechanistic link between telomeres and a tumor suppressor mechanism supports the hypothesis that replicative aging fulfills a tumor suppressor function and motivates previously unknown antitumor and antiaging strategies.

Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by the progressive loss of neurons mainly in the frontal and temporal lobes of the brain. Mutations (e.g., V337M, N297K) in the microtubule-associated protein TAU (MAPT) are responsible 5–20% of familial FTD cases and have been associated with defects in organelle trafficking that plays a critical role in the proper function of cells, including transport of essential molecules and degradation of waste products. Due to the critical role of TAU mutations in microtubule stabilization and organelle transportation, it is of great interest to study these molecular mechanisms to develop effective therapeutic strategies. Therefore, herein, we analyzed mitochondrial and lysosomal trafficking in disease-specific spinal motor neurons by using live cell imaging in undirected (uncompartmentalized) and directed (compartmentalized) cell culture systems. While V337M neurons only expressed 3R TAU, the N297K mutant neurons expressed both 3R and 4R TAU. Axonal trafficking was affected differentially in V337M and N297 MAPT mutated neurons. These findings suggest that the MAPT mutations V337M and N297K impaired axon physiology differentially, which highlights the need for mutation- and/or 3R/4R TAU-specific therapeutic approaches.

A middle-aged woman with a history of stage IV anaplastic lymphoma kinase (ALK)–positive non–small cell lung cancer (NSCLC) treated with crizotinib, an oral small-molecule tyrosine kinase inhibitor of ALK and other oncogenic kinases, presented with several months of peripheral visual field loss in her left eye. Four years earlier, she was diagnosed with stage IIIA NSCLC, which was managed with pneumonectomy, adjuvant chemotherapy, and radiotherapy. Seven months later, she underwent localized radiotherapy for a metastatic iliac lesion. Further testing revealed tumor positivity for the EML4-ALK gene (OMIM 607442) rearrangement, and the patient started crizotinib therapy. One month before presentation, she had an eye examination at another office and was prescribed new glasses, which did not improve her visual field deficit. One week before presentation, surveillance magnetic resonance imaging (MRI) showed a new 4-mm metastatic lesion in her right temporal lobe. On presentation, the patient’s visual acuity was 20/25 OD and 20/20 −2 OS. Tonometry showed pressures of 16 mm Hg OD and 14 mm Hg OS. Pupillary examination showed a trace relative afferent pupillary defect in the left eye. The remainder of the anterior segment examination findings were within normal limits. Goldmann visual field testing revealed an inferior defect in the left eye (Figure 1).

Microglia, the brain's resident immune cells, are crucial for maintaining healthy brain homeostasis. However, as the brain ages, microglia can shift from a neuroprotective to a neurotoxic phenotype, contributing to chronic inflammation and promoting neurodegenerative processes. Despite the importance of understanding microglial aging, there are currently few human in vitro models to study these processes. To address this gap, we have developed a model in which human microglia undergo accelerated aging through inducible progerin expression. HMC3‐Progerin cells display key age‐related markers such as activation of the senescence‐associated secretory phenotype (SASP) as well as an increase in DNA damage. These prematurely aged HMC3 cells show a reduced response to LPS activation, exhibit impairments in essential microglial functions including decreased migration and phagocytosis as well as transcriptomic alterations including a shift observed in aging and neurodegeneration. Additionally, we observed an impaired stress response and a defect in nucleocytoplasmic transport, especially affecting the amyotrophic lateral sclerosis (ALS) associated protein FUS. This suggests that microglia play a contributory role in driving neurodegenerative processes in the aging brain. Our microglia aging model offers a valuable tool for exploring how aged microglia affect brain function, enhancing our understanding of their role in brain aging.