Junyeop Kim, Yerim Hwang, Sumin Kim, Yujung Chang, Yunkyung Kim, Youngeun Kwon, Jongpil Kim
Partial cellular reprogramming via transient expression of Oct4, Sox2, Klf4, and c-Myc induces rejuvenation and reduces aged-cell phenotypes. In this study, we found that transcriptional activation of the endogenous Oct4 gene by using the CRISPR/dCas9 activator system can efficiently ameliorate hallmarks of aging in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). We observed that the dCas9-Oct4 activator induced epigenetic remodeling, as evidenced by increased H3K9me3 and decreased H4K20me3 levels, without tumorization...
March 25, 2023: Aging Cell
Vivekananda Budamagunta, Ashok Kumar, Asha Rani, Linda Bean, Sahana Manohar-Sindhu, Yang Yang, Daohong Zhou, Thomas C Foster
We examine similar and differential effects of two senolytic treatments, ABT-263 and dasatinib + quercetin (D + Q), in preserving cognition, markers of peripheral senescence, and markers of brain aging thought to underlie cognitive decline. Male F344 rats were treated from 12 to 18 months of age with D + Q, ABT-263, or vehicle, and were compared to young (6 months). Both senolytic treatments rescued memory, preserved the blood-brain barrier (BBB) integrity, and prevented the age-related decline in hippocampal N-methyl-D-aspartate receptor (NMDAR) function associated with impaired cognition...
March 23, 2023: Aging Cell
Joaquim Sol, Èlia Obis, Natalia Mota-Martorell, Irene Pradas, Jose Daniel Galo-Licona, Meritxell Martin-Garí, Anna Fernández-Bernal, Marta Ortega-Bravo, Jordi Mayneris-Perxachs, Consuelo Borrás, José Viña, Mónica de la Fuente, Ianire Mate, Carles Biarnes, Salvador Pedraza, Joan C Vilanova, Ramon Brugada, Rafel Ramos, Joaquin Serena, Lluís Ramió-Torrentà, Víctor Pineda, Pepus Daunis-I-Estadella, Santiago Thió-Henestrosa, Jordi Barretina, Josep Garre-Olmo, Manuel Portero-Otin, José Manuel Fernández-Real, Josep Puig, Mariona Jové, Reinald Pamplona
Aging biology entails a cell/tissue deregulated metabolism that affects all levels of biological organization. Therefore, the application of "omic" techniques that are closer to phenotype, such as metabolomics, to the study of the aging process should be a turning point in the definition of cellular processes involved. The main objective of the present study was to describe the changes in plasma metabolome associated with biological aging and the role of sex in the metabolic regulation during aging. A high-throughput untargeted metabolomic analysis was applied in plasma samples to detect hub metabolites and biomarkers of aging incorporating a sex/gender perspective...
March 23, 2023: Aging Cell
Daniel Kolbe, Nicolas A da Silva, Janina Dose, Guillermo G Torres, Amke Caliebe, Ben Krause-Kyora, Almut Nebel
Variation in apolipoprotein E (APOE) has been shown to have the strongest genetic effect on human longevity. The aim of this study was to unravel the evolutionary history of the three major APOE alleles in Europe by analysing ancient samples up to 12,000 years old. We detected significant allele frequency shifts between populations and over time. Our analyses indicated that selection led to large frequency differences between the earliest European populations (i.e., hunter-gatherers vs. first farmers), possibly due to changes in diet/lifestyle...
March 23, 2023: Aging Cell
Devin Wahl, Meghan E Smith, Cali M McEntee, Alyssa N Cavalier, Shelby C Osburn, Samuel D Burke, Randy A Grant, David Nerguizian, Daniel S Lark, Christopher D Link, Thomas J LaRocca
Aging is the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease. Major hallmarks of brain aging include neuroinflammation/immune activation and reduced neuronal health/function. These processes contribute to cognitive dysfunction (a key risk factor for Alzheimer's disease), but their upstream causes are incompletely understood. Age-related increases in transposable element (TE) transcripts might contribute to reduced cognitive function with brain aging, as the reverse transcriptase inhibitor 3TC reduces inflammation in peripheral tissues and TE transcripts have been linked with tau pathology in Alzheimer's disease...
March 22, 2023: Aging Cell
Dorina Zöphel, Lea Kaschek, Romy Steiner, Sandra Janku, Hsin-Fang Chang, Annette Lis
Numerous alterations in CD8+ T cells contribute to impaired immune responses in elderly individuals. However, the discrimination between cell-intrinsic dysfunctions and microenvironmental changes is challenging. TCR transgenic OT-I mice are utilized to investigate CD8+ T-cell immunity, but their immunodeficient phenotype hampers their use especially in aging. Here, we demonstrate that using a heterozygous OT-I model minimizes the current limitations and provides a valuable tool to assess antigen-specific T-cell responses even at old age...
March 22, 2023: Aging Cell
Pablo Salmón, Neal J Dawson, Caroline Millet, Colin Selman, Pat Monaghan
Mitochondrial dysfunction is considered a highly conserved hallmark of ageing. However, most of the studies in both model and non-model organisms are cross-sectional in design; therefore, little is known, at the individual level, on how mitochondrial function changes with age, its link to early developmental conditions or its relationship with survival. Here we manipulated the postnatal growth in zebra finches (Taeniopygia guttata) via dietary modification that induced accelerated growth without changing adult body size...
March 20, 2023: Aging Cell
Johan K Lassen, Tingting Wang, Kirstine L Nielsen, Jørgen B Hasselstrøm, Mogens Johannsen, Palle Villesen
Untargeted metabolomics is the study of all detectable small molecules, and in geroscience, metabolomics has shown great potential to describe the biological age-a complex trait impacted by many factors. Unfortunately, the sample sizes are often insufficient to achieve sufficient power and minimize potential biases caused by, for example, demographic factors. In this study, we present the analysis of biological age in ~10,000 toxicologic routine blood measurements. The untargeted screening samples obtained from ultra-high pressure liquid chromatography-quadruple time of flight mass spectrometry (UHPLC- QTOF) cover + 300 batches and + 30 months, lack pooled quality controls, lack controlled sample collection, and has previously only been used in small-scale studies...
March 19, 2023: Aging Cell
Sascha Jung, Javier Arcos Hodar, Antonio Del Sol
The quantification of the biological age of cells yields great promises for accelerating the discovery of novel rejuvenation strategies. Here, we present MultiTIMER, the first multi-tissue aging clock that measures the biological, rather than chronological, age of cells from their transcriptional profiles by evaluating key cellular processes. We applied MultiTIMER to more than 70,000 transcriptional profiles and demonstrate that it accurately responds to cellular stressors and known interventions while informing about dysregulated cellular functions...
March 16, 2023: Aging Cell
Martin Rey-Millet, Mélanie Pousse, Chan Soithong, Jing Ye, Aaron Mendez-Bermudez, Eric Gilson
Aging is a continuous process leading to physiological deterioration with age. One of the factors contributing to aging is telomere shortening, causing alterations in the protein protective complex named shelterin and replicative senescence. Here, we address the question of the link between this telomere shortening and the transcriptional changes occurring in senescent cells. We found that in replicative senescent cells, the genes whose expression escaped repression are enriched in subtelomeres. The shelterin protein TRF2 and the nuclear lamina factor Lamin B1, both downregulated in senescent cells, are involved in the regulation of some but not all of these subtelomeric genes, suggesting complex mechanisms of transcriptional regulation...
March 15, 2023: Aging Cell
Dorothy E Vatner, Marko Oydanich, Jie Zhang, Sara C Campbell, Stephen F Vatner
Enhanced exercise capacity is not only a feature of healthful aging, but also a therapy for aging patients and patients with cardiovascular disease. Disruption of the Regulator of G Protein Signaling 14 (RGS14) in mice extends healthful lifespan, mediated by increased brown adipose tissue (BAT). Accordingly, we determined whether RGS14 knockout (KO) mice exhibit enhanced exercise capacity and the role of BAT in mediating exercise capacity. Exercise was performed on a treadmill and exercise capacity was assessed by maximal running distance and work to exhaustion...
March 10, 2023: Aging Cell
Sankara Naynar Palani, Durai Sellegounder, Phillip Wibisono, Yiyong Liu
Studies in diverse species have associated higher temperatures with shorter lifespan and lower temperatures with longer lifespan. These inverse effects of temperature on longevity are traditionally explained using the rate of living theory, which posits that higher temperatures increase chemical reaction rates, thus speeding up the aging process. Recent studies have identified specific molecules and cells that affect the longevity response to temperature, indicating that this response is regulated, not simply thermodynamic...
March 9, 2023: Aging Cell
Zhiyuan Guan, Xiao Jin, Zhiqiang Guan, Shengfu Liu, Kun Tao, Liying Luo
Ferroptosis is an iron-dependent cell death that has been found to aggravate the progression of osteoarthritis (OA) and gut microbiota- OA axis refers to the bidirectional information network between the gut microbiota and OA, which may provide a new way to protect the OA. However, the role of gut microbiota-derived metabolites in ferroptosis-relative osteoarthritis remains unclear. The objective of this study was to analyze the protective effect of gut microbiota and its metabolite capsiate (CAT) on ferroptosis-relative osteoarthritis in vivo and in vitro experiments...
March 8, 2023: Aging Cell
Deng Wu, Xiaoman Bi, Peihu Li, Dahua Xu, Jianmin Qiu, Kongning Li, Shaojiang Zheng, Kim Hei-Man Chow
The immune system plays a central role in many processes of age-related disorders and it remains unclear if the innate immune system may play roles in shaping extreme longevity. By an integrated analysis with multiple bulk and single cell transcriptomic, so as DNA methylomic datasets of white blood cells, a previously unappreciated yet commonly activated status of the innate monocyte phagocytic activities is identified. Detailed analyses revealed that the life cycle of these monocytes is enhanced and primed to a M2-like macrophage phenotype...
March 8, 2023: Aging Cell
Yang Yu, Xiaoyu Song, Xiaoxun Wang, Lixia Zheng, Guojing Ma, Weiwei Liu, Han Su, Xiyan Liu, Tingting Liu, Liu Cao, Difei Wang
Sirt1 is an NAD+ -dependent deacetylase that protects against premature aging and cell senescence. Aging accompanied by oxidative stress leads to a decrease in Sirt1 levels and activity, but the regulatory mechanism that connects these events remains unclear. Here, we reported that Nur77, which shares similar biological pathways with Sirt1, was also decreased with age in multiple organs. Our in vivo and in vitro results revealed that Nur77 and Sirt1 decreased during aging and oxidative stress-induced cell senescence...
March 7, 2023: Aging Cell
Jiahn Choi, Michele Houston, Ruixuan Wang, Kenny Ye, Wenge Li, Xusheng Zhang, Derek M Huffman, Leonard H Augenlicht
The intestinal epithelium consists of cells derived from continuously cycling Lgr5hi intestinal stem cells (Lgr5hi ISCs) that mature developmentally in an ordered fashion as the cells progress along the crypt-luminal axis. Perturbed function of Lgr5hi ISCs with aging is documented, but the consequent impact on overall mucosal homeostasis has not been defined. Using single-cell RNA sequencing, the progressive maturation of progeny was dissected in the mouse intestine, which revealed that transcriptional reprogramming with aging in Lgr5hi ISCs retarded the maturation of cells in their progression along the crypt-luminal axis...
March 2, 2023: Aging Cell
Hyo Min Kim, Shinheun Kim, Jueun Sim, Boo Soo Ma, Insung Yong, Youngmin Jo, Taek-Soo Kim, Jae-Byum Chang, Sung-Hye Park, Yong Jeong, Pilnam Kim
Collagen is a prominent target of nonenzymatic glycation, which is a hallmark of aging and causes functional alteration of the matrix. Here, we uncover glycation-mediated structural and functional changes in the collagen-enriched meningeal membrane of the human and mouse brain. Using an in vitro culture platform mimicking the meningeal membrane composed of fibrillar collagen, we showed that the accumulation of advanced glycation end products (AGEs) in the collagen membrane is responsible for glycation-mediated matrix remodeling...
February 28, 2023: Aging Cell
Xiuli Dan, Beimeng Yang, Ross A McDevitt, Samuel Gray, Xixia Chu, Quia Claybourne, David M Figueroa, Yongqing Zhang, Deborah L Croteau, Vilhelm A Bohr
Olfactory dysfunction is a prevalent symptom and an early marker of age-related neurodegenerative diseases in humans, including Alzheimer's and Parkinson's Diseases. However, as olfactory dysfunction is also a common symptom of normal aging, it is important to identify associated behavioral and mechanistic changes that underlie olfactory dysfunction in nonpathological aging. In the present study, we systematically investigated age-related behavioral changes in four specific domains of olfaction and the molecular basis in C57BL/6J mice...
February 27, 2023: Aging Cell
Lihong Sheng, Emily J Shields, Janko Gospocic, Masato Sorida, Linyang Ju, China N Byrns, Faith Carranza, Shelley L Berger, Nancy Bonini, Roberto Bonasio
Glia have an emergent role in brain aging and disease. In the Drosophila melanogaster brain, ensheathing glia function as phagocytic cells and respond to acute neuronal damage, analogous to mammalian microglia. We previously reported changes in glia composition over the life of ants and fruit flies, including a decline in the relative proportion of ensheathing glia with time. How these changes influence brain health and life expectancy is unknown. Here, we show that ensheathing glia but not astrocytes decrease in number during Drosophila melanogaster brain aging...
February 24, 2023: Aging Cell
Emin Onur Karakaslar, Neerja Katiyar, Muneer Hasham, Ahrim Youn, Siddhartha Sharma, Cheng-Han Chung, Radu Marches, Ron Korstanje, Jacques Banchereau, Duygu Ucar
Diverse mouse strains have different health and life spans, mimicking the diversity among humans. To capture conserved aging signatures, we studied long-lived C57BL/6J and short-lived NZO/HILtJ mouse strains by profiling transcriptomes and epigenomes of immune cells from peripheral blood and the spleen from young and old mice. Transcriptional activation of the AP-1 transcription factor complex, particularly Fos, Junb, and Jun genes, was the most significant and conserved aging signature across tissues and strains...
February 24, 2023: Aging Cell
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