bims-caglex 2024-03-24 papers

Front Aging. 2023 ;4 1258184

Identification of dihydromyricetin as a natural DNA methylation inhibitor with rejuvenating activity in human skin.

Cassandra Falckenhayn, Agata Bienkowska, Jörn Söhle, Katrin Wegner, Guenter Raddatz, Boris Kristof, Dirk Kuck, Ralf Siegner, Ronny Kaufmann, Julia Korn, Sascha Baumann, Daniela Lange, Andreas Schepky, Henry Völzke, Lars Kaderali, Marc Winnefeld, Frank Lyko, Elke Grönniger.

Changes in DNA methylation patterning have been reported to be a key hallmark of aged human skin. The altered DNA methylation patterns are correlated with deregulated gene expression and impaired tissue functionality, leading to the well-known skin aging phenotype. Searching for small molecules, which correct the aged methylation pattern therefore represents a novel and attractive strategy for the identification of anti-aging compounds. DNMT1 maintains epigenetic information by copying methylation patterns from the parental (methylated) strand to the newly synthesized strand after DNA replication. We hypothesized that a modest inhibition of this process promotes the restoration of the ground-state epigenetic pattern, thereby inducing rejuvenating effects. In this study, we screened a library of 1800 natural substances and 640 FDA-approved drugs and identified the well-known antioxidant and anti-inflammatory molecule dihydromyricetin (DHM) as an inhibitor of the DNA methyltransferase DNMT1. DHM is the active ingredient of several plants with medicinal use and showed robust inhibition of DNMT1 in biochemical assays. We also analyzed the effect of DHM in cultivated keratinocytes by array-based methylation profiling and observed a moderate, but significant global hypomethylation effect upon treatment. To further characterize DHM-induced methylation changes, we used published DNA methylation clocks and newly established age predictors to demonstrate that the DHM-induced methylation change is associated with a reduction in the biological age of the cells. Further studies also revealed re-activation of age-dependently hypermethylated and silenced genes in vivo and a reduction in age-dependent epidermal thinning in a 3-dimensional skin model. Our findings thus establish DHM as an epigenetic inhibitor with rejuvenating effects for aged human skin.

Keywords: DNA methylation; DNAm age clock; DNMT1 inhibition; dihydromyricetin; rejuvenation; skin

DOI: https://doi.org/10.3389/fragi.2023.1258184

J Gerontol A Biol Sci Med Sci. 2024 Mar 22. pii: glae083. [Epub ahead of print]

Exercise to Mitigate Cerebrovascular Aging: A Geroscience Perspective.

Amani M Norling, Lewis A Lipsitz.

Aging is characterized by a progressive loss of cellular functions that increase the risk of developing chronic diseases, vascular dysfunction, and neurodegenerative conditions. The field of geroscience has identified cellular and molecular hallmarks of aging that may serve as targets for future interventions to reduce the risk of age-related disease and disability. These hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Several studies show that exercise may favorably impact these processes and thereby have anti-aging properties. The primary mechanisms through which exercise confers protective benefits in the brain are still incompletely understood. To better understand these effects and leverage them to help promote brain health, we present current findings supporting the notion that adaptive responses to exercise play a pivotal role in mitigating the hallmarks of aging and their effects on the aging cerebrovasculature, and ultimately contribute to the maintenance of brain function across the health span.

Keywords: brain; cardiorespiratory fitness; cognition; hallmarks of aging

DOI: https://doi.org/10.1093/gerona/glae083

J Orthop Translat. 2024 Mar;45 56-65

Mechanisms and therapeutic strategies for senescence-associated secretory phenotype in the intervertebral disc degeneration microenvironment.

Yang Liu, Yiming Dou, Xun Sun, Qiang Yang.

As a permanent state of cell cycle arrest, cellular senescence has become an important factor in aging and age-related diseases. As a central regulator of physiology and pathology associated with cellular senescence, the senescence associated secretory phenotype can create an inflammatory and catabolic environment through autocrine and paracrine ways, ultimately affecting tissue microstructure. As an age-related disease, the correlation between intervertebral disc degeneration and cellular senescence has been confirmed by many studies. Various pathological factors in the microenvironment of intervertebral disc degeneration promote senescent cells to produce and accumulate and express excessive senescence associated secretory phenotype. In this case, senescence associated secretory phenotype has received considerable attention as a potential target for delaying or treating disc degeneration. Therefore, we reviewed the latest research progress of senescence associated secretory phenotype, related regulatory mechanisms and intervertebral disc cell senescence treatment strategies. It is expected that further understanding of the underlying mechanism between cellular senescence pathology and intervertebral disc degeneration will help to formulate reasonable senescence regulation strategies, so as to achieve ideal therapeutic effects.
The translational potential of this article: Existing treatment strategies often fall short in addressing the challenge of repairing intervertebral disc Intervertebral disc degeneration（IVD） degeneration. The accumulation of senescent cells and the continuous release of senescence-associated secretory phenotype (SASP) perpetually impede disc homeostasis and hinder tissue regeneration. This impairment in repair capability presents a significant obstacle to the practical clinical implementation of strategies for intervertebral disc degeneration. As a result, we present a comprehensive overview of the latest advancements in research, the associated regulatory mechanisms, and strategies for treating SASP in IVD cells. This article aims to investigate effective interventions for delaying the onset and progression of age-related intervertebral disc degeneration. In an era where the aging population is becoming increasingly prominent, this endeavor holds paramount practical and translational significance.

Keywords: Cell senescence; Intervertebral disc degeneration; SASP; Senotherapeutics

DOI: https://doi.org/10.1016/j.jot.2024.02.003

Aging Cell. 2024 Mar 17. e14145

MicroRNA-7 deficiency ameliorates d-galactose-induced aging in mice by regulating senescence of Kupffer cells.

Ya Wang, Hui Qiu, Shipeng Chen, Dongmei Li, Xu Zhao, Mengmeng Guo, Nana Li, Chao Chen, Ming Qin, Ya Zhou, Daimin Xiao, Juanjuan Zhao, Lin Xu.

Aging is intricately linked to immune system dysfunction. Recent studies have highlighted the biological function of microRNA-7 (miR-7) as a novel regulator of immune cell function and related diseases. However, the potential role of miR-7 in aging remains unexplored. Here, we investigated the contribution of miR-7 to d-gal-induced aging in mice, focusing on its regulation of senescent Kupffer cells. Our findings revealed that miR-7 deficiency significantly ameliorated the aging process, characterized by enhanced CD4+ T-cell activation. However, the adoptive transfer of miR-7-deficient CD4+ T cells failed to improve the age-related phenotype. Further analysis showed that miR-7 deficiency significantly reduced IL-1β production in liver tissue, and inhibiting IL-1β in vivo slowed down the aging process in mice. Notably, IL-1β is mainly produced by senescent Kupffer cells in the liver tissue of aging mice, and miR-7 expression was significantly up-regulated in these cells. Mechanistically, KLF4, a target of miR-7, was down-regulated in senescent Kupffer cells in aging mouse model. Furthermore, miR-7 deficiency also modulated the NF-κB activation and IL-1β production in senescent Kupffer cells through KLF4. In conclusion, our findings unveil the role of miR-7 in d-gal-induced aging in mice, highlighting its regulation of KLF4/NF-κB/IL-1β pathways in senescent Kupffer cells. This research may enhance our understanding of miRNA-based aging immune cells and offer new avenues for new intervention strategies in aging process.

Keywords: IL-1β; KLF4; aging; microRNA-7; senescent Kupffer cells

DOI: https://doi.org/10.1111/acel.14145

Biophys Rep. 2023 Oct 31. 9(5): 232-240

An efficient protocol for studying human pluripotent stem cell-derived myotube senescence.

Qian Zhao, Ying Jing, Shuai Ma, Weiqi Zhang, Jing Qu, Si Wang, Guang-Hui Liu.

Sarcopenia, an age-related skeletal muscle condition characterized by a progressive decline in muscle mass and function, is linked to increased vulnerability, a higher likelihood of falls, and higher mortality rates in older individuals. A comprehensive understanding of the intricate mechanisms driving skeletal muscle aging is of great significance in both scientific and clinical fields. Consequently, myotube models that facilitate studying regulatory mechanisms underlying skeletal muscle aging are important tools required to advance intervention strategies against skeletal muscle aging and associated disorders. Here, we provide a detailed protocol to generate human pluripotent stem cells-derived myotubes and describe their applications in aging studies, as well as a troubleshooting for potential problems. Overall, this protocol serves as a valuable methodological reference for exploring the role and mechanism of genes involved in skeletal muscle aging.

Keywords: Differentiation; Human pluripotent stem cell; In vitro; Myotube; Senescence

DOI: https://doi.org/10.52601/bpr.2023.230013