BUFFALO, NY- July 17, 2024 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 13, entitled, “Modulating in vitro lung fibroblast activation via senolysis of senescent human alveolar epithelial cells.”

Idiopathic pulmonary fibrosis (IPF) is an age-related disease with poor prognosis and limited therapeutic options. Activation of lung fibroblasts and differentiation to myofibroblasts are the principal effectors of disease pathology, but damage and senescence of alveolar epithelial cells, specifically type II (ATII) cells, has recently been identified as a potential trigger event for the progressive disease cycle. Targeting ATII senescence and the senescence-associated secretory phenotype (SASP) is an attractive therapeutic strategy; however, translatable primary human cell models that enable mechanistic studies and drug development are lacking.

In this new study, researchers Joseph S. Spina, Tracy L. Carr, Lucy A. Phillips, Heather L. Knight, Nancy E. Crosbie, Sarah M. Lloyd, Manisha A. Jhala, Tony J. Lam, Jozsef Karman, Meghan E. Clements, Tovah A. Day, Justin D. Crane, and William J. Housley from AbbVie Bioresearch Center and Northeastern University describe a novel system of conditioned medium (CM) transfer from bleomycin-induced senescent primary alveolar epithelial cells (AEC) onto normal human lung fibroblasts (NHLF) that demonstrates an enhanced fibrotic transcriptional and secretory phenotype compared to non-senescent AEC CM treatment or direct bleomycin damage of the NHLFs. 

“In the current study, we confirm the presence of senescent cell populations within the human IPF lung, as well as assess primary cell reagents for sensitivity to senescent cell targeting therapies.”

In this system, the bleomycin-treated AECs exhibited classical hallmarks of cellular senescence, including SASP and a gene expression profile that resembles aberrant epithelial cells of the IPF lung. Fibroblast activation by CM transfer was attenuated by pre-treatment of senescent AECs with the senolytic Navitoclax and AD80, but not with the standard of care agent Nintedanib or senomorphic JAK-targeting drugs (e.g., ABT-317, ruxolitinib). This model provided a relevant human system for profiling novel senescence-targeting therapeutics for IPF drug development.

“Taken together, the model described herein provides a physiologically relevant, primary human cell system to study the effects of alveolar epithelial cell senescence on lung fibroblasts in the context of chronic fibrotic lung disease.”

DOI - https://doi.org/10.18632/aging.205994

Corresponding author - Tovah A. Day - t.day@northeastern.edu

Video short - https://www.youtube.com/watch?v=rpmo2PlGDKc

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About Aging-US

The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population.

The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.)

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Aging (Aging-US)

Modulating Lung Fibroblast Activation via Senolysis of Senescent Human Alveolar Epithelial Cells

BUFFALO, NY- January 22, 2025 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) on December 12, 2024, Volume 16, Issue 22, titled “Arginase-II gene deficiency reduces skeletal muscle aging in mice.”

Researchers Matteo Caretti, Duilio Michele Potenza, Guillaume Ajalbert, Urs Albrecht, Xiu-Fen Ming, Andrea Brenna, and Zhihong Yang from the University of Fribourg found that removing a specific gene, called arginase-II (Arg-II), can slow down muscle aging in mice. Their research showed that older mice lacking this gene stayed more active and had healthier skeletal muscles compared to normal aging mice. This discovery could lead to new treatments to help people maintain muscle strength and mobility as they become older.

As people age, their muscles naturally get weaker, leading to reduced physical activity and overall quality of life. This condition, known as sarcopenia, occurs because of muscle fiber loss, inflammation, and scar tissue buildup. The study found that the Arg-II gene contributes to this process.

The research team compared normal mice with mice lacking the Arg-II gene and discovered that in general, the mice without the gene had improved muscle health, reduced inflammation, and fewer signs of age-related muscle decline. It was also found that older male mice deficient in the Arg-II gene were more active, particularly during their peak nighttime activity. These mice had stronger muscles and performed better in physical tests. Interestingly, the benefits of Arg-II gene removal were more pronounced in male mice compared to females, suggesting that hormonal or genetic differences might play a role in age-related muscle loss.

“The improved phenotype of arg-ii-/- mice in aging is associated with reduced sarcopenia, cellular senescence, inflammation, and fibrosis, whereas age-associated decline of microvascular endothelial cell density, satellite cell numbers, and muscle fiber types in skeletal muscle is prevented in arg-ii-/- mice.”

ARG-II protein was not found in muscle fibers but instead in surrounding cells such as fibroblasts and blood vessel cells, which makes scientists believe this gene influences muscle aging indirectly. Independently of that, the findings suggest that targeting the Arg-II gene could help slow down age-related muscle deterioration and improve muscle function in older adults. 

"[...] we demonstrate an increased arg-ii gene expression level in aging skeletal muscle and found Arg-II protein expression in endothelial cells and fibroblasts, but not in skeletal muscle fibers, macrophages, and satellite cells."​

While these results are promising, further research is needed to determine whether blocking the Arg-II gene in humans could provide similar benefits. Furthermore, understanding why male and female mice responded differently to the gene removal will be essential before personalized treatments for age-related muscle loss. If future studies confirm these findings in humans, targeting Arg-II could become a valuable strategy to help adults maintain muscle strength, mobility, and overall quality of life as they age.

DOI - https://doi.org/10.18632/aging.206173

Corresponding authors - Andrea Brenna - andrea.brenna@unifr.ch, and Zhihong Yang - zhihong.yang@unifr.ch

Video short - https://www.youtube.com/watch?v=uDxSCO2Y7-w

About Aging-US

The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population.

The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.)

Please visit our website at https://www.Aging-US.com​​.

MEDIA@IMPACTJOURNALS.COM

Arginase-II Deficiency Slows Skeletal Muscle Aging in Mice

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The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population.

The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.)

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