bims-caglex 2024-06-23 papers

J Eur Acad Dermatol Venereol. 2024 Jul;38 Suppl 4 5-14

Looking for the philosopher's stone: Emerging approaches to target the hallmarks of aging in the skin.

Senescence and epigenetic alterations are two important hallmarks of cellular aging. During aging, cells subjected to stress undergo many cycles of damage and repair before finally entering either apoptosis or senescence, a permanent state of cell cycle arrest. The first biomarkers of senescence to be identified were increased ß-galactosidase activity and induction of p16INK4a. Another feature of senescent cells is the senescence-associated secretory phenotype (SASP), a complex secretome containing more than 80 pro-inflammatory factors including metalloproteinases, growth factors, chemokines and cytokines. The secretome is regulated through a dynamic process involving a self-amplifying autocrine feedback loop and activation of the immune system. Senescent cells play positive and negative roles depending on the composition of their SASP and may participate in various processes including wound healing and tumour suppression, as well as cell regeneration, embryogenesis, tumorigenesis, inflammation and finally aging. The SASP is also a biomarker of age, biological aging and age-related diseases. Recent advances in anti-age research have shown that senescence can be now prevented or delayed by clearing the senescent cells or mitigating the effects of SASP factors, which can be achieved by a healthy lifestyle (exercise and diet), and senolytics and senomorphics, respectively. An alternative is tissue rejuvenation, which can be achieved by stimulating aged stem cells and reprogramming deprogrammed aged cells. These non-clinical findings will open up new avenues of clinical research into the development of treatments capable of preventing or treating age-related pathologies in humans.

DOI: https://doi.org/10.1111/jdv.19820

Adv Sci (Weinh). 2024 Jun 17. e2401012

β-Galactosidase-Triggered Photodynamic Elimination of Senescent Cells with a Boron Dipyrromethene-Based Photosensitizer.

Jacky C H Chu, Blanca Escriche-Navarro, Junlong Xiong, Alba García-Fernández, Ramón Martínez-Máñez, Dennis K P Ng.

Senescence is a cellular response having physiological and reparative functions to preserve tissue homeostasis and suppress tumor growth. However, the accumulation of senescent cells would cause deleterious effects that lead to age-related dysfunctions and cancer progression. Hence, selective detection and elimination of senescent cells are crucial yet remain a challenge. A β-galactosidase (β-gal)-activated boron dipyrromethene (BODIPY)-based photosensitizer (compound 1) is reported here that can selectively detect and eradicate senescent cells. It contains a galactose moiety connected to a pyridinium BODIPY via a self-immolative nitrophenylene linker, of which the photoactivity is effectively quenched. Upon interactions with the senescence-associated β-gal, it undergoes enzymatic hydrolysis followed by self-immolation, leading to the release of an activated BODIPY moiety by which the fluorescence emission and singlet oxygen generation are restored. The ability of 1 to detect and eliminate senescent cells is demonstrated in vitro and in vivo, using SK-Mel-103 tumor-bearing mice treated with senescence-inducing therapy. The results demonstrate that 1 can be selectively activated in senescent cells to trigger a robust senolytic effect upon irradiation. This study breaks new ground in the design and application of new senolytic agents based on photodynamic therapy.

Keywords: boron dipyrromethene; photodynamic therapy; senescent cells; singlet oxygen; β‐galactosidase

DOI: https://doi.org/10.1002/advs.202401012

Foods. 2024 May 27. pii: 1673. [Epub ahead of print]13(11):

Rosa roxburghii Fruit Extracts Upregulate Telomerase Activity and Ameliorate Cell Replicative Senescence.

Yan Huang, Haoyue Peng, Yifan Wu, Shengcheng Deng, Fahuan Ge, Wenbin Ma, Xue Zhou, Zhou Songyang.

Anti-aging functional foods benefit the elderly. Telomeres are chromosomal ends that maintain genome stability extended by telomerase catalytic subunit TERT. Due to the end-replication problem, telomeres shorten after each cell cycle without telomerase in most human cells, and eventually the cell enters the senescence stage. Natural products can attenuate the aging process by increasing telomerase activity, such as TA-65. However, TA-65 is expensive. Other Chinese natural products may achieve comparable effects. Here, we found that Rosa roxburghii fruit extracts effectively increase TERT expression and telomerase activity in cultured human mesenchymal stem cells. Both R. roxburghii fruit extracts obtained by freeze-drying and spray-drying increased the activity of telomerase. R. roxburghii fruit extracts were able to reduce reactive oxygen species levels, enhance superoxide dismutase activity, and reduce DNA damage caused by oxidative stress or radiation. R. roxburghii fruit extracts promoted cell proliferation, improved senescent cell morphology, delayed replicative cellular senescence, attenuated cell cycle suppressors, and alleviated the senescence-associated secretory phenotype. Transcriptome and metabolic profiling revealed that R. roxburghii fruit extracts promote DNA replication and telomere maintenance pathways and decrease triglyceride levels. Overall, we provide a theoretical basis for the application of R. roxburghii fruit as an anti-aging product.

Keywords: Rosa roxburghii fruit; cell senescence; telomerase

DOI: https://doi.org/10.3390/foods13111673

Science. 2024 Jun 21. 384(6702): 1300-1301

Cellular senescence in normal physiology.

João Pedro de Magalhães.

Long associated with aging, senescent cells can promote health and have physiological roles.

DOI: https://doi.org/10.1126/science.adj7050

Trends Mol Med. 2024 Jun 17. pii: S1471-4914(24)00134-5. [Epub ahead of print]

Senescence and tissue fibrosis: opportunities for therapeutic targeting.

Steven O'Reilly, Pei-Suen Tsou, John Varga.

Cellular senescence is a key hallmark of aging. It has now emerged as a key mediator in normal tissue turnover and is associated with a variety of age-related diseases, including organ-specific fibrosis and systemic sclerosis (SSc). This review discusses the recent evidence of the role of senescence in tissue fibrosis, with an emphasis on SSc, a systemic autoimmune rheumatic disease. We discuss the physiological role of these cells, their role in fibrosis, and that targeting these cells specifically could be a new therapeutic avenue in fibrotic disease. We argue that targeting senescent cells, with senolytics or senomorphs, is a viable therapeutic target in fibrotic diseases which remain largely intractable.

Keywords: SASP; fibrosis; myofibroblasts; senescence; systemic sclerosis

DOI: https://doi.org/10.1016/j.molmed.2024.05.012

Nat Commun. 2024 Jun 18. 15(1): 5148

Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease.

Santiago E Sanchez, Yuchao Gu, Yan Wang, Anudeep Golla, Annika Martin, William Shomali, Dirk Hockemeyer, Sharon A Savage, Steven E Artandi.

Telomere length is an important biomarker of organismal aging and cellular replicative potential, but existing measurement methods are limited in resolution and accuracy. Here, we deploy digital telomere measurement (DTM) by nanopore sequencing to understand how distributions of human telomere length change with age and disease. We measure telomere attrition and de novo elongation with up to 30 bp resolution in genetically defined populations of human cells, in blood cells from healthy donors and in blood cells from patients with genetic defects in telomere maintenance. We find that human aging is accompanied by a progressive loss of long telomeres and an accumulation of shorter telomeres. In patients with defects in telomere maintenance, the accumulation of short telomeres is more pronounced and correlates with phenotypic severity. We apply machine learning to train a binary classification model that distinguishes healthy individuals from those with telomere biology disorders. This sequencing and bioinformatic pipeline will advance our understanding of telomere maintenance mechanisms and the use of telomere length as a clinical biomarker of aging and disease.

DOI: https://doi.org/10.1038/s41467-024-49007-4