Chronological lifespan in stationary culture: from yeast to human cells. Zoya N. Demidenko

Chronological lifespan in stationary culture: from yeast to human cells

A decade ago, Mikhail Blagosklonny predicted that cellular senescence is driven by mitogenic pathways, when the cell cycle is blocked and actual growth is impossible [1]. In particular, the mitogen- and nutrientsensing mTOR (Target of Rapamycin) pathway drives either cell mass growth or aging [2]. Rapamycin prevents conversion of reversible cell cycle arrest to senescence [3-11]. When the cell cycle is blocked, but mTOR is still active, then cells become senescent. This process was named gerogenic conversion or simply geroconversion [12]. Rapamycin did not by-pass arrest but suppress geroconversion. Cells remained resting but not senescent. The discovery of mTOR-dependent geroconversion allowed Blagosklonny to connect cellular aging to age-related diseases and organismal aging [13, 14]. Furthermore, this predicted that rapamycin is a gerosuppressant, which could be used to prevent age-related diseases by slowing down the aging process [14]. Independently, it was discovered that rapamycin suppresses chronological aging of yeast cells [15]. Chronological lifespan of yeast cells in stationary culture is the most fruitful model in aging research and dozens of papers have been published in Nature, Science, Cell and Cell Cycle. Although yeast model was so useful to identify genes involved in mammalian aging, the reason remained unclear. Yeast only loosely resemble post-mitotic cells in human tissues. Unfortunately, there was no model of mammalian chronological aging in cell culture. In one model developed by Fabrizio and Valter Longo [16] as well as by Matt Kaeberlein and Brian K. Kennedy [17], yeast chronological senescence (CS) is caused by acidosis due to overproduction of acetic acid. Obviously, neither replicative nor accelerated senescence of human cells resembles yeast CS in the stationary culture. Surprisingly, the exact replica was so well known and so trivial that it was overlooked by decades. Here Leontieva and Blagosklonny describe the mammalian cellular model: a neglected flask with overgrown cancer cells that turn medium “yellow” (due to lactate accumulation). Such flasks left and forgotten over weekend could be found in any CO2-incubator. The paper is simultaneously startling and obvious. It is obvious from an everyday experience that highly glycollytic cells can destroy cell culture. But like it was known to most researches (90 years ago) that fungi can destroy bacterial culture, it took a special insight to recognize the potential of this seemingly useless phenomenon. There is an intriguing parallel between penicillin and rapamycin. As described in this issue of Aging, mTOR pathway is involved in glycolytic phenotype, causing self-poisoning due to overproduction of lactic acid. By decreasing lactate production, rapamycin prevents chronological senescence (CS). CS can be manipulated genetically and pharmacologically. Most importantly, the same agents that suppress geroconversion, organismal aging and cancer also suppress CS. This study does not break any dogma because there was no dogma as the field did not exist. This paper opens a new filed in both aging and cancer research. Blagosklonny and collaborators are currently preparing follow-up papers with special emphasis to cancer research: the ability of rapamycin to decrease lactate production independently of respiration, selection of highly glycolytic cancer cell clones, tumor progression and resistance to therapy. Many questions will be answered. But this first paper defines the field, providing description of the phenomenon, its mechanism and the ways of pharmacological manipulation. It illuminates the place of yeast CS in aging research and its indirect (via common signaling pathways) relevance to cancer and organismal aging. It also rules out altruistic (programmed) aging of yeast because no one would suspect altruistic nature of cancer cells. I invite the readers to enjoy this first paper in the filed of mammalian cell chronological senescence.

oncotarget submission Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko , Ph.D. is Executive Manager of the Oncotarget journal . Oncotarget publishes high-impact research papers of general interest and outstanding significance and novelty in all areas of biology and medicine: in translational, basic and clinical research including but not limited to cancer research, oncogenes, oncoproteins and tumor suppressors, signaling pathways as potential targets for therapeutic intervention, shared targets in different diseases (cancer, benign tumors, atherosclerosis, eukaryotic infections, metabolic syndrome and other age-related diseases), chemotherapy, and new therapeutic strategies. After earning her Ph.D. in molecular biology, Zoya was awarded a Fogarty post-doctoral Fellowship from the National Institutes of Health in Bethesda, MD. After successful completion of post-doctoral training, she continued her professional career at George Washington University and Albert Einstein School of Medicine . In 2005 she cofounded the startup company Oncotarget Inc. which is focused on the development of anti-aging and anti-cancer drugs. Her research interests include signal transduction, cell cycle and cellular senescence, and their pharmacological targeting. In 2009 she cofounded the publishing house Impact Journals which specializes in publishing scientific journals. In 2011 she was selected to be a Member of the National Association of Professional Women .
https://www.semanticscholar.org/author/Zoya-N.-Demidenko/4772760


oncotarget impact factor 2021
When public mention today’s medicine, accuracy plays one of the most important roles and human lives are literally dependent on it. Hence, any researches pertaining to medicine are required to comply with the highest standards. The problem today is that any outcomes of researches can be posted online and used as a reference without being properly verified and validated. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this challenge and attempted to generate an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been founded back in 2010. The key principle of this journal is related to Altmetric scores that are used as a quality indicator. That assists both readers and authors to quality-check publications with Altmetric Article Reports that provide “real-time feedback containing data summary related to a particular publication.” Oncotarget website provides a full publications list with respective scores higher than 100 as well as reports discussed previously. Mikhail (Misha) Blagosklonny proud to share his new approach and hopes it creates the necessary assistance to anybody, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This article was published back in 2018 by Oncotarget and completed by different experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study mentions that “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and provides an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The publication has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that most of readers are aiming to understand the very meaning of it. Based on the Altmetric website, the score indicates “how many people have been exposed to and engaged with a scholarly output.” Hence, the publication about melanoma, was utilized for citations in different news articles 69 times. Moreover, it was mentioned in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their report on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study 
Another Oncotarget’s research with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This research has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have seen a concise overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do receive helpful scientific facts. Oncotarget is glad to have the chance to share with online readers this highly appreciated and top-quality information, that is trustworthy and reliable.
http://www.impactjournals.com/oncoscience/index.php?abs=14

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