Lifestyle vs. pharmacological interventions for healthy aging

The fountain of youth, the elixir of life, the Philosopher’s stone, or an analogous mythical object to remedy the scourges of aging, has been sought after throughout the history of humankind, up to the present day. In modern times, inventing a drug that prevents the aging-linked decline in organ function, expands the years of life spent in good health, or even increases lifespan promises fame and fortune for the discoverer. Vitamins, anti-oxidants, resveratrol and other alleged sirtuin activators, caloric restriction, nicotinamide adenine dinucleotide (NAD+) and its biosynthetic precursors, young blood and growth and differentiation factor 11 (GDF 11), senolytics, rapamycin and rapalogs, metformin as well as numerous other compounds and treatments all were (or still are) considered as the magic bullet for “anti-aging” effects in the last couple of years [1]. However, for most, if not all of them, preclinical results in animal models were difficult to translate to humans, unexpected adverse effects in animals or humans were reported, and/or clinical trials showing any efficacy in healthy young and old individuals are still elusive [1]. Importantly, aging per se is not recognized as a disease, and so-called “anti-aging” effects are often difficult to disentangle from disease prevention. For example, it is not entirely clear whether the beneficial outcome of caloric restriction in non-human primates is due to a reduction of numerous diseases observed in control-fed primates (whatever control levels mean in a laboratory context for these animals), or if true “anti-aging” effects were achieved [2]. In stark contrast to the currently proposed putative “anti-aging” drugs, a combination of various lifestyle-based approaches clearly achieves the best epidemiological risk profile for healthy aging, with minimal or no adverse effects (Figure 1). Moreover, some of these approaches, for example exercise training, are not only highly efficient in preventing certain chronic diseases, but also in the treatment of numerous pathologies [3]. However, the molecular basis of the health beneficial effect of exercise remains largely enigmatic. For example, novel protective pathways elicited by exercise training, e.g. via the effect of the central regulator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) on mitochondrial calcium handling, endoplasmic reticulum stress, tubular aggregates and cell death in old muscle, highlight the complexity of the training response and some of the consequences for muscle aging in sedentary or active individuals [4]. In fact, exercise remains the only currently available intervention to mitigate, and even reverse the age-related decline in muscle mass and function, known as sarcopenia. As in other diseases, the usage of anabolic steroids and growth hormones for the treatment of sarcopenia has largely failed, due to lack of efficacy in non-replacement therapies and unacceptable adverse effects. Moreover, since the molecular underpinnings of the etiology and progression of sarcopenia are unknown, a more targeted pharmacological intervention remains elusive. In recent years, the controversial concept of designing and deploying so-called exercise “mimetics”, pharmacological compounds that induce effects similar to those observed after bona fide training, has gained traction to circumvent the inherent problem of insufficient mechanistic knowledge [5]. The ongoing broad discussion about exercise “mimetics” to a large extent mirrors that about potential “anti-aging” drugs. In both fields, it is difficult to reconcile how pharmacological modulation of specific pathways would address the complex, pleiotropic, multi-faceted and systemic plasticity observed in exercise adaptation and the aging process, respectively [6]. Intriguingly, besides the overlap in some compounds proposed to work as exercise, caloric restriction “mimetics” and “anti-aging” drugs, such as resveratrol [5], other compounds exert seemingly diametrically opposite effects. For example, the anti-anabolism elicited by putative “anti-aging” drugs such as rapamycin, or the inhibition of insulin and insulin-like growth factor signaling in experimental models, are opposed to the anabolic action that is desired in exercise in general, but most particularly in resistance training. Indeed, the activity of the mammalian target of rapamycin complex 1 (mTORC1) is elevated in resistance-trained muscle, and rapamycin efficiently blocks muscle hypertrophy in certain paradigms. Similarly, metformin and resveratrol impaired beneficial adaptations to endurance exercise in some trials, even though mechanistically, these two compounds could have been expected to initiate endurance training-like effects [1,5]. These observations emphasize the complexity of cellular and organismal adaptation to exercise and aging that impedes the development of pharmacological monotherapies. Thus, the next years will not only reveal whether promising preclinical results with such compounds will stand the test of time in human trials, but also indicate the compatibility with other interventions and treatments. However, as long as data about clinical efficacy and safety of exercise “mimetics” and “anti-aging” drugs are missing (and probably even beyond that), lifestyle-based interventions remain the mainstay approach to minimize the risk for diseases, reduce morbidity and mortality and most importantly, improve healthspan in aging [7]. The old adage “use it or lose it” should thus serve as a reminder that regular physical activity is directly and strongly linked to health in the young and the elderly [8].

Figure 1. How to age in a healthy manner. Examples of behavioral and lifestyle aspects that reduce the risk for developing chronic diseases, help in mitigating pathological events, and decrease morbidity and mortality, thus collectively contributing to healthy aging. At the moment, it is unclear how a single or even multiple pharmacological agents can elicit a similar broad and complex response.

oncotarget impact factor
When general population speak of today’s medicine, precision plays one of the most important roles and people’s lives are literally dependent on it. Likewise, any researches related to medicine are necessary to meet the highest standards. The issue nowadays is that any outcomes of researches can be posted online and used as a reference without being thoroughly checked and approved. Mikhail (Misha) Blagosklonny of Oncotarget perfectly understood this issue and tried to come up with an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been founded back in 2010. The major principle of this journal is based on Altmetric scores that are used as a quality measure. That allows both readers and authors to verify publications with Altmetric Article Reports that create “real-time feedback containing data summary related to a particular publication.” Oncotarget website provides a full publications list with respective scores above 100 as well as reports discussed above. Mikhail (Misha) Blagosklonny glad to share his new approach and hopes it creates the required help to anybody, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This study was published back in 2018 by Oncotarget and completed by several 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 discusses “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 article has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that majority of readers are aiming to comprehend 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.” Likewise, the article about melanoma, was used for citations in various news articles 69 times. In addition, it was referred to in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their news on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study
Another Oncotarget’s study with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This article has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have seen a brief overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do get useful scientific facts. Oncotarget is proud to have the ability to share with online customers this highly appreciated and high-quality information, that is trustworthy and reliable.
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oncotarget Misha Blagosklonny
Mikhail (Misha) V. Blagosklonny graduated with an MD and PhD from First Pavlov State Medical University of St. Petersburg, Russia. Dr. Mikhail V. Blagosklonny has then immigrated to the United States, where he received the prestigious Fogarty Fellowship from the National Institutes of Health. During his fellowship in Leonard Neckers’ lab at the National Cancer Institute (NCI), he was a co-author of 18 publications on various biomedical themes, including targeting HSP90, p53, Bcl2, Erb2, and Raf-1. He also was the last author for a clinical phase I/II trial article.
After authoring seven papers during a brief yet productive senior research fellowship in the El-Deiry Cancer Research Lab at the University of Pennsylvania, Dr. Blagosklonny returned to NCI to work with Tito Fojo. Together, they published 26 papers. Moreover, Dr. Blagosklonny published many of experimental research papers and theoretical papers as sole author. The abovementioned sole-author articles discussed two crucial topics. The first of these discussed selectively killing cancer cells with deregulated cell cycle or drug resistance via verifying their resistance. The outcomes and underlying notion were so revolutionary that they were incorrectly cited by other scientists as “reversal of resistance,” even though the publication was titled, “Exploiting of drug resistance instead of its reversal.” One big supporter of this concept was the world-famous scientist Arthur Pardee, with whom Dr. Blagosklonny co-authored a joint publication in 2001.
The second theme throughout Dr. Blagosklonny’s sole-author articles is a research method to develop knowledge by bringing several facts together from seemingly irrelevant areas. This results in new notions with testable forecasts, which in turn can be “tested” via analyzing the literature further. Likewise, the concept was co-authored by Arthur Pardee in a 2002 article in Nature. The first success of the new research methodology was the description of the feedback regulation of p53, as confirmed by the discovery of mdm2/p53 loop; and the explanation why mutant p53 is always overexpressed, published in 1997. The most important result revealed by Dr. Blagosklonny’s research methodology is the hyperfunction (or quasi-programmed) theory of aging and the revelation of rapamycin as an exclusively well-tolerated anti-aging drug, published in 2006. As mentioned in Scientific American, Michael Hall, who discovered mTOR in 1991, gives Dr. Blagosklonny credit for “connecting dots that others can’t even see.”
In 2002, Dr. Blagosklonny became associate professor of medicine at New York Medical College. He agreed to accept responsibilities as a senior scientist at Ordway Research Institute in Albany, New York, in 2005, before receiving another position at Roswell Park Cancer Institute as professor of oncology in 2009.
Since coming to Roswell Park Comprehensive Cancer Center in 2009, Dr. Blagosklonny has studied the prevention of cancer (an age-related disease) via stopping organism aging - in other words, “preventing cancer via staying young.” His laboratory closely worked together with Andrei Gudkov’s and conducted research on the suppression of cellular senescence, namely suppression of cellular conversion from healthy quiescence to permanent senescence. This led to the discovery of additional anti-aging medicines beyond rapamycin. The cell culture studies were complemented by studies in mice, including several models like normal and aging mice, p53-deficient mice, and mice on a high-fat diet.
Dr. Blagosklonny has also published extensively on the stoppage of cellular senescence via rapamycin and other mTOR inhibitors, life extension and cancer stoppage in mice, and combinations of anti-aging medicines to be taken by humans. A rapamycin-based combination of seven clinically available medications has been named the “Koschei Formula” and is now used for the treatment of aging in patients at the Alan Green Clinic in Little Neck, New York.
https://www.scientificamerican.com/article/a-new-path-to-longevity/

oncotarget predatory 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 .
http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=2037