Mikhail (Misha) V. Blagosklonny, MD, PhD, has been appointed Member/Professor of Oncology at Roswell Park Cancer Institute, Buffalo, NY. His appointment started April 15, 2009. Dr. Blagosklonny is an author of over 170 research articles, reviews and book chapters. He is Founding Editor and Editor-in-Chief of Cell Cycle and also Associate Editor of Cancer Biology & Therapy, Cancer Research, Cell Death & Differentiation, Autophagy, International Journal of Cancer, American Journal of Pathology, and PLOS ONE. His research interests range from molecular and cellular biology to clinical investigations and include signal transduction, cell cycle, cellular senescence, anticancer therapeutics with emphasis on translation of basic science into new anticancer strategies. He extended the study of signal transduction pathways from cancer to aging, revealing potential targets for slowing down aging and age-related diseases. “Misha is a pre-eminent researcher, who developed unique concepts in cancer biology and therapy ,” according to Andrei V. Gudkov, Senior Vice-President of Basic Science at Roswell Park and Chairman of the Department of Cell Stress Biology. “The presence of Misha will facilitate the development of new anti-cancer strategies and methods of cancer therapy and prevention. Here at Roswell, we are very enthusiastic about his recruitment. We share numerous ideas and approaches, including protection of normal cells from radio- and chemotherapy, selective combinations of anticancer drugs, tissue-specific therapy (anti-tissue therapy) of cancer, and prevention of cancer by slowing down organismal aging”.
Cellular senescence happens in 2 steps: cell cycle arrest followed, or sometimes preceded, by gerogenic conversion (geroconversion). Geroconvesrion is a form of growth, a futile growth during cell cycle arrest. It converts reversible arrest to irreversible senescence. Geroconversion is driven by growth-promoting, mitogen-/nutrient-sensing pathways such as mTOR. Geroconversion leads to hyper-secretory, hypertrophic and pro-inflammatory cellular phenotypes, hyperfunctions and malfunctions. On organismal level, geroconversion leads to age-related diseases and death. Rapamycin, a gerosuppressant, extends life span in diverse species from yeast to mammals. Stress-and oncogene-induced accelerated senescence, replicative senescence in vitro and life-long cellular aging in vivo all can be described by 2-step model.
The United States Patent Office has made an official policy of refusing to grant patents for perpetual motion machines (perpetuum mobile) without a working model. Should we adopt a similar policy for manuscripts claiming that aging is caused by molecular damage by any means such as free radicals, radiation, and errors during normal molecular processes? Is the time ripe? Although thousands of publications suggest that aging is caused by damage, mostly by free radicals, an increasing body of evidence rules out accumulation of random molecular damage as a cause of aging.
11. Blagosklonny MV. Cell Cycle 2006; 5:2087 - 102; http://dx.doi.org/10.4161/cc.5.18.3288; PMID: 17012837 [Taylor & Francis Online], [PubMed], [Web of Science ®] View all references-77. Blagosklonny MV. Aging (Albany NY) 2012; 4:861 - 77; PMID: 23425777 [PubMed] View all references And it does not matter how many publications are (seemingly) in agreement with the prevailing dogma: it is the evidence against it that counts. And where are studies showing that prevention of damage extends lifespan (an equivalent of “a working model”)? Most studies represent just wishful interpretations of ambivalent data. Consider a prototypical example. Radiation of rats (or their brains) caused damage, overwhelmed repair, increased free radicals, activated signal transduction pathways, and so on. Furthermore, such rats live a shorter life. Is that the evidence for damage-induced aging? Certainly not! Sure enough, if investigators would shoot rats with rifles or guns, rats would have a shorter lifespan. But we all agree that rifles are not a cause of our aging. There are a billion ways to shorten lifespan and impair health, which have nothing to do with aging: from mutations of blood-clotting factors and lamin to vitamin deficiency and famine. Examples with radiation and rifles are obvious. But they can be more subtle. Calorie restriction and inhibition of the insulin pathway increase lifespan. Yet, these interventions may not extend lifespan in the absence of a particular transcription factor. Does this mean that this transcription factor is involved in aging? Not always. Imagine if an investigator would shoot a rifle at a calorie-restricted animal… Yes, then calorie restriction will not extend lifespan. Still, we all agree that rifles are not involved in aging. In contrast, an intervention that increases lifespan is important in its own right, albeit even in this case it might be unrelated to aging. For example, medical interventions such as coronary stents and defibrillation can greatly extend human lifespan without affecting aging. These interventions increase aging tolerance, namely the ability to survive despite the aging process, such as atherosclerosis.
77. Blagosklonny MV. Aging (Albany NY) 2012; 4:861 - 77; PMID: 23425777 [PubMed] View all references In contrast, calorie restriction and rapamycin can extend lifespan by slowing down aging, preventing atherosclerosis. Inhibition of components of the MTOR (mechanistic target of rapamycin) pathway prevents cellular conversion from quiescence to senescence (geroconversion) and extends lifespan in yeast, worm, flies, and mice. In worm, knockout of PI3K (an activator of MTOR) extends lifespan 10-fold.
88. Ayyadevara S, et al.. Aging Cell 2008; 7:13 - 22; http://dx.doi.org/10.1111/j.1474-9726.2007.00348.x; PMID: 17996009 [CrossRef], [PubMed], [Web of Science ®] View all references So partial, or complete, inactivation of aging-promoting genes (gerogenes) increases lifespan. There is a second sign indicating that life-extending intervention is in fact due to slowing down aging. Genuine anti-aging interventions must be harmful early in life during the growth phase of the organism.
77. Blagosklonny MV. Aging (Albany NY) 2012; 4:861 - 77; PMID: 23425777 [PubMed] View all references Gerogenes are beneficial in young animals, at the cost of aging later in life. For example, MTOR is essential, and its knockout is lethal in mouse embryos. Definitely, treatment with rapamycin and calorie restriction is unfavorable during organismal growth. And knockout of PI3K in worm slows development, so that such a worm would not survive in the wild. Only laboratory conditions allowed us to detect the tremendous life extension later in life. On the other hand, everything that is harmful from day 1 (radiation or mutated lamin) cannot be a cause of aging.
77. Blagosklonny MV. Aging (Albany NY) 2012; 4:861 - 77; PMID: 23425777 [PubMed] View all references
The view that aging is caused by accumulated damage is very intuitive, because everything around us accumulates damage. Still, many aspects do not fit precisely this intuition, and, oddly enough, the damage theory suggests that these cases are programmed for a purpose. One famous misconception is that death is programmed in Pacific salmon (in reality, it is quasi-programmed). Menopause is thought to be programmed to benefit grandchildren. In reality, menopause is a clear cut aging-related disease, which has no adaptive value.
77. Blagosklonny MV. Aging (Albany NY) 2012; 4:861 - 77; PMID: 23425777 [PubMed] View all references Aging and its obligatory manifestations, namely age-related diseases, are not programmed but quasi-programmed. A quasi-program is a harmful, useless, aimless, unintended continuation of organismal growth programs, driven in part by MTOR.
77. Blagosklonny MV. Aging (Albany NY) 2012; 4:861 - 77; PMID: 23425777 [PubMed] View all references Similarly, cellular aging is a continuation of cellular growth driven by MTOR (and other gerogenic pathways) and manifested by increased cellular functions (hyperfunctions), leading to alterations of homeostasis and age-related diseases, which, in turn, lead to damage: not molecular damage but instead non-random organ damage.
77. Blagosklonny MV. Aging (Albany NY) 2012; 4:861 - 77; PMID: 23425777 [PubMed] View all references Importantly, pharmacological inhibitors of gerogenic pathways are available. Most importantly, some of them, like rapamycin and metformin, are clinically approved, well-tolerated drugs. Thus, the notion that aging is driven by growth-promoting (gerogenic) signaling pathways has already yielded anti-aging drugs. Today is not the day to discuss competing theories. This is the past. The real arena now is clinical applications of rapalogs (e.g., rapamycin) and other gerosuppressants to prevent age-related diseases and extend healthy lifespan.
99. Blagosklonny MV. Aging (Albany NY) 2012; 4:547 - 52; PMID: 22915707 [PubMed] View all references And on this arena a fierce competition is just started.
This article discusses that the traditional analogy of an aging organism with a rusting (albeit self-repairing) car is misleading. The true analogy is a speeding car that enters a low-speed zone and damages itself because it does not and cannot slow down. For such a car without brakes (and actually without a driver), aging from rusting never occurs. Using simple analogies (although turning gerontology upside down), this article discusses the origin of aging, how overactivation of the mTOR (Target of Rapamycin) pathway causes aging, why aging causes damage (organ damage) not damage causes aging, the link between aging and age-related diseases, slow aging versus aging tolerance and suppression of aging with rapamycin.
The Gotham Prize was awarded to Alex Varshavsky for "Targeting the absence", a strategy employing negative targets of cancer therapy. This is a brilliant example of therapeutic engineering: designing a sequence of events that leads to the selective killing of one type of cell, while sparing all others. A complex molecular device ( Varshavsky's Demon) examines DNA, recognizes the present target in normal cells and kills cancer cells. The strategy is limited by the delivery ( transfection or infection) of DNA-based devices into each cell of our body. How can we overcome this limitation? Can therapeutic engineering be applied to small drugs? Can each small molecule reach a cell separately and, once in a cell, exert orchestrated action governed by cellular context? Here I describe how a combination of small drugs can acquire a demonic power to check, choose and selectively kill. The cytotoxicity is restricted to cells lacking ( or having) one of the targets. For example, in the presence of a normal target, one drug can cancel the cytotoxic action of another drug. And by increasing a number of targets, we can increase the precision and power of such 'restrictive' combinations. Here I discuss restrictive combinations of currently available drugs that could be tested in clinical trials. Could then these combinations cure cancer today? And what does 'cure' really mean? This article suggests the answer.