Roswell Park Cancer Institute

Buffalo, NY, United States

Roswell Park Cancer Institute

Buffalo, NY, United States
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Blagosklonny M.V.,Roswell Park Cancer Institute
Aging | Year: 2013

Making headlines, a thought-provocative paper by Neff, Ehninger and coworkers claims that rapamycin extends life span but has limited effects on aging. How is that possibly possible. And what is aging if not an increase of the probability of death with age. I discuss that the JCI paper actually shows that rapamycin slows aging and also extends lifespan regardless of its direct anti-cancer activities. Aging is, in part, MTOR-driven: a purposeless continuation of developmental growth. Rapamycin affects the same processes in young and old animals: young animals' traits and phenotypes, which continuations become hyperfunctional, harmful and lethal later in life. © Blagosklonny.


Cell cycle arrest is not yet senescence. When the cell cycle is arrested, an inappropriate growth-promotion converts an arrest into senescence (geroconversion). By inhibiting the growth-promoting mTOR pathway, rapamycin decelerates geroconversion of the arrested cells. And as a striking example, while causing arrest, p53 may decelerate or suppress geroconversion (in some conditions). Here I discuss the meaning of geroconversion and also the terms gerogenes, gerossuppressors, gerosuppressants, gerogenic pathways, gero-promoters, hyperfunction and feedback resistance, regenerative potential, hypertrophy and secondary atrophy, pro-gerogenic and gerogenic cells. © Blagosklonny.


Blagosklonny M.V.,Roswell Park Cancer Institute
Cell Cycle | Year: 2010

Although it has been known since 1917 that calorie restriction (CR) decelerates aging, the topic remains highly controversial. What might be the reason? Here I discuss that the anti-aging effect of CR rules out accumulation of DNA damage and failure of maintenance as a cause of aging. Instead, it suggests that aging is driven in part by the nutrient-sensing TOR (target of rapamycin) network. CR deactivates the TOR pathway, thus slowing aging and delaying diseases of aging. Humans are not an exception and CR must increase both maximal and healthy lifespan in humans to the same degree as it does in other mammals. Unlike mice, however, humans benefit from medical care, which prolongs lifespan despite accelerated aging in non-restricted individuals. Therefore in humans the effect of CR may be somewhat blunted. Still how much does CR extend human lifespan? And could this extension be surpassed by gerosuppressants such as rapamycin? © 2010 Landes Bioscience.


Blagosklonny M.V.,Roswell Park Cancer Institute
Aging | Year: 2012

Recent discoveries suggest that aging is neither driven by accumulation of molecular damage of any cause, nor by random damage of any kind. Some predictions of a new theory, quasi-programmed hyperfunction, have already been confirmed and a clinically-available drug slows aging and delays diseases in animals. The relationship between diseases and aging becomes easily apparent. Yet, the essence of aging turns out to be so startling that the theory cannot be instantly accepted and any possible arguments are raised for its disposal. I discuss that these arguments actually support a new theory. Are any questions remaining? And might accumulation of molecular damage still play a peculiar role in aging?. © Blagosklonny.


Blagosklonny M.V.,Roswell Park Cancer Institute
American Journal of Pathology | Year: 2012

Atherosclerosis, hypertension, obesity, diabetic complications, cancer, benign prostate hyperplasia, Alzheimer and Parkinson diseases, age-related macular degeneration, osteoarthritis, osteoporosis, and seborrheic keratosis are strongly associated with aging, implying a common underlying process. Each disease is treated separately and, in most cases, symptomatically. Suppression of aging itself should delay or treat all age-related diseases, thus increasing healthy life span and maximal longevity. But, is it possible to slow down aging? Recent evidence indicates that the target of rapamycin signaling pathway is involved in cellular senescence and organismal aging. Preclinical and clinical studies demonstrated the therapeutic effects of rapamycin in diverse age-related diseases. One simple reason why a single drug is indicated for so many age-related diseases is that it inhibits the aging process. © 2012 American Society for Investigative Pathology.


Blagosklonny M.V.,Roswell Park Cancer Institute
Cell Cycle | Year: 2013

Aging is not and cannot be programmed. Instead, aging is a continuation of developmental growth, driven by genetic pathways such as mTOR. Ironically, this is often misunderstood as a sort of programmed aging. In contrast, aging is a purposeless quasi-program or, figuratively, a shadow of actual programs. © 2013 Landes Bioscience.


Dy G.K.,Roswell Park Cancer Institute | Adjei A.A.,Roswell Park Cancer Institute
CA Cancer Journal for Clinicians | Year: 2013

Answer questions and earn CME/CNE Advances in genomics and molecular biology have identified aberrant proteins in cancer cells that are attractive targets for cancer therapy. Because these proteins are overexpressed or dysregulated in cancer cells compared with normal cells, it was assumed that their inhibitors will be narrowly targeted and relatively nontoxic. However, this hope has not been achieved. Current targeted agents exhibit the same frequency and severity of toxicities as traditional cytotoxic agents, with the main difference being the nature of the toxic effects. Thus, the classical chemotherapy toxicities of alopecia, myelosuppression, mucositis, nausea, and vomiting have been generally replaced by vascular, dermatologic, endocrine, coagulation, immunologic, ocular, and pulmonary toxicities. These toxicities need to be recognized, prevented, and optimally managed. © 2013 American Cancer Society, Inc.


Organic isothiocyanates (ITCs), which are characterized by the presence of an -N=C=S group, are among the most extensively studied cancer chemopreventive agents and show highly promising chemopreventive activities. Numerous studies have shown that ITCs can inhibit both carcinogenesis and cancer growth in a variety of animal models. Many cruciferous vegetables, which are commonly consumed by humans, are rich sources of these compounds. Of particular interest are their high bioavailability, their shared metabolic profile and their ability to target a wide array of cancer-related cellular proteins. This review is focused on discussing the molecular basis of these intriguing properties of ITCs, with a particular emphasis on the concept that cellular uptake and metabolism of ITCs and at least some of their major chemopreventive activities are all initiated through direct reaction of the carbon atom of the -N=C=S group of the ITCs with cysteine sulfhydryl groups of glutathione (GSH) and of proteins. This knowledge deepens our understanding about the biological activities of ITCs and may facilitate further research and development of these compounds for cancer prevention and treatment. © The Author 2011. Published by Oxford University Press. All rights reserved.


Blagosklonny M.V.,Roswell Park Cancer Institute
Cell Cycle | Year: 2014

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 growthpromoting, 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 oncogeneinduced accelerated senescence, replicative senescence in vitro and life-long cellular aging in vivo all can be described by 2-step model. © 2014 Taylor & Francis Group, LLC.


Dy G.K.,Roswell Park Cancer Institute
CA: a cancer journal for clinicians | Year: 2013

Answer questions and earn CME/CNE Advances in genomics and molecular biology have identified aberrant proteins in cancer cells that are attractive targets for cancer therapy. Because these proteins are overexpressed or dysregulated in cancer cells compared with normal cells, it was assumed that their inhibitors will be narrowly targeted and relatively nontoxic. However, this hope has not been achieved. Current targeted agents exhibit the same frequency and severity of toxicities as traditional cytotoxic agents, with the main difference being the nature of the toxic effects. Thus, the classical chemotherapy toxicities of alopecia, myelosuppression, mucositis, nausea, and vomiting have been generally replaced by vascular, dermatologic, endocrine, coagulation, immunologic, ocular, and pulmonary toxicities. These toxicities need to be recognized, prevented, and optimally managed. Copyright © 2013 American Cancer Society, Inc.

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