M(o)TOR of aging: MTOR as a universal molecular hypothalamus

Blagosklonny, Mikhail V.

doi:10.18632/aging.100580

Cited by 27 publications

(18 citation statements)

References 57 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…mTOR is the central nutrient sensor that coordinates the various upstream signaling and environmental stimuli to regulate cell growth and fate [83]. mTOR is the key molecule that regulates cancer growth and the process of aging both in the presence or absence of CR [37].…”

Section: Discussionmentioning

confidence: 99%

Dietary energy balance modulates ovarian cancer progression and metastasis

et al. 2014

View full text Add to dashboard

A high energy balance, or caloric excess, accounts as a tumor promoting factor, while a negative energy balance via caloric restriction, has been shown to delay cancer progression. The effect of energy balance on ovarian cancer progression was investigated in an isogeneic immunocompetent mouse model of epithelial ovarian cancer kept on a regimen of regular diet, high energy diet (HED) and calorie restricted diet (CRD), prior to inoculating the animals intraperitoneally with the mouse ovarian surface epithelial ID8 cancer cells. Tumor evaluation revealed that mice group on HED displayed the most extensive tumor formation with the highest tumor score at all organ sites (diaphragm, peritoneum, bowel, liver, kidney, spleen), accompanied with increased levels of insulin, leptin, insulin growth factor-1 (IGF-1), monocyte chemoattractant protein-1 (MCP-1), VEGF and interleukin 6 (IL-6). On the other hand, the mice group on CRD exhibited the least tumor burden associated with a significant reduction in levels of insulin, IGF-1, leptin, MCP-1, VEGF and IL-6. Immunohistochemistry analysis of tumors from HED mice showed higher activation of Akt and mTOR with decreased adenosine monophosphate activated kinase (AMPK) and SIRT1 activation, while tumors from the CRD group exhibited the reverse profile. In conclusion, ovarian cancer growth and metastasis occurred more aggressively under HED conditions and was significantly curtailed under CRD. The suggested mechanism involves modulated secretion of growth factors, cytokines and altered regulation of AMPK and SIRT1 that converges on mTOR inhibition. While the role of a high energy state in ovarian cancer has not been confirnmed in the literature, the current findings support investigating the potential impact of diet modulation as adjunct to other anticancer therapies and as possible individualized treatment strategy of epithelial ovarian cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Dietary energy balance modulates ovarian cancer progression and metastasis

et al. 2014

View full text Add to dashboard

show abstract

“…An increasing number of experimental data suggest that aging in evolutionary distant model organisms, such as nematodes, fruit flies, and some mammals, is regulated through evolutionary conserved signaling pathways such as the insulin/IGF-1 pathway (Kenyon 2011) and mTOR (Blagosklonny 2012), which stands for "mammalian target of rapamycin", formally referred to as "mechanistic target of rapamycin" (MTOR), informally known as the "M(o)TOR of aging", and biochemically described as serine/threonine kinase (Hands et al 2009;Kapahi et al 2009;Katewa and Kapahi 2011;Sharp 2011;Kaeberlein and Martin 2016). Based on this, the theory of hyperfunction has been latterly formulated, including the important mTOR quasi-program rival to the DST, offering a completely different approach to numerous problems and paradoxes in current biogerontology, and allowing the prediction of completely new relationships (Blagosklonny 2008;2009;2010a;2010b;2013a;2013b;2013c;2013d;2013e;2013f). However, there were also some controversies.…”

Section: Introductionmentioning

confidence: 99%

Contemporary views on human aging and longevity

Chmielewski

Borysławski

Strzelec

2016

View full text Add to dashboard

Aging is currently stimulating intense interest of both researchers and the general public. In developed countries, the average life expectancy has increased by roughly 30 years within the last century, and human senescence has been delayed by around a decade. Although aging is arguably the most familiar aspect of human biology, its proximate and ultimate causes have not been elucidated fully and understood yet. Nowadays there are two main approaches to the ultimate causes of aging. These are deterministic and stochastic models. The proximate theories constitute a distinct group of explanations. They focus on mechanistic causes of aging. In this view, there is no reason to believe that there is only one biological mechanism responsible for aging. The aging process is highly complex and results from an accumulation of random molecular damage. Currently, the disposable soma theory (DST), proposed by Thomas Kirkwood, is the most influential and coherent line of reasoning in biogerontology. This model does not postulate any particular mechanism underpinning somatic defense. Therefore, it is compatible with various models, including mechanistic and evolutionary explanations. Recently, however, an interesting theory of hyper-function of mTOR as a more direct cause of aging has been formulated by Mikhail Blagosklonny, offering an entirely different approach to numerous problems and paradoxes in current biogerontology. In this view, aging is quasi-programmed, which means that it is an aimless continuation of developmental growth. This mTOR-centric model allows the prediction of completely new relationships. The aim of this article is to present and compare the views of both parties in the dispute, based on the results of some recent experimental studies, and the contemporary knowledge of selected major aspects of human aging and longevity

show abstract

“…Yet, the unusual enrichment of these pathways in yeast and worms definitely highlights their importance in determination of longevity for these taxa specifically. For vertebrates, we found a significant enrichment in Neuroactive ligand-receptor interaction, which could reflect the importance of neuroendocrine regulation of aging and longevity in higher organisms (Dilman et al 1986; Frolkis 1988; Blagosklonny 2013).…”

Section: Resultsmentioning

confidence: 78%