MTOR & Aging and Cancer

In this article-blog, i will review the litterature on MTOR (Section A) and then analyses MTOR pathway in relation to the aging process (Section B) and cancer (Section C)

Text under construction

Section A

Over the last decade, more than 5,000 papers have been published about TOR, an enzyme inhibited by the drug rapamycin—a drug used experimentally to extend lifespan, but already in use clinically to prevent the rejection of kidney transplants. “Patients, who received rapamycin due to [kidney] transplantation, had a peculiar “side effect”: a decrease in cancer incidence.” In a set of 15 patients who had biopsy-proven Kaposi’s sarcoma, a cancer that often affects the skin, within three months after starting rapamycin therapy, “all cutaneous Kaposi’s sarcoma lesions had disappeared in all patients.”

This makes sense, given that TOR “functions as a master regulator of cellular growth and proliferation.” For example, TOR is “upregulated in nearly 100% of advanced human [prostate cancers].” Maybe that’s why dairy consumption has been found to be “a major dietary risk factor.” We used to think it was just all the hormones in milk, but maybe prostate cancer initiation and progression is also promoted by cow’s milk stimulation of TOR.

“Our understanding of mammalian milk has changed from a “simple food” to a species-specific endocrine-signaling system,” which activates TOR, “promotes cell growth and proliferation and suppresses [our body’s internal housecleaning mechanisms].” Now, normally, “milk-mediated” TOR stimulation “is restricted only to” infancy, where we really need that constant signal to our cells to grow and divide.

“From an evolutionary perspective, it can be concluded that the persistent ‘abuse’ of the growth-promoting signaling system of bovine milk by [drinking milk] over [our] entire life span maintains the most important hallmark of cancer biology,…sustained proliferative signaling”—grow, grow, grow.

TOR appears to play a role in breast cancer, too. Higher TOR expression has been noted in breast cancer tumors, and associated with more aggressive disease, and lower survival rate among breast cancer patients.

This could explain why women hospitalized for anorexia may end up with only half the risk of breast cancer. “Severe caloric restriction in humans may confer protection [against] invasive breast cancer” by suppressing TOR activation. But we don’t have to starve ourselves to suppress TOR; just reducing animal protein intake can attenuate overall TOR activity.

“Moreover, [diets] emphasizing plants, especially cruciferous vegetables, not only decrease [TOR] activation…[they also] provide natural plant-derived inhibitors of TOR in broccoli, and green tea and soy, and turmeric, and grapes, along with other fruits and vegetables, such as onions, strawberries, blueberries, mangoes, and the skin of cucumbers.

Maybe that’s why plant-based diets are associated with lower risk for many cancers—the “down-regulation” of TOR. So, “[a]re we finally on the threshold of being able to fundamentally alter human ageing…” and age-related disease? “Only time will tell, but if the pace and direction of recent progress are any indication, the next [5,000 studies on TOR] should prove very interesting indeed.”

J L Jewell, K L Guan. Nutrient signaling to mTOR and cell growth. Trends Biochem Sci 2013 38(5):233 – 242.

X Wang, C G Proud. MTORC1 signaling: What we still don’t know. J Mol Cell Biol 2011 3(4):206 – 220.

J D Weber, D H Gutmann. Deconvoluting mTOR biology. Cell Cycle 2012 11(2):236 – 248.

S C Johnson, P S Rabinovitch, M Kaeberlein. MTOR is a key modulator of ageing and age-related disease. Nature 2013 493(7432):338 – 345.

C H Jung, H Kim, J Ahn, T I Jeon, D H Lee, T Y Ha. Fisetin regulates obesity by targeting mTORC1 signaling. J. Nutr. Biochem. 2013 24(8):1547 – 1554.

M F McCarty. MTORC1 activity as a determinant of cancer risk–rationalizing the cancer-preventive effects of adiponectin, metformin, rapamycin, and low-protein vegan diets. Med Hypotheses 2011 77(4):642 – 648.

M V Blagosklonny. Rapalogs in cancer prevention: Anti-aging or anticancer? Cancer Biol Ther 2012 13(14):1349 – 1354.

Y Suh, F Afaq, N Khan, J J Johnson, F H Khusro, H Mukhtar. Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis 2010 31(8):1424 – 1433.

R F Lamb. Amino acid sensing mechanisms: An Achilles heel in cancer? FEBS J. 2012 279(15):2624 – 2631.

K B Michels, A Ekbom. Caloric restriction and incidence of breast cancer. Jama 2004 291(10):1226 – 1230.

G Stallone, A Schena, B Infante, S Di Paolo, A Loverre, G Maggio, E Ranieri, L Gesualdo, F P Schena, G Grandaliano. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med 2005 352(13):1317 – 1323.

U Wazir, R F Newbold, W G Jiang, A K Sharma, K Mokbel. Prognostic and therapeutic implications of mTORC1 and Rictor expression in human breast cancer. Oncol Rep 2013 29(5):1969 – 1974.

B C Melnik, S M John, P Carrera-Bastos, L Cordain. The impact of cow’s milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer. Nutr Metab (Lond) 2012 9(1):74.

Section C


Nutr Metab (Lond). 2012 Aug 14;9(1):74. doi: 10.1186/1743-7075-9-74.

The impact of cow’s milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer.

Melnik BC1, John SM, Carrera-Bastos P, Cordain L.

Author information


Prostate cancer (PCa) is dependent on androgen receptor signaling and aberrations of the PI3K-Akt-mTORC1 pathway mediating excessive and sustained growth signaling. The nutrient-sensitive kinase mTORC1 is upregulated in nearly 100% of advanced human PCas. Oncogenic mTORC1 signaling activates key subsets of mRNAs that cooperate in distinct steps of PCa initiation and progression. Epidemiological evidence points to increased dairy protein consumption as a major dietary risk factor for the development of PCa. mTORC1 is a master regulator of protein synthesis, lipid synthesis and autophagy pathways that couple nutrient sensing to cell growth and cancer. This review provides evidence that PCa initiation and progression are promoted by cow´s milk, but not human milk, stimulation of mTORC1 signaling. Mammalian milk is presented as an endocrine signaling system, which activates mTORC1, promotes cell growth and proliferation and suppresses autophagy. Naturally, milk-mediated mTORC1 signaling is restricted only to the postnatal growth phase of mammals. However, persistent consumption of cow´s milk proteins in humans provide highly insulinotropic branched-chain amino acids (BCAAs) provided by milk´s fast hydrolysable whey proteins, which elevate postprandial plasma insulin levels, and increase hepatic IGF-1 plasma concentrations by casein-derived amino acids. BCAAs, insulin and IGF-1 are pivotal activating signals of mTORC1. Increased cow´s milk protein-mediated mTORC1 signaling along with constant exposure to commercial cow´s milk estrogens derived from pregnant cows may explain the observed association between high dairy consumption and increased risk of PCa in Westernized societies. As well-balanced mTORC1-signaling plays an important role in appropriate prostate morphogenesis and differentiation, exaggerated mTORC1-signaling by high cow´s milk consumption predominantly during critical growth phases of prostate development and differentiation may exert long-term adverse effects on prostate health. Attenuation of mTORC1 signaling by contemporary Paleolithic diets and restriction of dairy protein intake, especially during mTORC1-dependent phases of prostate development and differentiation, may offer protection from the most common dairy-promoted cancer in men of Western societies.

PMID: 22891897 PMCID: PMC3499189 DOI: 10.1186/1743-7075-9-74

Free PMC Article

Why Do We Age?

Caloric Restriction vs. Animal Protein Restriction

More on dairy and prostate cancer in Prostate Cancer & Organic Milk vs. Almond Milk.

This story continues in my next video: Saving Lives by Treating Acne With Diet.

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Genetics. 2011 Dec; 189(4): 1177–1201.

doi:  10.1534/genetics.111.133363

PMCID: PMC3241408

Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control

Robbie Loewith*,1 and Michael N. Hall†,1

J. Thorner, Communicating editor

Author information ► Article notes ► Copyright and License information ►

This article has been cited by other articles in PMC.

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TOR (Target Of Rapamycin) is a highly conserved protein kinase that is important in both fundamental and clinical biology. In fundamental biology, TOR is a nutrient-sensitive, central controller of cell growth and aging. In clinical biology, TOR is implicated in many diseases and is the target of the drug rapamycin used in three different therapeutic areas. The yeast Saccharomyces cerevisiae has played a prominent role in both the discovery of TOR and the elucidation of its function. Here we review the TOR signaling network in S. cerevisiae.

THE contributors to this GENETICS set of reviews were asked to focus on the developments in their field since 1991, the year the last yeast monographs were published. Coincidentally, Target Of Rapamycin (TOR) was discovered in 1991. We thus have the whole TOR story to tell, from the beginning, in a review that marks the 20th anniversary of TOR. As we review TOR signaling in Saccharomyces cerevisiae, the reader is referred to other reviews for descriptions of TOR in other organisms (Wullschleger et al. 2006; Polak and Hall 2009; Soulard et al. 2009; Caron et al. 2010; Kim and Guan 2011; Zoncu et al. 2011).

The story of the TOR-signaling network begins with a remarkable drug, rapamycin (Abraham and Wiederrecht 1996; Benjamin et al. 2011). Rapamycin is a lipophilic macrolide and a natural secondary metabolite produced by Streptomyces hygroscopicus, a bacterium isolated from a soil sample collected in Rapa-Nui (Easter Island) in 1965—hence the name rapamycin. Rapamycin was originally purified in the early 1970s as an antifungal agent. Although it effectively inhibits fungi, it was discarded as an antifungal agent because of its then undesirable immunosuppressive side effects. Years later, it was “rediscovered” as a T-cell inhibitor and as an immunosuppressant for the treatment of allograft rejection. Preclinical studies subsequently showed that rapamycin and its derivatives, CCI-779 (Wyeth-Ayerst) and RAD001 (Novartis), also strongly inhibit the proliferation of tumor cells. Rapamycin received clinical approval in 1999 for use in the prevention of organ rejection in kidney transplant patients, and additional applications as an immunosuppressive agent have since been developed. CCI-779 (Torisel) and RAD001 (Afinitor) were approved in 2007 and 2009, respectively, for treatment of advanced kidney cancer. Rapamycin is effective against tumors because it blocks the growth of tumor cells directly and because of the indirect effect of preventing the growth of new blood vessels (angiogenesis) that supply oxygen and nutrients to the tumor cells (Guba et al. 2002). Finally, rapamycin-eluting stents prevent restenosis after angioplasty. Thus, rapamycin has clinical applications in three major therapeutic areas: organ transplantation, cancer, and coronary artery disease. What do fungi and the seemingly very different conditions of transplant rejection, cancer, and restenosis have in common in their underlying biology such that all can be treated with the same drug? All three conditions (and the spread of pathogenic fungi) are due to ectopic or otherwise undesirable cell growth, suggesting that the molecular target of rapamycin is a central controller of cell growth. TOR is indeed dedicated to controlling cell growth, but what is this target and how does it control cell growth?

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The Early Days

Studies to identify the cellular target of rapamycin and to elucidate the drug’s mode of action were initiated in the late 1980s by several groups working with yeast (Heitman et al. 1991a; Cafferkey et al. 1993; Kunz et al. 1993) and mammalian cells (Brown et al. 1994; Chiu et al. 1994; Sabatini et al. 1994; Sabers et al. 1995). At that time, rapamycin was known to inhibit the vertebrate immune system by blocking a signaling pathway in helper T cells that mediates cell cycle (G1) progression in response to the lymphokine IL-2. However, the molecular mode of action of the drug was not known other than it possibly involved binding and inhibiting the cytosolic peptidyl-prolyl cis-trans isomerase FKBP12 (FK506-binding protein 12), also known as an immunophilin (Schreiber 1991). Furthermore, the observation that rapamycin inhibited cell cycle progression in yeast as in mammalian cells suggested that the molecular target was conserved from yeast to vertebrates and that yeast cells could thus be exploited to identify the target of rapamycin (Heitman et al. 1991a). It should be noted that the early researchers were interested not only in understanding rapamycin’s mechanism of action, but also in using rapamycin as a probe to identify novel proliferation-controlling signaling pathways (Kunz and Hall 1993). In the late 1980s, significantly less was known about signaling pathways than today; indeed, few and only incomplete pathways were known.

The early studies in yeast first focused on identifying an FKBP (FK506-binding protein) (Heitman et al. 1991b; Koltin et al. 1991; Tanida et al. 1991; Wiederrecht et al. 1991). FKBP12 had previously been identified in mammalian cell extracts as a rapamycin (and FK506)-binding protein. Yeast FKBP was purified to homogeneity using an FK506 column and partially sequenced. The protein sequence information was used to design degenerate oligonucleotides that were then used to isolate the FKBP-encoding gene FPR1 (Heitman et al. 1991b). The predicted amino acid sequence of yeast Fpr1 was 54% identical to that of the concurrently characterized human FKBP12, providing further support that the mode of action of rapamycin was conserved from yeast to humans. Curiously, disruption of the FKBP gene in yeast (FPR1) revealed that FKBP is not essential for growth (Heitman et al. 1991b; Koltin et al. 1991; Tanida et al. 1991; Wiederrecht et al. 1991). Additional FKBPs and cyclophilins (also an immunophilin and proline isomerase) were subsequently discovered and cloned, and again single and multiple disruptions were constructed without consequential loss of viability (Heitman et al. 1991b, 1992; Davis et al. 1992; Kunz and Hall 1993; Dolinski et al. 1997). The finding that FPR1 disruption did not affect viability was paradoxical because FKBP was believed to be the in vivo binding protein/target for the toxic effect of rapamycin. Why did inhibition of FKBP by rapamycin block growth whereas inhibition of FKBP by disruption of the FPR1 gene have no effect on growth? The subsequent finding that an FPR1 disruption confers rapamycin resistance (Heitman et al. 1991a,b), combined with the observation that some drug analogs are not immunosuppressive despite being able to bind and inhibit FKBP12 proline isomerase (Schreiber 1991), provided the answer to the above question and led to the well-established model of immunosuppressive drug action: an immunophilin-drug complex (e.g., FKBP-rapamycin) gains a new toxic activity that acts on another target. In other words, FKBP is only a cofactor or receptor required by the drug to act on something else; FKBP itself is not the target required for viability. This mode of drug action also applies to the well-known immunosuppressants cyclosporin A and FK506 (from cyclophilin–cyclosporin A and FKBP–FK506 complexes) and is conserved from yeast to humans (Schreiber 1991). These early studies in yeast were the first of many that have since contributed to an understanding of rapamycin action and TOR signaling even in mammalian cells (Crespo and Hall 2002), illustrating that a model organism such as yeast is valuable in both basic and biomedical research.

To identify the target of the FKBP–rapamycin complex, rapamycin-resistant yeast mutants were selected (Heitman et al. 1991a; Cafferkey et al. 1993). As expected, fpr1 mutants defective in FKBP were recovered, but also obtained were mutants altered in either one of two novel genes termed TOR1 and TOR2. The fpr1 mutations were common and recessive. Interestingly, the TOR1 and TOR2 mutations were rare and dominant. The TOR1 and TOR2 genes were cloned, on the basis of the dominant rapamycin-resistance phenotype of the mutant alleles, and sequenced (Cafferkey et al. 1993; Kunz et al. 1993; Helliwell et al. 1994). Both TOR1 and TOR2 proteins are 282 kDa in size (2470 and 2474 amino acids, respectively) and 67% identical. TOR1 and TOR2 are also the founding members of the PI kinase-related protein kinase (PIKK) family of atypical Ser/Thr-specific kinases (other members include TEL1, ATM, DNA-PK, and MEC1) (Keith and Schreiber 1995). Although the catalytic domain of all members of this protein kinase family resembles the catalytic domain of lipid kinases (PI3K and PI4K), no PIKK family member has lipid kinase activity, and the significance of the resemblance to lipid kinases is unknown. Two reports in 1995—before TOR was shown to be a protein kinase—claimed that yeast and mammalian TOR had lipid kinase (PI4K) activity, but these findings were never confirmed and are now thought to have been due to a contaminating PI4K. Disruption of TOR1 and TOR2 in combination caused a growth arrest similar to that caused by rapamycin treatment, suggesting that TOR1 and TOR2 are indeed the targets of FKBP–rapamycin and that the FKBP–rapamycin complex inhibits TOR activity (Kunz et al. 1993). It was subsequently demonstrated that the FKBP–rapamycin complex binds directly to TOR1 and TOR2 (Stan et al. 1994; Lorenz and Heitman 1995; Zheng et al. 1995) and that TOR is widely conserved both structurally and as the target of FKBP–rapamycin (Schmelzle and Hall 2000). However, S. cerevisiae is unusual in having two TOR genes whereas almost all other eukaryotes, including plants, worms, flies, and mammals, have a single TOR gene. As described below, this additional complexity in S. cerevisiae helped the analysis of TOR signaling because it allowed differentiating two functionally different signaling branches on the basis of different requirements for the two TORs.

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Aging (Albany NY). 2017 Aug; 9(8): 1863–1864.

Published online 2017 Aug 29. doi:  10.18632/aging.101287

PMCID: PMC5611980

Anti-aging effects of coffee

Keita Takahashi and Akihito Ishigami

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There are numerous habitual coffee drinkers in the world, and elderly people are no exception. Recently, coffee has been recognized as an effective beverage for healthful aging, especially with respect to maladies such as cardiovascular disease [1] and mild cognitive impairment [2]. Moreover, several human studies have revealed that habitual coffee intake reduces the all-cause mortality in Japanese and several other population groups [3,4] and mortality from heart disease and cerebrovascular disease [3]. Coffee contains caffeine and many kinds of polyphenols. Caffeine has several effects on aging, especially through inhibiting the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and prolonging the life span of fission yeast [5]. Moreover, the polyphenol chlorogenic acid has many beneficial effects, e.g., lowering fat accumulation in diet-induced obese mice by downregulating sterol regulatory element-binding protein 1 [6]. These studies indicate that one of the most consumed beverages, coffee, has potential anti-aging effects that contribute to the prevention of age-related diseases. However, the mechanisms and effects of coffee are not fully understood with respect to aging or age-related diseases.

Recently, we elucidated the effects of caffeine-containing regular coffee and decaffeinated coffee consumption on aged mice (Fig.


1) [7]. Regular coffee consumption increased the nocturnal activity of aged mice, including their food intake, water consumption, and locomotor activity, without disrupting the circadian rhythm. We observed no body, liver, or adipose tissue weight changes among all groups during the experimental period. However, we found that regular coffee consumption increased the energy expenditure estimated from CO2 excretion and the respiration exchange ratio. To investigate what was excreted in aged mice that consumed coffee, we carried out biochemical and biomolecular analyses. As a result, both regular and decaffeinated coffee consumption were found to reduce free fatty acid levels in the plasma of aged mice. Additionally, both regular and decaffeinated coffee intake increased ATP levels in the liver of aged mice. Protein analyses by western blotting revealed that decaffeinated coffee increased protein levels of peroxisome proliferator-activated receptor (PPAR) α, which is involved in lipid β-oxidation, when compared with the control mice. Interestingly, the total and phosphorylated (Ser2448) mTOR levels in the liver were decreased by consuming coffee containin

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