Rapamycin extends life span of Rb1+/− mice by inhibiting neuroendocrine tumors

Livi, Carolina B.; Hardman, Rulon L.; Christy, Barbara A.; Dodds, Sherry G.; Jones, Diane; Williams, Charnae; Strong, Randy; Bokov, Alex; Javors, Martin A.; Ikeno, Yuji; Hubbard, Gene B.; Hasty, Paul; Sharp, Zelton D

doi:10.18632/aging.100533

Cited by 73 publications

(61 citation statements)

References 35 publications

(71 reference statements)

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“…We showed that reduced neoplasia is an eRapa‐mediated longevity extension mechanism in spontaneous neoplasia models (Livi et al ., 2013; Hasty et al ., 2014) and potentially in wild‐type mice (Miller et al ., 2011). T cells and IFN‐γ mediate cancer immune surveillance (Mittal et al ., 2014).…”

Section: Resultsmentioning

confidence: 99%

“…We previously demonstrated significant lifespan extension in neoplasia‐prone Rb +/− and Apc Min/+ mice (Livi et al ., 2013; Hasty et al ., 2014). We interpret the eRapa‐mediated 3.3‐ to 12‐fold augmented lifespan extension of IFN‐γ −/− and RAG2 −/− mice versus modest lifespan extension in syngeneic BL6 mice (Zhang et al ., 2014) as consistent with cancer and infection prevention as lifespan extension mechanisms of eRapa, seen in exaggerated form in these mice that are highly susceptible to cancers and infections.…”

Section: Discussionmentioning

confidence: 99%

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Chronic mTOR inhibition in mice with rapamycin alters T , B , myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

et al. 2015

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SummaryThe mammalian (mechanistic) target of rapamycin (mTOR) regulates critical immune processes that remain incompletely defined. Interest in mTOR inhibitor drugs is heightened by recent demonstrations that the mTOR inhibitor rapamycin extends lifespan and healthspan in mice. Rapamycin or related analogues (rapalogues) also mitigate age‐related debilities including increasing antigen‐specific immunity, improving vaccine responses in elderly humans, and treating cancers and autoimmunity, suggesting important new clinical applications. Nonetheless, immune toxicity concerns for long‐term mTOR inhibition, particularly immunosuppression, persist. Although mTOR is pivotal to fundamental, important immune pathways, little is reported on immune effects of mTOR inhibition in lifespan or healthspan extension, or with chronic mTOR inhibitor use. We comprehensively analyzed immune effects of rapamycin as used in lifespan extension studies. Gene expression profiling found many and novel changes in genes affecting differentiation, function, homeostasis, exhaustion, cell death, and inflammation in distinct T‐ and B‐lymphocyte and myeloid cell subpopulations. Immune functions relevant to aging and inflammation, and to cancer and infections, and innate lymphoid cell effects were validated in vitro and in vivo. Rapamycin markedly prolonged lifespan and healthspan in cancer‐ and infection‐prone mice supporting disease mitigation as a mechanism for mTOR suppression‐mediated longevity extension. It modestly altered gut metagenomes, and some metagenomic effects were linked to immune outcomes. Our data show novel mTOR inhibitor immune effects meriting further studies in relation to longevity and healthspan extension.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chronic mTOR inhibition in mice with rapamycin alters T , B , myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

et al. 2015

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“…For example, if rapamycin suppresses aging, it will prevent any cancer including those with p53 and Rb mutations or ErbB activation. In fact, rapamycin prevents cancer in p53-deficient and Rb-deficient mice 150 - 153 as well as common cancers in normal mice 154 - 160 . Metformin, which affects the mTOR pathway and slows aging, also prevents a variety of cancers 161 - 165 .…”

Section: Cancer Preventionmentioning

confidence: 99%

Selective anti-cancer agents as anti-aging drugs

Blagosklonny¹

2013

Cancer Biology & Therapy

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Recent groundbreaking discoveries have revealed that IGF-1, Ras, MEK, AMPK, TSC1/2, FOXO, PI3K, mTOR, S6K, and NFκB are involved in the aging process. This is remarkable because the same signaling molecules, oncoproteins and tumor suppressors, are well-known targets for cancer therapy. Furthermore, anti-cancer drugs aimed at some of these targets have been already developed. This arsenal could be potentially employed for anti-aging interventions (given that similar signaling molecules are involved in both cancer and aging). In cancer, intrinsic and acquired resistance, tumor heterogeneity, adaptation, and genetic instability of cancer cells all hinder cancer-directed therapy. But for anti-aging applications, these hurdles are irrelevant. For example, since anti-aging interventions should be aimed at normal postmitotic cells, no selection for resistance is expected. At low doses, certain agents may decelerate aging and age-related diseases. Importantly, deceleration of aging can in turn postpone cancer, which is an age-related disease.

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“…Thus, the current data show that increased longevity is associated with little change in end-of-life pathology. Because cancer is the primary cause of death in UM-HET3 and C57BL (14)(15)(16)(17).…”

Section: A Comprehensive Assessment Of Aging In Micementioning

confidence: 99%

Rapamycin, anti-aging, and avoiding the fate of Tithonus

Richardson

2013

J. Clin. Invest.

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The discovery that rapamycin increased the lifespan of mice was recognized by Science as one of the top 10 scientific breakthroughs of 2009. In addition to increasing lifespan, Neff and colleagues show that while rapamycin improves several functions/pathologies that change with age, it has little effect on the majority of the physiological and structural parameters they evaluated. What do these data tell us about the ability of rapamycin to delay aging and improve quality of life, i.e., prevent the fate of Tithonus?The Tithonus effect The consequences of longevity without health and vigor are dramatically portrayed in the Greek myth about Tithonus, a prince of Troy. After the goddess Eos kidnapped him, she asked Zeus to make Tithonus immortal. Unfortunately, Eos forgot to ask for eternal youth. (1) reported that rapamycin (also known as sirolimus) increased both mean and maximum lifespan of mice, demonstrating that all competing causes of mortality (i.e., age-related diseases) are delayed and suggesting that rapamycin slows aging. Because rapamycin is approved by the FDA for transplant and cancer patients, this discovery has enormous translational potential; however, before taking a potential anti-aging therapy to humans, it is necessary to demonstrate that the agent does not produce a "Tithonus phenotype," where the increase in lifespan is accompanied by more disability and disease and a greater loss of physiological functions, i.e., a reduced quality of life. A comprehensive assessment of aging in miceIn this issue of the JCI, Neff et al. (2) describe the results from their large-scale study of the effect of rapamycin on more than 150 aging phenotypes across 25 different tissues in male C57BL/6 mice. They identified several aging phenotypes that were improved by rapamycin, in particular behavior/cognition, several immune parameters, and a number of pathological lesions. The effect of rapamycin on cognition is particularly important in an aging context because this physiological domain is critical for the quality of life in humans. Neff et al. (2) showed that learning and memory were improved. Halloran et al. (3) and Majumder et al. (4) also found that rapamycin improved the performance of old mice. Furthermore, rapamycin was previously observed to restore memory in transgenic mouse models of Alzheimer's disease (5-7). Thus, the current data indicate that rapamycin has a robust effect on cognitive performance in mice.Neff et al. (2) found that the vast majority of parameters they measured were not significantly altered by rapamycin, including vision, hearing, and cardiac and skeletal muscle function, all of which are important to quality of life. Rapamycin has been found to improve cardiac function in old mice (P. Rabinovitch, personal communication) and in Lmna -/-mice (8). While Neff et al. (2) saw no effect of rapamycin on muscle function using measurements of grip strength and rotarod performance (a measure of muscle function as well as balance and motor coordination), Zhang et al. (9) found that rotarod ...

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Rapamycin extends life span of Rb1+/− mice by inhibiting neuroendocrine tumors

Cited by 73 publications

References 35 publications

Chronic mTOR inhibition in mice with rapamycin alters T , B , myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

Chronic mTOR inhibition in mice with rapamycin alters T , B , myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

Selective anti-cancer agents as anti-aging drugs

Rapamycin, anti-aging, and avoiding the fate of Tithonus

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