Ageing: A midlife longevity drug?

Nature (Impact Factor: 41.46). 08/2009; 460(7253):331-2. DOI: 10.1038/460331a
Source: PubMed


The small molecule rapamycin, already approved for clinical use for various human disorders, has been found to significantly increase lifespan in mice. Is this a step towards an anti-ageing drug for people?

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Available from: Matt Kaeberlein,
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    • "There are, however, age-dependent changes in male C57BL/6 mice which are not prevented by rapamycin, and some of the protective effects of this drug appear to reflect immediate benefits rather than delay in age-dependent change (Neff et al., 2013). The documented decline in TOR activity seen in DR rodents (Sun et al., 2009) supports the idea (Kaeberlein & Kennedy, 2009) that lower TOR function may be responsible for lifespan extension in both kinds of mice. Our data do not disprove this idea, but they do document many differences between DR and rapamycin effects on characteristics postulated to play a role in age-dependent pathophysiology (Figs 3 and 4). "
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    ABSTRACT: Rapamycin, an inhibitor of mTOR kinase, increased median lifespan of genetically heterogeneous mice by 23% (males) to 26% (females) when tested at a dose three-fold higher than that used in our previous studies; maximal longevity was also increased in both sexes. Rapamycin increased lifespan more in females than in males at each dose evaluated, perhaps reflecting sexual dimorphism in blood levels of this drug. Some of the endocrine and metabolic changes seen in diet-restricted mice are not seen in mice exposed to rapamycin, and the pattern of expression of hepatic genes involved in xenobiotic metabolism is also quite distinct in rapamycin-treated and diet restricted mice, suggesting that these two interventions for extending mouse lifespan differ in many respects. This article is protected by copyright. All rights reserved.
    Aging cell 12/2013; 13(3). DOI:10.1111/acel.12194 · 6.34 Impact Factor
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    • "Because Rapa inhibits the major nutrient signaling pathway in eukaryote cells and because DR limits the dietary intake of an organism, it is logical that investigators initially speculated that rapamycin increased lifespan in mice by 'mimicking' the downstream signaling effects of DR without changes in body weight or reduction in food consumption (Kaeberlein & Kennedy, 2009). There were also suggestions that DR and Rapa may be similar because one of the inputs that negatively regulate mTOR signaling is through the availability of amino acids. "
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    ABSTRACT: Rapamycin (Rapa) and dietary restriction (DR) have consistently been shown to increase lifespan. To investigate whether Rapa and DR affect similar pathways in mice, we compared the effects of feeding mice ad libitum (AL), Rapa, DR, or a combination of Rapa and DR (Rapa + DR) on the transcriptome and metabolome of the liver. The principal component analysis shows that Rapa and DR are distinct groups. Over 2500 genes are significantly changed with either Rapa or DR when compared with mice fed AL; more than 80% are unique to DR or Rapa. A similar observation was made when genes were grouped into pathways; two-thirds of the pathways were uniquely changed by DR or Rapa. The metabolome shows an even greater difference between Rapa and DR; no metabolites in Rapa-treated mice were changed significantly from AL mice, whereas 173 metabolites were changed in the DR mice. Interestingly, the number of genes significantly changed by Rapa + DR when compared with AL is twice as large as the number of genes significantly altered by either DR or Rapa alone. In summary, the global effects of DR or Rapa on the liver are quite different and a combination of Rapa and DR results in alterations in a large number of genes and metabolites that are not significantly changed by either manipulation alone, suggesting that a combination of DR and Rapa would be more effective in extending longevity than either treatment alone.
    Aging cell 12/2013; 13(2). DOI:10.1111/acel.12175 · 6.34 Impact Factor
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    • "Rapamycin was selected for inclusion in the initial ITP cohort, but because of problems associated with developing a stable formulation of the drug in the mouse chow, the animals did not begin receiving rapamycin until about 600 days of age [132]. The rapamycin was delivered in a microencapsulated form suitable for enteric release at a dose of 14 mg/kg and resulted in a significant lifespan extension of about 15% in females and 10% in males [105]. "
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    ABSTRACT: The mechanistic target of rapamycin (mTOR) is a highly conserved protein that regulates growth and proliferation in response to environmental and hormonal cues. Broadly speaking, organisms are constantly faced with the challenge of interpreting their environment and making a decision between "grow or do not grow." mTOR is a major component of the network that makes this decision at the cellular level and, to some extent, the tissue and organismal level as well. Although overly simplistic, this framework can be useful when considering the myriad functions ascribed to mTOR and the pleiotropic phenotypes associated with genetic or pharmacological modulation of mTOR signaling. In this review, I will consider mTOR function in this context and attempt to summarize and interpret the growing body of literature demonstrating interesting and varied effects of mTOR inhibitors. These include robust effects on a multitude of age-related parameters and pathologies, as well as several other processes not obviously linked to aging or age-related disease.
    11/2013; 2013(1):849186. DOI:10.1155/2013/849186
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