mTOR inhibition improves immune function in the elderly

@article{Mannick2014mTORII,
  title={mTOR inhibition improves immune function in the elderly},
  author={Joan B. Mannick and Giuseppe Del Giudice and Maria Lattanzi and Nicholas M. Valiante and Jens Praestgaard and Baisong Huang and Michael Arthur Lonetto and Holden Terry Maecker and John M. Kovarik and Simon Carson and David J. Glass and Lloyd B. Klickstein},
  journal={Science Translational Medicine},
  year={2014},
  volume={6},
  pages={268ra179 - 268ra179}
}
mTOR inhibition by RAD001 improves immune responses in elderly volunteers receiving an influenza vaccination. mTOR and Human Aging Inhibition of mTOR signaling extends life span and delays the onset of aging-related diseases in all species studied to date. These findings suggest that the mTOR pathway regulates aging. However, it is unknown if mTOR inhibition has beneficial effects on aging in humans. To begin to address this question, Mannick et al. evaluated the effects of the mTOR inhibitor… 
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TLDR
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TLDR
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References

SHOWING 1-10 OF 38 REFERENCES
mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells
TLDR
In old mice, rapamycin increased life span, restored the self-renewal and hematopoiesis of HSCs, and enabled effective vaccination against a lethal challenge with influenza virus.
The Gracefully Aging Immune System
TLDR
The conference “Ageing and Immunity” recently held in Siena, Italy, has reviewed and discussed several possible causes of immune senescence, as well as strategies for counteracting this waning of immune responsiveness and for restoring immunocompetence.
Late‐life rapamycin treatment reverses age‐related heart dysfunction
TLDR
It is proposed that late‐life rapamycin therapy not only extends the lifespan of mammals, but also confers functional benefits to a number of tissues and mechanistically implicates an improvement in contractile function and antihypertrophic signaling in the aged heart with a reduction in age‐related inflammation.
Rapamycin slows aging in mice
TLDR
It is reported here that many forms of age‐dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as age-dependent decline in spontaneous activity, occur more slowly in rapamycin‐treated mice, suggesting strongly thatRapamycin retards multiple aspects of aging in mice, in addition to any beneficial effects it may have on neoplastic disease.
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
TLDR
It is reported that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age.
mTOR regulates memory CD8 T cell differentiation
TLDR
It is shown that mTOR (mammalian target of rapamycin, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what was expected, the immunosuppressive drug Rapamycin has immunostimulatory effects on the generation of memoryCD8 T cells.
mTOR modulates the antibody response to provide cross-protective immunity to lethal influenza infections
TLDR
It is found that rapamycin, an immunosuppressive drug that inhibits the kinase mTOR, promoted cross-strain protection against lethal infection with influenza virus of various subtypes when administered during immunization with influenzairus subtype H3N2.
Partial restoration of T‐cell function in aged mice by in vitro blockade of the PD‐1/ PD‐L1 pathway
TLDR
The data suggest that blockade of the PD‐1/PD‐L1 pathway is not likely to be efficient at restoring exhausted T‐cell responses in aged hosts, although improving the responses ofPD‐1− T cells may prove to be a helpful strategy in enhancing primary responses.
Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data.
  • C. Tanaka, T. O'reilly, H. Lane
  • Biology, Medicine
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2008
TLDR
A direct-link PK/PD model predicting the time course of S6K1 inhibition during weekly and dailyEverolimus administration allowed extrapolation from preclinical studies and first clinical results to select optimal doses and regimens of everolimus to explore in future clinical trials.
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