mTOR inhibition improves immune function in the elderly

  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},
  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… 
TORC1 inhibition as an immunotherapy to reduce infections in the elderly
Positive results indicate that selective TORC1 inhibition with a combination of BEZ235 and RAD001 may be efficacious as immunotherapy to reduce infections, a leading cause of death in the elderly.
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
The data show novel mTOR inhibitor immune effects meriting further studies in relation to longevity and healthspan extension, and comprehensively analyzed immune effects of rapamycin as used in lifespan extension studies.
Intermittent mTOR Inhibition Reverses Kidney Aging in Old Rats.
The authors found a striking reversal in the expression of age-regulated genes in the kidney, many of which linked to inflammation and fibrosis, together with a reduction in the severity of nephropathy lesions in aged rats.
Chronic mechanistic target of rapamycin inhibition: preventing cancer to delay aging, or vice versa?.
There is a great need for the eRapa findings to be a proof of concept for the development of new and more comprehensive approaches to cancer prevention that are safe and also mitigate other deleterious effects of aging.
Effects of rapamycin on growth hormone receptor knockout mice
It is reported that mTORC2 plays a positive role in regulating longevity via maintenance, or enhancement, of whole-body homeostasis in GHR-KO mice, and drastic reduction of mTORc2 plays important roles in impaired longevity in G HR- KO mice via disruption of entire-bodyHomeostasis.
Neuroimaging Biomarkers of mTOR Inhibition on Vascular and Metabolic Functions in Aging Brain and Alzheimer’s Disease
Recent findings of in vivo metabolic and vascular measures using non-invasive, multimodal neuroimaging methods in rodent models for brain aging and AD may have tremendous implications in future clinical trials of neurological disorders in aging populations.
Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice
It is shown that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice and this transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine.
Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system
An intermittent rapamycin dosing schedule with minimal effects on glucose tolerance is identified and it is found that this schedule has a reduced impact on pyruvate tolerance, fasting glucose and insulin levels, beta cell function, and the immune system compared to daily Rapamycin treatment.


mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells
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
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
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
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
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
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
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
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
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.