Rapamycin, a potent immunomodulatory drug, has shown promise in the amelioration of numerous age-associated diseases including cancer, Alzheimer's disease and cardiac hypertrophy. Yet the elderly, the population most likely to receive therapeutic rapamycin, are already at increased risk for infectious disease; thus concern exists that rapamycin may exacerbate age-associated immune dysfunctions and worsen infection outcomes. Herein, we examined the impact of enteric delivered rapamycin monotherapy (eRapa) on the susceptibility of aged (22-24month) C57BL/6 mice to Streptococcus pneumoniae, the leading bacterial cause of community-acquired pneumonia. Following challenge with S. pneumoniae, administration of eRapa conferred modest protection against mortality. Reduced mortality was the result of diminished lung damage rather than reduced bacterial burden. eRapa had no effect on basal levels of Interleukin (IL)-1α, IL-6, IL-10, IL-12p70, KC, Interferon-γ, Tumor necrosis factor α and Monocyte chemotactic protein-1 in whole lung homogenates or during pneumococcal pneumonia. Previously we have demonstrated that cellular senescence enhances permissiveness for bacterial pneumonia through increased expression of the bacterial ligands Laminin receptor (LR), Platelet-activating factor receptor (PAFr) and Cytokeratin 10 (K10). These proteins are co-opted by S. pneumoniae and other respiratory tract pathogens for host cell attachment during lung infection. UM-HET3 mice on eRapa had reduced lung cellular senescence as determined by levels of the senescence markers p21 and pRB, but not mH2A.1. Mice on eRapa also had marked reductions in PAFr, LR, and K10. We conclude that eRapa protected aged mice against pneumonia through reduced lung cellular senescence, which in turn, lowered bacterial ligand expression.
"Rapamycin delivered once every 5 days has a reduced impact on the immune system The immunosuppressive effects of rapamycin are a potential barrier to widespread use of rapamycin as a therapy for age-related diseases (Lamming et al., 2013b), although the dosing strategy utilized may be of major importance. The true impact of rapamycin on the immune system is still unclear, and rapamycin may not be generally immunosuppressive— indeed, rapamycin treatment improves survival in mouse models of infection (Hinojosa et al., 2012; Hasty et al., 2014) and improves the response to vaccines in both nonhuman primates (Turner et al., 2011) and elderly humans (Mannick et al., 2014). However, in addition to a reported increase in viral and fungal infections in humans taking rapamycin (Mahe et al., 2005), even short-term low-dose rapamycin decreases defense against bacterial and viral pathogens in mice (Goldberg et al., 2014). "
[Show abstract][Hide abstract] ABSTRACT: Inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway by the FDA-approved drug rapamycin has been shown to promote lifespan and delay age-related diseases in model organisms including mice. Unfortunately, rapamycin has potentially serious side effects in humans, including glucose intolerance and immunosuppression, which may preclude the long-term prophylactic use of rapamycin as a therapy for age-related diseases. While the beneficial effects of rapamycin are largely mediated by the inhibition of mTOR complex 1 (mTORC1), which is acutely sensitive to rapamycin, many of the negative side effects are mediated by the inhibition of a second mTOR-containing complex, mTORC2, which is much less sensitive to rapamycin. We hypothesized that different rapamycin dosing schedules or the use of FDA-approved rapamycin analogs with different pharmacokinetics might expand the therapeutic window of rapamycin by more specifically targeting mTORC1. Here, we identified an intermittent rapamycin dosing schedule with minimal effects on glucose tolerance, and we find 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. Further, we find that the FDA-approved rapamycin analogs everolimus and temsirolimus efficiently inhibit mTORC1 while having a reduced impact on glucose and pyruvate tolerance. Our results suggest that many of the negative side effects of rapamycin treatment can be mitigated through intermittent dosing or the use of rapamycin analogs.
"Meth-R-dependent extension of cellular lifespan in vivo likely has significant implications for the rate of mouse aging, especially given a recent study showing that selective clearance of p16(Ink4a)-positive senescent cells rescues age-related pathologies in a progeroid mouse model . Just as intriguing is a recent study that revealed that rapamycin treatment, which extends mouse lifespan, reduces the incidence of senescent cells in vivo
. Our findings provide strong support for a causal relationship between Meth-R-induced stress resistance, extended replicative lifespan and improvements in rodent healthspan. "
[Show abstract][Hide abstract] ABSTRACT: A methionine-restricted diet robustly improves healthspan in key model organisms. For example, methionine restriction reduces age-related pathologies and extends lifespan up to 45% in rodents. However, the mechanisms underlying these benefits remain largely unknown. We tested whether the yeast chronological aging assay could model the benefits of methionine restriction, and found that this intervention extends lifespan when enforced by either dietary or genetic approaches, and furthermore, that the observed lifespan extension is due primarily to reduced acid accumulation. In addition, methionine restriction-induced lifespan extension requires the activity of the retrograde response, which regulates nuclear gene expression in response to changes in mitochondrial function. Consistent with an involvement of stress-responsive retrograde signaling, we also found that methionine-restricted yeast are more stress tolerant than control cells. Prompted by these findings in yeast, we tested the effects of genetic methionine restriction on the stress tolerance and replicative lifespans of cultured mouse and human fibroblasts. We found that such methionine-restricted mammalian cells are resistant to numerous cytotoxic stresses, and are substantially longer-lived than control cells. In addition, similar to yeast, the extended lifespan of methionine-restricted mammalian cells is associated with NFκB-mediated retrograde signaling. Overall, our data suggest that improved stress tolerance and extension of replicative lifespan may contribute to the improved healthspan observed in methionine-restricted rodents, and also support the possibility that manipulation of the pathways engaged by methionine restriction may improve healthspan in humans.
PLoS ONE 05/2014; 9(5):e97729. DOI:10.1371/journal.pone.0097729 · 3.23 Impact Factor
"It is an intriguing hypothesis that a reduced accumulation of senescent cells, similar to our in vitro results, may contribute to the long-lived phenotype seen in mice treated with rapamycin (Harrison et al., 2009) or with reduced activity in signaling pathways upstream of mTOR, such as the GH/IGF-I axis (Bartke, 2011). Studies are beginning to emerge suggesting that rapamycin feeding may reduce senescence in mice (Hinojosa et al., 2012), although further work is required in this area. Future studies may reveal whether a reduction in the burden of cellular senescence contributes to the long life of these experimental models and may provide a target to ameliorate the aging process. "
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