Article

Enteric-delivered rapamycin enhances resistance of aged mice to pneumococcal pneumonia through reduced cellular senescence

Department of Microbiology & Immunology, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, United States.
Experimental gerontology (Impact Factor: 3.53). 09/2012; 47(12). DOI: 10.1016/j.exger.2012.08.013
Source: PubMed

ABSTRACT 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.

1 Follower
 · 
326 Views
  • Source
    • "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. "
    Experimental Gerontology 07/2013; 48(7):692–693. DOI:10.1016/j.exger.2013.05.035 · 3.53 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Coordinated expression of mitochondrial and nuclear genes is required to maintain proper mitochondrial function. However, the precise mechanisms that ensure this coordination are not well defined. We find that signaling from mitochondria to the nucleus is influenced by mTOR activity via changes in autophagy and p62/SQSTM1 turnover. Reducing mTOR activity increases autophagic flux, enhances mitochondrial membrane potential, reduces reactive oxygen species within the cell, and increases replicative lifespan. These effects appear to be mediated in part by an interaction between p62/SQSTM1 and Keap1. This interaction allows nuclear accumulation of the nuclear factor erythroid 2-like 2 (NFE2L2, also known as nuclear factor related factor 2 or NRF2), increased expression of the nuclear respiratory factor 1 (NRF1), and increased expression of nuclear-encoded mitochondrial genes, such as the mitochondrial transcription factor A, and mitochondrial-encoded genes involved in oxidative phosphorylation. These findings reveal a portion of the intracellular signaling network that couples mitochondrial turnover with mitochondrial renewal to maintain homeostasis within the cell and suggest mechanisms whereby a reduction in mTOR activity may enhance longevity. This article is protected by copyright. All rights reserved.
    Aging cell 06/2013; 12(6). DOI:10.1111/acel.12122 · 5.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Target of rapamycin inhibition by rapamycin feeding has previously been shown to extend life in genetically heterogeneous mice. To examine whether it similarly affected mouse health, we fed encapsulated rapamycin or a control diet to C57BL/6Nia mice of both sexes starting at 19 months of age. We performed a range of health assessments 6 and 12 months later. Rapamycin feeding significantly reduced mTOR activity in most but not all tissues. It also reduced total and resting metabolic rate during the light (inactive) phase of the light:dark cycle in females only but had no effect on spontaneous activity or metabolism during the dark (active) phase of either sex. Males only had less fragmented sleep when fed rapamycin, whereas stride length and rotarod performance were improved in both sexes. Survival was also improved by this late-life rapamycin feeding, and some pathological lesions were delayed. We found no adverse health consequences associated with rapamycin treatment.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 05/2013; 69A(2). DOI:10.1093/gerona/glt056 · 4.98 Impact Factor
Show more