scholarly journals TORC1 inhibition as an immunotherapy to reduce infections in the elderly

2017 ◽  
Author(s):  
Joan B. Mannick ◽  
Melody Morris ◽  
Hans-Ulrich P. Hockey ◽  
Guglielmo Roma ◽  
Martin Beibel ◽  
...  
Keyword(s):  
Immune Function ◽  
Low Dose ◽  
Mtor Inhibitor ◽  
Study Drug ◽  
The Elderly ◽  
Model Organisms ◽  
Elderly Subjects ◽  
Infection Rates ◽  
Mtor Inhibition ◽  
Inhibitor Regimen

AbstractmTOR inhibition extends lifespan and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this Phase 2a clinical trial was to determine if low dose mTOR inhibitor therapy enhanced immune function and thereby decreased infection rates in elderly subjects. The results indicate that 6 weeks of treatment with a low dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor (that selectively inhibits TORC1 downstream of mTOR) was safe, significantly decreased the rate of infections reported by elderly subjects for a year following study drug initiation, upregulated antiviral gene expression, and significantly improved influenza vaccination response. Thus 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.One Sentence SummaryTreatment of elderly subjects with a low dose mTOR inhibitor regimen that selectively inhibits TORC1 significantly decreased infection rates

Combination of antiangiogenic therapy using the mTOR inhibitor RAD001 (everolimus) and low-dose chemotherapy for locally advanced and/or metastatic pancreatic cancer: Dose-finding study.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 360-360
Author(s):  
Mareile Joka ◽  
Stefan Hubert Boeck ◽  
Christian Hosius ◽  
Laetitia Decroix ◽  
Christoph May ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Low Dose ◽  
Mtor Inhibitor ◽  
Antiangiogenic Therapy ◽  
Locally Advanced ◽  
Study Drug ◽  
Dose Finding ◽  
Metastatic Pancreatic Cancer ◽  
Low Dose Chemotherapy

360 Background: This was an open-label, multicenter two-arm combined phase I (dose finding, cohort 1-5)/II (dose expansion) study of continuous doses of RAD001 every 2nd day or every day in combination with escalating low dose gemcitabine in patients (pts) with locally advanced and/or metastatic pancreatic cancer. The primary objective was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). The secondary objectives were to characterize safety and tolerability and to evaluate preliminary efficacy (ORR). Methods: A total of 27 pts were enrolled in phase I. All of these were analyzed in the safety population and 23 pts in the MTD-determining population. In total, 21 pts completed the study. Results: The MTD was determined to be 500mg/m2/week gemcitabine and 5mg/d RAD001 (cohort 4, 7 pts treated). In total, 3 DLTs occured: hepatic toxicity and unknown DLT as worsed case assumption in cohort 5 and hepatic toxicity in cohort 4. Overall, 25 of 27 pts (92.59%) reported at least one AE. Thrombocytopenia was most frequent AE, followed by leukopenia and nausea. In the individual dose groups, thrombocytopenia was most common in cohorts 1, 2 and 5, leukopenia in cohort 3 and nausea in cohort 4. The majority of pts experienced AEs with suspected relation to study drug (81.48%), AEs leading to dose adjustments or temporary interruption (77.78%) or required concomitant medication (66.67%). A total of 11 pts (40.74%) experienced SAEs. Two pts died during the study (not related to study drug). 4 pts were dicontinued permanently due to 2 AEs and 2 SAEs. ORR was 13%. None of the pts reported complete response (CR), the progressive disease rate was 13%. The clinical benefit rate was 78.3%. Conclusions: The present study was prematurely terminated due to slow recruitment and the dose expansion phase (phase II) was not started. In phase I, the MTD was determined to be 500mg/m2/week Gemcitabine and 5mg/d RAD001. No new safety concerns were identified for combination of antiangiogenic therapy using the mTOR- inhibitor RAD001 (Everolimus) and low dose chemotherapy for locally advanced and/or metastatic pancreatic cancer.

mTOR inhibition improves immune function in the elderly

2014 ◽  
Vol 6 (268) ◽  
pp. 268ra179-268ra179 ◽  
Author(s):  
J. B. Mannick ◽  
G. Del Giudice ◽  
M. Lattanzi ◽  
N. M. Valiante ◽  
J. Praestgaard ◽  
...  
Keyword(s):  
Immune Function ◽  
The Elderly ◽  
Mtor Inhibition

scholarly journals TORC1 INHIBITION AS AN IMMUNOTHERAPY TO DECREASE INFECTIONS IN THE ELDERLY

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S811-S811
Author(s):  
Joan Mannick
Keyword(s):  
Immune Function ◽  
The Elderly ◽  
Therapeutic Benefit ◽  
Elderly Subjects ◽  
Two Phase ◽  
Related Condition ◽  
Preclinical Species ◽  
Extended Lifespan ◽  
Tract Infections ◽  
Old Mice

Abstract Inhibition of TORC1 has extended lifespan in multiple preclinical species. Thus drugs inhibiting TORC1 may have therapeutic benefit for aging-related conditions in humans. An aging-related condition that improves with TORC1 inhibition in old mice is immunosenescence (the aging-related decline in immune function). Immunosenescence leads to increased rates of infections including respiratory tract infections (RTIs) in the elderly. In two Phase 2 clinical trials in over 900 elderly subjects, the TORC1 inhibitor RTB101 was observed to improve immune function and decrease the incidence of RTIs. Decreasing the incidence of RTIs is important because RTIs are the fourth leading cause of hospitalization in people age 65 and above. Based on these findings, two Phase 3 studies are underway to determine whether RTB101 given for 16 weeks during winter cold and flu season decreases relative to placebo the percentage of elderly subjects with illnesses associated with RTIs.

scholarly journals Extra Virgin Olive Oil Prevents the Age-Related Shifts of the Distribution of HDL Subclasses and Improves Their Functionality

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2235
Author(s):  
Alyann Otrante ◽  
Amal Trigui ◽  
Roua Walha ◽  
Hicham Berrougui ◽  
Tamas Fulop ◽  
...  
Keyword(s):  
Olive Oil ◽  
Virgin Olive Oil ◽  
Density Lipoprotein ◽  
Extra Virgin Olive Oil ◽  
The Elderly ◽  
High Density ◽  
Lipoprotein Cholesterol ◽  
Elderly Subjects ◽  
Age Related ◽  
Young Subjects

High-density lipoproteins (HDL) maintain cholesterol homeostasis through the role they play in regulating reverse cholesterol transport (RCT), a process by which excess cholesterol is transported back to the liver for elimination. However, RCT can be altered in the presence of cardiovascular risk factors, such as aging, which contributes to the increase in the incidence of cardiovascular diseases (CVD). The present study was aimed at investigating the effect of extra virgin olive oil (EVOO) intake on the cholesterol efflux capacity (CEC) of HDL, and to elucidate on the mechanisms by which EVOO intake improves the anti-atherogenic activity of HDL. A total of 84 healthy women and men were enrolled and were distributed, according to age, into two groups: 27 young (31.81 ± 6.79 years) and 57 elderly (70.72 ± 5.6 years) subjects. The subjects in both groups were given 25 mL/d of extra virgin olive oil (EVOO) for 12 weeks. CEC was measured using J774 macrophages radiolabeled with tritiated cholesterol ((3H) cholesterol). HDL subclass distributions were analyzed using the Quantimetrix Lipoprint® system. The HDL from the elderly subjects exhibited a lower level of CEC, at 11.12% (p < 0.0001), than the HDL from the young subjects. The CEC of the elderly subjects returned to normal levels following 12 weeks of EVOO intake. An analysis of the distribution of HDL subclasses showed that HDL from the elderly subjects were composed of lower levels of large HDL (L-HDL) (p < 0.03) and higher levels of small HDL (S-HDL) (p < 0.002) compared to HDL from the young subjects. A multiple linear regression analysis revealed a positive correlation between CEC and L-HDL levels (r = 0.35 and p < 0.001) as well as an inverse correlation between CEC and S-HDL levels (r = −0.27 and p < 0.01). This correlation remained significant even when several variables, including age, sex, and BMI as well as low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and glucose levels (β = 0.28, p < 0.002, and β = 0.24, p = 0.01) were accounted for. Consuming EVOO for 12 weeks modulated the age-related difference in the distribution of HDL subclasses by reducing the level of S-HDL and increasing the level of intermediate-HDL/large-HDL (I-HDL/L-HDL) in the elderly subjects. The age-related alteration of the CEC of HDL was due, in part, to an alteration in the distribution of HDL subclasses. A diet enriched in EVOO improved the functionality of HDL through an increase in I-HDL/L-HDL and a decrease in S-HDL.

scholarly journals POS1288 TUBERCULOUS SPONDYLODISCITIS IN ELDERLY: EPIDEMIOLOGY, CLINICAL, FEATURES, TREATMENT AND OUTCOMES

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 926.1-926
Author(s):  
M. Mrabet ◽  
S. Boussaid ◽  
S. Jemmali ◽  
H. Sahli ◽  
H. Ajlani ◽  
...  
Keyword(s):  
Clinical Features ◽  
The Elderly ◽  
Lumbar Pain ◽  
Elderly Subjects ◽  
Normocytic Anemia ◽  
Imaging Features ◽  
X Rays ◽  
Significant Difference ◽  
Young Subjects ◽  
Tuberculous Spondylodiscitis

Background:Tuberculosis is still endemic all over the world. The incidence of tuberculous spondylodiscitis (TS) is steadily increasing. Clinical features and outcomes of this affection are various and depending on various parameters, including age.Objectives:Our objective was to explore the differences in presentation and the results of further investigations and the prognosis of TS between young and elderly subjects.Methods:We conduct a retrospective and descriptive study in a single rheumatology department. Data were collected from files of patients hospitalized in the past 20 years (2000-2020) who have been diagnosed with TS. We carried out a comparative study concerning the clinical biological, imaging features and outcomes between young subjects and subjects aged over 65 years.Results:Fifty-two cases of TS were collected (37F/15M). The mean age of the population was 55.21 years ± 17.79 [19-91]. Thirty-three patients (69.2%) were classified as young versus 16 elderly patients (30.8%), with female predominance in both groups (69.4% and 75% respectively, p = 0.57). Young subjects was more frequently vaccinated (88.9%) by Bacillus Calmette–Guérin (BCG) (p < 0.001). A delayed diagnosis was noted in both groups (p = 0.24). Lumbar spine involvement was the most common (57.7%). In the two age ranges, the onset of the disease was progressive (p = 0.22), characterized by segmental spine stiffness (p = 0.57) and lumbar pain with general signs (p = 0.27), such as: impaired general condition, fever, night sweats and weight loss. Biological inflammatory syndrome and normochrome normocytic anemia were encountered in both cases (p = 0.08 and p = 0.2, respectively). Standard X-rays and Computed tomography were more performed in young subjects (94.4% and 69.4%, respectively; p < 0.001), unlike magnetic resonance imaging which was more common in elderly subjects but with no statistically significant difference (p = 0.22). Disc pinch, erosion of vertebral plateaus and vertebral collapse were the major signs (82.7%, 65.4% and 67.3%, respectively). Clinical, biological and imaging arguments contributed to positive diagnosis in both groups (p = 0.24). Common medical treatment was anti-tuberculosis: Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E) and physical treatment such as immobilization witch was more common in the eldery (56.3%, p = 0.16). The evolution of the disease was characterized by a clear improvement of young subjects during the second week of treatment (p < 0.001). A more frequent clinical improvement in older subjects was during the fourth week but with no statistically significant difference (p = 0.13). The occurrence of immediate complications was more frequent in the elderly (p = 0.23) with a predominance for drug complications (56.3%) such as: hepatic cytolysis (12.5%), hyperuricemia (18.8%) and major intolerance to anti-tuberculosis (18.8%).Conclusion:TS is a frequent condition that needs to be treated rapidly. the clinical presentation of TS in the elderly is less noisy which leads to more frequent complications and mortality.Disclosure of Interests:None declared

scholarly journals Bifidobacteriummicrobiota and parameters of immune function in elderly subjects

2008 ◽  
Vol 53 (1) ◽  
pp. 18-25 ◽  
Author(s):  
Arthur C. Ouwehand ◽  
Nynke Bergsma ◽  
Riikka Parhiala ◽  
Sampo Lahtinen ◽  
Miguel Gueimonde ◽  
...  
Keyword(s):  
Immune Function ◽  
Elderly Subjects

Decreased Neutrophil Cyclic AMP Response to Isoprenaline Stimulation in the Elderly

1983 ◽  
Vol 65 (2) ◽  
pp. 155-157 ◽  
Author(s):  
T. G. Cotter ◽  
K. O'Malley
Keyword(s):  
Monoclonal Antibodies ◽  
Cyclic Amp ◽  
The Elderly ◽  
Population Heterogeneity ◽  
Elderly Subjects ◽  
Age Related ◽  
Significant Difference ◽  
Young Subjects ◽  
Drug Free

1. Neutrophils from drug-free elderly subjects produced approximately 50% less cyclic AMP in response to isoprenaline than did neutrophils from young subjects. A significant difference in basal cyclic AMP levels was also evident (elderly 2.8 ± 0.37; young 4.9 ± 0.36 pmol of cAMP/107 cells; P < 0.05). 2. With a range of anti-neutrophil monoclonal antibodies no evidence of age-related neutrophil population heterogeneity was found. 3. These findings indicate that the age-related decline in β-adrenoceptor responsiveness is not due to changes in the neutrophil population. 4. The present results support the hypothesis that there is a generalized decline in β-adrenoceptor-mediated responsiveness in the elderly.

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