Intermittent rapamycin feeding recapitulates some effects of continuous treatment while maintaining lifespan extension.

OBJECTIVE: Rapamycin, a powerful geroprotective drug, can have detrimental effects when administered chronically. We determined whether intermittent treatment of mice can reduce negative effects while maintaining benefits of chronic treatment. METHODS: From 6 months of age, male and female C3B6F1 hybrid mice were either continuously fed with 42 mg/kg rapamycin, or intermittently fed by alternating weekly feeding of 42 mg/kg rapamycin food with weekly control feeding. Survival of these mice compared to control animals was measured. Furthermore, longitudinal phenotyping including metabolic (body composition, GTT, ITT, indirect calorimetry) and fitness phenotypes (treadmil, rotarod, electrocardiography and open field) was performed. Organ specific pathology was assessed at 24 months of age. RESULTS: Chronic rapamycin treatment induced glucose intolerance, which was partially ameliorated by intermittent treatment. Chronic and intermittent rapamycin treatments increased lifespan equally in males, while in females chronic treatment resulted in slightly higher survival. The two treatments had equivalent effects on testicular degeneration, heart fibrosis and liver lipidosis. In males, the two treatment regimes led to a similar increase in motor coordination, heart rate and Q-T interval, and reduction in spleen weight, while in females, they equally reduced BAT inflammation and spleen weight and maintained heart rate and Q-T interval. However, other health parameters, including age related pathologies, were better prevented by continuous treatment. CONCLUSIONS: Intermittent rapamycin treatment is effective in prolonging lifespan and reduces some side-effects of chronic treatment, but chronic treatment is more beneficial to healthspan.

Dynamics of Human Anelloviruses in Plasma and Clinical Outcomes Following Kidney Transplantation.

BACKGROUND: Torque teno virus, the major member of the genus Alphatorquevirus , is an emerging biomarker of the net state of immunosuppression after kidney transplantation. Genetic diversity constitutes a main feature of the Anelloviridae family, although its posttransplant dynamics and clinical correlates are largely unknown. METHODS: The relative abundance of Alphatorquevirus , Betatorquevirus , and Gammatorquevirus genera was investigated by high-throughput sequencing in plasma specimens obtained at various points during the first posttransplant year (n = 91 recipients). Total loads of all members of the Anelloviridae family were also quantified by an "in-house" polymerase chain reaction assay targeting conserved DNA sequences (n = 195 recipients). In addition to viral kinetics, clinical study outcomes included serious infection, immunosuppression-related adverse event (opportunistic infection and cancer)' and acute rejection. RESULTS: Alphatorquevirus DNA was detected in all patients at every point, with an increase from pretransplantation to month 1. A variable proportion of recipients had detectable Betatorquevirus and Gammatorquevirus at lower frequencies. At least 1 change in the predominant genus (mainly as early transition to Alphatorquevirus predominance) was shown in 35.6% of evaluable patients. Total anelloviruses DNA levels increased from baseline to month 1, to peak by month 3 and decrease thereafter, and were higher in patients treated with T-cell depleting agents. There was a significant albeit weak-to-moderate correlation between total anelloviruses and TTV DNA levels. No associations were found between the predominant Anelloviridae genus or total anelloviruses DNA levels and clinical outcomes. CONCLUSIONS: Our study provides novel insight into the evolution of the anellome after kidney transplantation.

Diversity and dynamic changes of anelloviruses in plasma following allogeneic hematopoietic stem cell transplantation.

Monitoring of alphatorquevirus (torque teno virus [TTV]) DNA in plasma may prove to be useful to assess the net state of immune competence following allogeneic hematopoietic stem cell transplantation (allo-HSCT). There are scarce data published on the prevalence of beta (torque teno mini virus [TTMV]) and gammatorqueviruses (torque teno midi virus [TTMDV]) and, in particular, on the dynamics of anelloviruses in allo-HSCT patients. Twenty-five allo-HSCT recipients with available plasma specimens obtained before conditioning and after engraftment were included. Degenerated primers targeting a highly conserved genomic sequence across all anelloviruses were designed for genomic amplification and high-throughput sequencing. Co-detection of TTV, TTMV, and TTMDV both in pre-transplant and post-engraftment plasma specimens was documented in more than two-thirds of patients. The use of quantitative real-time polymerase chain reaction (PCR) assays targeting TTMV and TTMDV in addition to TTV may add value to TTV-specific PCR assays in the inference of the net state of immunosuppresion or immune competence in this clinical setting.