No abstract

Metagenomic sequencing of fracture fluid from South Africa recovered a nearly complete “Candidatus Bathyarchaeota” archaeon genome. The metagenome-assembled genome of BE326-BA-RLH contains genes involved in methane metabolism and dissimilatory nitrate reduction.

Background Aging is associated with progressive declines in immune responses leading to increased risk of severe infection and diminished vaccination responses. Influenza (flu) is a leading killer of older adults despite availability of seasonal vaccines. Geroscience-guided interventions targeting biological aging could offer transformational approaches to reverse broad declines in immune responses with aging. Here, we evaluated effects of metformin, an FDA approved diabetes drug and candidate anti-aging drug, on flu vaccination responses and markers of immunological resilience in a pilot and feasibility double-blinded placebo-controlled study. Results Healthy older adults (non-diabetic/non-prediabetic, age: 74.4 ± 1.7 years) were randomized to metformin (n = 8, 1500 mg extended release/daily) or placebo (n = 7) treatment for 20 weeks and were vaccinated with high-dose flu vaccine after 10 weeks of treatment. Peripheral blood mononuclear cells (PBMCs), serum, and plasma were collected prior to treatment, immediately prior to vaccination, and 1, 5, and 10 weeks post vaccination. Increased serum antibody titers were observed post vaccination with no significant differences between groups. Metformin treatment led to trending increases in circulating T follicular helper cells post-vaccination. Furthermore, 20 weeks of metformin treatment reduced expression of exhaustion marker CD57 in circulating CD4 T cells. Conclusions Pre-vaccination metformin treatment improved some components of flu vaccine responses and reduced some markers of T cell exhaustion without serious adverse events in nondiabetic older adults. Thus, our findings highlight the potential utility of metformin to improve flu vaccine responses and reduce age-related immune exhaustion in older adults, providing improved immunological resilience in nondiabetic older adults.

Aging results in the accumulation of senescent cells which can cause dysfunction in many contexts but the effects on immune responses remain unclear. Here, we aimed to probe the effects of clearing senescent cells in aged mice on the immune response to influenza infection. We utilized a powerful p16 trimodality reporter mouse model (p16-3MR): under the control of the p16 promoter, these mice express cassettes encoding luciferase, RFP, and herpesvirus thymidine kinase (HSV-TK). p16 is commonly upregulated in senescent cells so this model allows us to selectively delete those cells by treating with ganciclovir (GCV), which will induce apoptosis in cells expressing HSV-TK. We hypothesized that while p16-expressing senescent cells may exacerbate dysfunctional responses to a primary infection, they may play a protective role in resolving inflammation and fostering memory cell generation. We found that deletion of p16-expressing cells enhanced viral clearance and decreased infiltration of pro-inflammatory flu-specific CD8 T cells during the primary response to infection. Conversely, at 30 days post infection, there were fewer flu-specific CD8 memory T cells and lower amounts of anti-viral antibodies in the lungs of GCV treated mice. We also observed perturbations in memory T cell trafficking in GCV treated mice. Furthermore, GCV treated mice were unable to mount an effective memory response and were unable to control viral load following a heterosubtypic challenge. This suggests that targeting senescent cells may potentiate primary responses while limiting the ability to form durable and protective immune memory with age.