Patients with type 2 diabetes (T2D) have a lower risk of Mycobacterium tuberculosis infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence, when being treated with metformin. However, a detailed mechanistic understanding of these protective effects is lacking. Here, we use mass cytometry to show that metformin treatment expands a population of memory-like antigen-inexperienced CD8+CXCR3+ T cells in naive mice, and in healthy individuals and patients with T2D. Metformin-educated CD8+ T cells have increased (i) mitochondrial mass, oxidative phosphorylation, and fatty acid oxidation; (ii) survival capacity; and (iii) anti-mycobacterial properties. CD8+ T cells from Cxcr3−/− mice do not exhibit this metformin-mediated metabolic programming. In BCG-vaccinated mice and guinea pigs, metformin enhances immunogenicity and protective efficacy against M. tuberculosis challenge. Collectively, these results demonstrate an important function of CD8+ T cells in metformin-derived host metabolic-fitness towards M. tuberculosis infection.

Coronavirus disease 2019 (COVID-19) is a respiratory infectious disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is characterized by having a heterogeneous disease course, ranging from asymptomatic and mild symptoms to more severe and critical cases. In most cases the severity of COVID-19 is related to host factors, especially deregulation of the immune response in patients. Even if COVID-19 indiscriminately affects individuals of different age group, ethnicity and economic status; most severe cases and disproportional mortality occur in elderly individuals. This point out that aging is one risk factor for unfavourable clinical outcomes among COVID-19 patients. The biology of aging is a complex process; Aging can alter the structure and function of cells, tissues, and organs resulting in impaired response to stress. Alongside with other systems, the immune system is also affected with the aging process. Immunosenescence is an age associated change in the immune system that affects the overall response to immunological challenges in the elderly. Similarly, apart from the normal inflammatory process, aging is associated with a low grade, sterile, chronic inflammation which is termed as inflammaging. We hypothesized that inflammaging and immunosenescence could play an important role in SARS-CoV-2 pathogenesis and poor recovery from COVID-19 in elderly individuals. This review summarizes the changes in the immune system with age and how these changes play part in the pathogenesis of SARS-CoV-2 and clinical outcome of COVID-19 which could add to the understanding of age associated targeted immunotherapy in the elderly.

Aging is the main risk factor for developing diabetes and other age-related diseases. One of the most common features of age-related comorbidities is the presence of low-grade chronic inflammation. This is also the case of metabolic syndrome and diabetes. At the subclinical level, a pro-inflammatory phenotype was shown to be associated with Type-2 diabetes mellitus (T2DM). This low to mid-grade inflammation is also present in elderly individuals and has been termed inflammaging. Whether inflammation is a component of aging or exclusively associated with age-related diseases in not entirely known. We used clinical data and biological readouts in a group of individuals stratified by age, diabetes status and comorbidities to investigate this aspect. While aging is the main predisposing factor for several diseases there is a concomitant increased level of pro-inflammatory cytokines. DM patients show an increased level of sTNFRll, sICAM-1, and TIMP-1 when compared to Healthy, Non-DM and Pre-DM individuals. These inflammatory molecules are also associated with insulin resistance and metabolic syndrome in Non-DM and pre-DM individuals. We also show that metformin monotherapy was associated with significantly lower levels of inflammatory molecules, like TNFα, sTNFRI, and sTNFRII, when compared to other monotherapies. Longitudinal follow up indicates a higher proportion of death occurs in individuals taking other monotherapies compared to metformin monotherapy. Together our finding shows that chronic inflammation is present in healthy elderly individuals and exacerbated with diabetes patients. Likewise, metformin could help target age-related chronic inflammation in general, and reduce the predisposition to comorbidities and mortality.