Reactive oxygen species (ROS) have been long considered simply as harmful by-products of metabolism, which damage cellular proteins, lipids, and nucleic acids. ROS are also known as a weapon of phagocytes, employed against pathogens invading the host. However, during the last decade, an understanding has emerged that ROS also have important roles as signaling messengers in a multitude of pathways, in all cells, tissues, and organs. T lymphocytes are the key players of the adaptive immune response, which both coordinate other immune cells and destroy malignant and virus-infected cells. ROS have been extensively implicated in T-cell hyporesponsiveness, apoptosis, and activation. It has also become evident that the source, the kinetics, and the localization of ROS production all influence cell responses. Thus, the characterization of the precise mechanisms by which ROS are involved in the regulation of T-cell functions is important for our understanding of the immune response and for the development of new therapeutic treatments against immune-mediated diseases. This review summarizes the 30-year-long history of research on ROS in T lymphocytes, with the emphasis on the physiological roles of ROS.

The widely accepted multiple-hit hypothesis of carcinogenesis states that cancers arise after several successive events. However, no consensus has been reached on the quantity and nature of these events, although “driver” mutations or epimutations are considered the most probable candidates. By using the largest publicly available cancer incidence statistics (20 million cases), I show that incidence of 20 most prevalent cancer types in relation to patients’ age closely follows the Erlang probability distribution (R2 = 0.9734–0.9999). The Erlang distribution describes the probability y of k independent random events occurring by the time x, but not earlier or later, with events happening on average every b time intervals. This fits well with the multiple-hit hypothesis and potentially allows to predict the number k of key carcinogenic events and the average time interval b between them, for each cancer type. Moreover, the amplitude parameter A likely predicts the maximal populational susceptibility to a given type of cancer. These parameters are estimated for 20 most common cancer types and provide numerical reference points for experimental research on cancer development.

Populations in developed nations throughout the world are rapidly aging, and the search for geroprotectors, or anti-aging interventions, has never been more important. Yet while hundreds of geroprotectors have extended lifespan in animal models, none have yet been approved for widespread use in humans. GeroScope is a computational tool that can aid prediction of novel geroprotectors from existing human gene expression data. GeroScope maps expression differences between samples from young and old subjects to aging-related signaling pathways, then profiles pathway activation strength (PAS) for each condition. Known substances are then screened and ranked for those most likely to target differential pathways and mimic the young signalome. Here we used GeroScope and shortlisted ten substances, all of which have lifespan-extending effects in animal models, and tested 6 of them for geroprotective effects in senescent human fibroblast cultures. PD-98059, a highly selective MEK1 inhibitor, showed both life-prolonging and rejuvenating effects. Natural compounds like N-acetyl-L-cysteine, Myricetin and Epigallocatechin gallate also improved several senescence-associated properties and were further investigated with pathway analysis. This work not only highlights several potential geroprotectors for further study, but also serves as a proof-of-concept for GeroScope, Oncofinder and other PAS-based methods in streamlining drug prediction, repurposing and personalized medicine.

Age-related diseases (ARDs) are the leading cause of death worldwide, and contribute to 90% of mortality in developed countries. Interestingly, the mortality rates of individual ARDs increase exponentially with age. Processes described by the exponential growth function typically involve a branching chain reaction or, more generally, a positive feedback loop. Here I propose that each ARD is mediated by one or several positive feedback loops (vicious cycles). I then identify critical vicious cycles in five major ARDs: atherosclerosis, hypertension, diabetes, Alzheimer's and Parkinson's. I also propose that the progression of ARDs can be halted by selectively interrupting the vicious cycles and suggest the most promising targets. An evolutionary perspective is also offered.

BackgroundIn the last decade, reactive oxygen species (ROS) production has been shown to occur upon T-cell receptor (TCR) stimulation and to affect TCR-mediated signalling. However, the exact reactive species that are produced, how ROS are generated and their requirement for T-cell activation, proliferation or cytokine production remain unclear, especially in the case of primary human T cells. Moreover, several groups have questioned that ROS are produced upon TCR stimulation.ResultsTo shed some light onto this issue, we specifically measured superoxide production upon TCR ligation in primary human and mouse T lymphocytes. We showed that superoxide is indeed produced and released into the extracellular space. Antioxidants, such as superoxide dismutase and ascorbate, abolished superoxide production, but surprisingly did not affect activation, proliferation and cytokine secretion in TCR-stimulated primary human T cells. It has been suggested that T cells produce ROS via the NADPH oxidase 2 (NOX2). Therefore, we investigated whether T-cell activation is affected in NOX2-deficient mice (gp91phox −/−). We found that T cells from these mice completely lack inducible superoxide production but display normal upregulation of activation markers and proliferation.ConclusionsCollectively, our data indicate that primary T cells produce extracellular superoxide upon TCR triggering, potentially via NOX2 at the plasma membrane. However, superoxide is not required for T-cell activation, proliferation and cytokine production.