Therapeutic Stimulation of Glycolytic ATP Production for Treating ROS-Mediated Cellular Senescence

Cellular senescence is conditioned through two interrelated processes, i.e., a reduction in adenosine triphosphate (ATP) and the enhancement of reactive oxygen species (ROS) production levels in mitochondria. ATP shortages primarily influence the energy-intensive synthesis of large biomolecules, such as deoxyribonucleic acid (DNA). In addition, as compared to small biomolecules, large biomolecules are more prone to ROS-mediated damaging effects. Based on the available evidence, we suggest that the stimulation of anaerobic glycolytic ROS-independent ATP production could restrain cellular senescence. Consistent with this notion, non-drug related intermittent hypoxia (IH)-based therapy could be effectively applied in sports medicine, as well as for supporting the physical activity of elderly patients and prophylactics of various age-related disorders. Moreover, drug therapy aiming to achieve the partial blockade of respiratory chain and downstream compensatory glycolysis enhancement could prove to be useful for treating cardiovascular, neurological and hormonal diseases. We maintain that non-drug/drug-related therapeutic interventions applied in combination over the entire lifespan could significantly rejuvenate and prolong a high quality of life for individuals

Immune-based, multifaceted inactivation of pathogenic T lymphocytes in treating autoimmune diseases

Immunotherapeutic treatment of autoimmune diseases should aim to inactivate autoaggressive memory T-cells and restore immune tolerance. It is envisaged that three approaches could be used to achieve this goal: stimulation of anti-idiotypic immune responses by vaccination with pathogenic T-cells; administration of suboptimal doses of antibodies (Abs) against two or more surface T-cell markers to provide selective Ab-mediated destruction of activated pathogenic memory T-cells; and induction of oral immune tolerance. The proposal entails the use of T-cell vaccination (TCV) or Ab-based therapy as an initial approach to reduce autoantigenic T-cell sensitization. Subsequently, the implementation of oral immunotherapy (OIT) is recommended to reinstate a consistent immune tolerance

LPS activation is required for migratory activity and antigen presentation by tolerogenic dendritic cells

Autoimmune pathologies are caused by a breakdown in self-tolerance. Tolerogenic dendritic cells (tolDC) are a promising immunotherapeutic tool for restoring self-tolerance in an antigen-specific manner. Studies about tolDC have focused largely on generating stable maturation-resistant DC, but few have fully addressed questions about the antigen-presenting and migratory capacities of these cells, prerequisites for successful immunotherapy. Here, we investigated whether human tolDC, generated with dexamethasone and the active form of vitamin D3, maintained their tolerogenic function upon activation with LPS (LPS-tolDC), while acquiring the ability to present exogenous autoantigen and to migrate in response to the CCR7 ligand CCL19. LPS activation led to important changes in the tolDC phenotype and function. LPS-tolDC, but not tolDC, expressed the chemokine receptor CCR7 and migrated in response to CCL19. Furthermore, LPS-tolDC were superior to tolDC in their ability to present type II collagen, a candidate autoantigen in rheumatoid arthritis. tolDC and LPS-tolDC had low stimulatory capacity for allogeneic, naïve T cells and skewed T cell polarization toward an anti-inflammatory phenotype, although LPS-tolDC induced significantly higher levels of IL-10 production by T cells. Our finding that LPS activation is essential for inducing migratory and antigen-presenting activity in tolDC is important for optimizing their therapeutic potential