Age-related changes in the immune system and the consequences of immunosenescence

The cellular and molecular hallmarks of aging include genomic instability, telomere attrition, epigenetic alterations, changes in intracellular signaling, cellular senescence, and mitochondrial dysfunction. These lead to complex remodeling and changes involving both the innate and adaptive immune systems. Besides age related changes in immune cells, the microenvironment in the lymphoid and non-lymphoid organs, as well as circulating factors interacting with the immune system also contribute to immunosenescence. Overall, immunosenescence is characterized by reduction of immune response, an increase in inflammatory and oxidation background (inflamm-aging), and production of autoantibodies. One of the most prominent age-related changes in the adaptive immune system is the decline in regenerative thymic capacity. Similar aging related defects have also been observed in stroma of the bone marrow. While lymphocytes in infants show a naive phenotype, memory phenotype predominates after midlife. Though immune responses against recall antigens may still be conserved, the ability to mount primary response against novel antigens declines with age. As a result, increased susceptibility to infections, and suboptimal vaccine response is observed in the elderly. Apart from functional alternation in immune cells, there is a low-grade persistent elevation in inflammatory molecules. Inflamm-aging may result from the accumulation of misfold proteins, compromised gut barrier function, chronic infection, obesity, etc. Furthermore, aging is associated with immune dysregulation, with defective resolution of immune response after activation, and impaired clearance of dead cells with sustained inflammation. Excessive inflammation not only impairs antigen specific immunity, but also leads to tissue damage. In fact, this may partly account for the increased mortality of COVID infection in the elderly. Apart from vulnerability to infection and weakened vaccine response, immunosenescence also plays an important role in cancer and autoimmunity in the elderly. Because of increased tissue damage and apoptosis, coupled with inflamm-aging, increased autoantibodies production is observed in the elderly. Nevertheless, there is an age-related increase in peripheral regulatory T cells. While there is an increase in autoimmunity with aging, this does not always translate into an increase in autoimmune disease. On the other hand, the increase in regulatory T cells, along with other immunosuppressive cells and the senescence associated proinflammatory environment, promotes tumor development and progression in the elderly. As immunosenescence has a significant impact on health and disease, better understanding on this process is crucial for research and development in the future geriatric health care.

Translesion Synthesis: From Cancer Resistance to Host-Pathogen Interactions

Genome instability mechanisms that characterize cancer initiation and subsequent therapy resistance are still less well understood. Recent evidence suggests that the REV1-dependent translesion synthesis (TLS) is the cornerstone for new mutation formation that primes genome instability, including intrinsic and acquired resistance to therapy. Remarkably, REV1 inhibition also switches the biology of cisplatin-dependent cell death response from apoptosis to senescence, suggesting that REV1 functions beyond a DNA damage polymerase. Furthermore, we discovered two unexpected phenotypes of REV1 TLS polymerase: a) REV1 inhibition triggers autophagy that associated with radioresistance. b) By means of striking preliminary data we show that REV1 inhibition limits SARS-CoV-2 RNA virus propagation, which we recently reported to cause hostcell DNA damage response and telomere instability. These new observations add to the repertoire of REV1- dependent genome instability pathways significant to understanding a wide repertoire of human diseases, including cancer pathogenesis.

The consequences of viral infection on host DNA damage response: a focus on SARS-CoVs.

DNA damage and genome instability in host cells are introduced by many viruses during their life cycles. Severe acute respiratory syndrome coronaviruses (SARS-CoVs) manipulation of DNA damage response (DDR) is an important area of research that is still understudied. Elucidation of the direct and indirect interactions between SARS-CoVs and DDR not only provides important insights into how the viruses exploit DDR pathways in host cells but also contributes to our understanding of their pathogenicity. Here, we present the known interactions of both SARS-CoV and SARS-CoV-2 with DDR pathways of the host cells, to further understand the consequences of infection on genome integrity. Since this area of research is in its early stages, we try to connect the unlinked dots to speculate and propose different consequences on DDR mechanisms. This review provides new research scopes that can be further investigated in vitro and in vivo, opening new avenues for the development of anti-SARS-CoV-2 drugs.

Never Cared for What They Do: High Structural Stability of Guanine-Quadruplexes in the Presence of Strand-Break Damage

DNA integrity is an important factor that assures genome stability and, more generally, the viability of cells and organisms. In the presence of DNA damage, the normal cell cycle is perturbed when cells activate their repair processes. Although efficient, the repair system is not always able to ensure complete restoration of gene integrity. In these cases, mutations not only may occur, but the accumulation of lesions can either lead to carcinogenesis or reach a threshold that induces apoptosis and programmed cell death. Among the different types of DNA lesions, strand breaks produced by ionizing radiation are the most toxic due to the inherent difficultly of repair, which may lead to genomic instability. In this article we show, by using classical molecular simulation techniques, that compared to canonical double-helical B-DNA, guanine-quadruplex (G4) arrangements show remarkable structural stability, even in the presence of two strand breaks. Since G4-DNA is recognized for its regulatory roles in cell senescence and gene expression, including oncogenes, this stability may be related to an evolutionary cellular response aimed at minimizing the effects of ionizing radiation.

Mechanisms of Bone Marrow Failure and Leukemia Progression in Primary Human Fanconi Anemia Stem Cells in Novel FA PDX Model

The goal of this research proposal is to provide better treatments for Fanconi Anemia (FA), an inherited bone marrow failure disorder that affects approximately 1 in 100,000 children. The combination of hematopoietic stress and inherent genomic instability leads to cancer and accumulation of genetic defects is likely the cause of AML progression. We proposed to study primary human cell defective in the FA pathway to delineate pathways of leukemia progression and eventually prevent progression to bone marrow failure or progression to leukemia. Our two aims are to 1)identify molecular vulnerabilities and genetic changes promoting oncogenesis in FA deficient CD34+ cells in vitro and to 2) determine molecular changes at the root of disease progression in primary human FA bone marrow and test potential therapeutic approaches in vivo in MISTRG-kitMUT mice. To achieve this goal we have to i) obtain primary FA patient cells and ii) generate human FANC gene KO CD34+ cells. Note that the COVID pandemic has significantly impaired our progress since 3/15/2020. We have focused our efforts on generating FA defective cells via two mechanisms: a) shRNA mediated knockdown and b) via CRISPR/Cas9 mediated deletion. We have encountered 2 difficulties which we are still addressing: inefficiency of deleting FA genes and selection against deleted cells;silencing of rescue lentiviral vectors in primary hematopoietic cells. With COVID all work had to halt and mouse work was minimal we are expanding colonies and actively transplanting primary FA samples with goal to further optimize engineering of FA samples and transplantation in MISTRG mice.

Clinical update on the use of mesenchymal stem cells in COVID-19

The COVID-19 pandemic has evoked the scientific community to combine all efforts needed to find a cure for the disease. With the limited therapeutic effects of pharmacological therapies, attention has been drawn to alternative ones such as stem-cell based therapy particularly with mesenchymal stem cells (MSCs). Recently, a large number of clinical trials are ongoing to evaluate the safety and efficacy of MSCs in patients with COVID-19;however, only very few data are released. Thereby, we anxiously await the results of FDA-approved trials to provide more definitive data on the use of MSCs in COVID-19 patients, especially the critically ill. Herein, we shed light on the therapeutic agents that have been tested and used for the treatment of COVID-19 and provide an insight into MSC-based approaches for COVID-19 at both preclinical and clinical levels.

Genoprotective activities of plant natural substances in cancer and chemopreventive strategies in the context of 3P medicine.

Severe durable changes may occur to the DNA structure caused by exogenous and endogenous risk factors initiating the process of carcinogenesis. By evidence, a large portion of malignancies have been demonstrated as being preventable. Moreover, the targeted prevention of cancer onset is possible, due to unique properties of plant bioactive compounds. Although genoprotective effects of phytochemicals have been well documented, there is an evident lack of articles which would systematically present the spectrum of anticancer effects by phytochemicals, plant extracts, and plant-derived diet applicable to stratified patient groups at the level of targeted primary (cancer development) and secondary (cancer progression and metastatic disease) prevention. Consequently, clinical implementation of knowledge accumulated in the area is still highly restricted. To stimulate coherent co-development of the dedicated plant bioactive compound investigation on one hand and comprehensive cancer preventive strategies on the other hand, the current paper highlights and deeply analyses relevant evidence available in the area. Key molecular mechanisms are presented to detail genoprotective and anticancer activities of plants and phytochemicals. Clinical implementation is discussed. Based on the presented evidence, advanced chemopreventive strategies in the context of 3P medicine are considered.